PMID,Authors,Title,Abstract,Journal_Title,Volume_Issue_Page,Publication_Year,Publication_Type,Mesh_Terms,Genes,Affiliation,Chemicals,Grant_Agency,Grant_Country,Grant_ID,Keyword
33202944,"Fattore L,Mancini R,Ciliberto G",Cancer Stem Cells and the Slow Cycling Phenotype: How to Cut the Gordian Knot Driving Resistance to Therapy in Melanoma.,"Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a ""phenotype switching"" plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely 1) kinases and metabolic changes, 2) melanoma-associated proteins, 3) Hippo pathway and 4) slow cycling/CSCs factors. Furthermore, we show how a protein-protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.",Cancers,vol.12:11:,2020,Journal Article,,,"Department of Research\, Advanced Diagnostics and Technological Innovation\, SAFU Laboratory\, Translational Research Area\, IRCCS Regina Elena National Cancer Institute\, 00144 Rome\, Italy.,Department of Clinical and Molecular Medicine\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00161 Rome\, Italy.,0000-0003-2851-8605Scientific Directorate\, IRCSS Regina Elena National Cancer Institute\, 00144 Rome\, Italy.",,"Italian Association for Cancer Research (AIRC) grat to G. Ciliberto,Italian Association for Cancer Research (AIRC) grant to R. Mancini,Lazioinova grant 2018 to R. Mancini,PRIN 2017 to G. Ciliberto and R. Mancini",",,,","IG15216,IG17009,n.85-2017-13750,2017HWTP2K)","OXPHOS,cancer stem cells,drug resistance,lipid metabolism,melanoma,slow cycling phenotype,target therapy"
33204897,"Brodie J,Zhou S,Makkuni D,Beadsmoore C,Mukhtyar C,Saada J,Bowles KM,Beigi B,Burton BJL",Erdheim-Chester Disease: Two cases from an ophthalmic perspective.,"We report two patients who presented initially to ophthalmology clinics with symptoms and signs of orbital inflammation that led to a diagnosis of Erdheim-Chester Disease (ECD).,ECD is a rare form of non-Langerhans cell histiocytosis (LCH) which is characterised by multi-system organ involvement and poor prognosis with standard therapies. Both patients were positive for the BRAF V600E mutation on genetic testing and were treated with the BRAF inhibitors Vemurafenib and Dabrafenib respectively. These cases highlight the variable clinical presentation and course of ECD\, the classical radiological and histopathological findings\, and the high degree of clinical suspicion necessary to reach this diagnosis.,The combination of xanthelasma and bilateral\, diffuse intraconal orbital masses must suggest to the clinician the possibility of ECD; and consideration to arrange further investigation with a full body CT or FDG PET/CT scan should be given\, even in the absence of wider systemic symptoms or signs. With the advent of targeted therapies such as BRAF inhibitors\, it is of even more importance that a diagnosis of ECD is established in a timely manner in order to give these patients the best chance of reduced morbidity and increased survival.",American journal of ophthalmology case reports,vol.20::100984,2020,Case Reports,,,"Department of Ophthalmology\, James Paget University Hospitals NHS Trust\, Great Yarmouth\, Norfolk\, United Kingdom.,Department of Ophthalmology\, James Paget University Hospitals NHS Trust\, Great Yarmouth\, Norfolk\, United Kingdom.,Department of Rheumatology\, James Paget University Hospitals NHS Trust\, Great Yarmouth\, Norfolk\, United Kingdom.,Department of Radiology\, Norfolk and Norwich University Hospital NHS Trust\, Norwich\, Norfolk\, United Kingdom.,Department of Rheumatology\, Norfolk and Norwich University Hospital NHS Trust\, Norwich\, Norfolk\, United Kingdom.,Department of Radiology\, Norfolk and Norwich University Hospital NHS Trust\, Norwich\, Norfolk\, United Kingdom.,Department of Medicine - Haematology\, Norfolk and Norwich University Hospital NHS Trust\, Norwich\, Norfolk\, United Kingdom.,Department of Ophthalmology\, Norfolk and Norwich University Hospital NHS Trust\, Norwich\, Norfolk\, United Kingdom.,Department of Ophthalmology\, James Paget University Hospitals NHS Trust\, Great Yarmouth\, Norfolk\, United Kingdom.",,,,,"BRAF,Erdheim-chester disease,Histiocytosis,Orbital inflammation,Orbital mass,Vemurafenib"
33205710,"Maeda S,Yoshitake R,Chambers JK,Uchida K,Eto S,Ikeda N,Nakagawa T,Nishimura R,Goto-Koshino Y,Yonezawa T,Momoi Y",BRAF Mutation Associates CCL17 Expression and Regulatory T Cell Recruitment in Urothelial Carcinoma of Dogs.,"Regulatory T cells may serve as targets in cancer immunotherapy. A previous study showed that the chemokine CCL17 and the receptor CCR4 play roles in regulatory T cell recruitment in canine urothelial carcinoma. In this article, we show that the BRAFV595E mutation is associated with tumor-produced CCL17 and regulatory T cell infiltration in dogs with urothelial carcinoma. In comparison with healthy dogs, dogs with urothelial carcinoma showed increased CCL17 mRNA expression in the bladder and elevated CCL17 protein concentration in urine. Immunohistochemistry showed increased levels of Foxp3+ regulatory T cells in the tumor tissues of urothelial carcinoma. The density of Foxp3+ regulatory T cells was positively correlated with CCL17 concentration in urine, indicating that CCL17 is involved in regulatory T cell recruitment. Moreover, tumor-infiltrating regulatory T cells and urine CCL17 concentration were associated with poor prognosis in dogs with urothelial carcinoma. The number of tumor-infiltrating regulatory T cells, CCL17 mRNA expression, and urine CCL17 concentration in cases with BRAFV595E mutation were higher than those in cases with wild-type BRAF. In vitro, high CCL17 production was detected in a canine urothelial carcinoma cell line with BRAFV595E mutation but not in an urothelial carcinoma cell line with wild-type BRAF. Dabrafenib, a BRAF inhibitor, decreased CCL17 production in the cell line with BRAFV595E mutation. These results suggest that BRAFV595E mutation induced CCL17 production and contributed to regulatory T cell recruitment in canine urothelial carcinoma.",Veterinary pathology,vol.::300985820967449,2020,Journal Article,,,"https://orcid.org/0000-0003-1413-1258Department of Veterinary Clinical Pathobiology\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,https://orcid.org/0000-0001-5273-7221Department of Veterinary Pathology\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,https://orcid.org/0000-0002-2302-799XDepartment of Veterinary Pathology\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Molecular Diagnostic Laboratory\, Veterinary Medical Center\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Clinical Pathobiology\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.,Department of Veterinary Clinical Pathobiology\, Graduate School of Agricultural and Life Sciences\, 13143The University of Tokyo\, Tokyo\, Japan.",,,,,"BRAF,antitumor immunity,cancer immunology,chemokines,dogs,transitional cell carcinoma,tumor microenvironment"
33208845,"Olsen DA,Thomsen CEB,Andersen RF,Madsen JS,Jakobsen A,Brandslund I",Decreased concentrations of intracellular signaling proteins in colon cancer patients with BRAF mutations.,"The activation of intracellular signaling pathways plays a critical role in cancer pathogenesis. The current study aims to quantify intracellular signaling proteins in localized colon cancer tissue to investigate the prognostic value of these biomarkers and elucidate their possible relations to mutation status. Colon cancer tissue and autologous reference tissue were collected from 176 patients who underwent colon cancer surgery. Assays were developed to quantify ERK, AKT and cyclin d using single-molecule array technology. KRAS/BRAF/PIK3CA mutation status was determined using droplet digital PCR. Patients with BRAF mutations had decreased concentrations of ERK (p = 0.0003), AKT (p = 0.0001) and cyclin d (p = 0.003), while no significant differences were found between patients with KRAS mutations and wild-type patients. None of the investigated proteins were associated with disease-free survival or overall survival when all patients were included. However, when patients were stratified according to mutation status, significant correlations with overall survival were seen for patients with BRAF mutations and AKT (p = 0.002) or ERK (p = 0.03) and for KRAS mutations and cyclin d (p = 0.01). Conclusions: A strong correlation exists between intracellular signaling protein concentrations and mutational BRAF status. Overall survival in colon cancer patients depends on both gene mutation status and signaling protein concentrations.",Scientific reports,vol.10:1:20113,2020,"Research Support, Non-U.S. Gov't",,,"Department of Biochemistry and Immunology\, Lillebaelt Hospital\, University Hospital of Southern Denmark\, Beriderbakken 4\, 7100\, Vejle\, Denmark. dorte.aalund.olsen@rsyd.dk.,Department of Oncology\, Lillebaelt Hospital\, University Hospital of Southern Denmark\, Vejle\, Denmark.,Department of Biochemistry and Immunology\, Lillebaelt Hospital\, University Hospital of Southern Denmark\, Beriderbakken 4\, 7100\, Vejle\, Denmark.,Department of Biochemistry and Immunology\, Lillebaelt Hospital\, University Hospital of Southern Denmark\, Beriderbakken 4\, 7100\, Vejle\, Denmark.,Department of Oncology\, Lillebaelt Hospital\, University Hospital of Southern Denmark\, Vejle\, Denmark.,Department of Biochemistry and Immunology\, Lillebaelt Hospital\, University Hospital of Southern Denmark\, Beriderbakken 4\, 7100\, Vejle\, Denmark.",,,,,
33209599,"Loong HH,Du N,Cheng C,Lin H,Guo J,Lin G,Li M,Jiang T,Shi Z,Cui Y,Jin X,Yao J,Xing Y,Yao M,Wang K,Mok TSK,Liu L","KRAS G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples.","Kirsten rat sarcoma vial oncogene (KRAS) is one of the most prevalent oncogenes in multiple cancer types\, but the incidence is different between the Asian and non-Asian populations. The recent development of KRAS G12C targeting drug has shown great promise. It is thus important to understand the genomic landscape of KRAS G12C in a specific population.,Sequencing data of 11\,951 tumor samples collected from 11/2016 to 7/2019 from multiple centres in China were analyzed for KRAS mutation status. Concomitant genomic aberrations were further analyzed in tumors with KRAS G12C mutations\, which were sequenced with comprehensive cancer panel including over 450 cancer-related genes. Smoking status and its correlation with KRAS were analyzed in 2\,235 lung cancer cases within this cohort.,KRAS mutations were identified in 1978 (16.6%) patient samples. Specifically\, KRAS G12C accounted for 14.5% (n=286) of all KRAS mutations. G12C was most commonly seen in lung cancer (4.3%)\, followed by colorectal cancer (2.5%) and biliary cancer (2.3%). Almost all patients (99.6%) with G12C mutations had concomitant genomic aberrations. These were most commonly associated with the RAS/RTK pathway including BRAF and PI3KCA mutations. Moreover\, KRAS mutation was positively correlated with smoking status in lung adenocarcinomas.,The overall incidence of KRAS G12C mutations remains low in the Chinese population. The most common tumor types harboring KRAS G12C mutations are in patients suffering from lung\, colorectal and biliary cancers.",Translational lung cancer research,vol.9:5:1759-1769,2020,Journal Article,,,"Department of Clinical Oncology\, The Chinese University of Hong Kong\, Hong Kong SAR\, China.,Department of Oncology\, First Affiliated Hospital\, Chinese PLA General Hospital\, Beijing\, China.,OrigiMed\, Shanghai\, China.,OrigiMed\, Shanghai\, China.,Division of Thoracic Surgery\, Tianjin First Central Hospital\, Tianjin\, China.,Department of Thoracic Oncology\, Fujian Cancer Hospital\, Fujian Medical University Cancer Hospital\, Fuzhou\, China.,Division of Thoracic Surgery\, Tianjin First Central Hospital\, Tianjin\, China.,Division of Thoracic Surgery\, Fourth Hospital of Hebei Medical University\, Shijiazhuang\, China.,Division of Thoracic Surgery\, Fourth Hospital of Hebei Medical University\, Shijiazhuang\, China.,Medical Oncology\, Fourth Hospital of Hebei Medical University\, Shijiazhuang\, China.,Division of Thoracic Surgery\, the Affiliated Hospital of Qingdao University\, Qingdao\, China.,OrigiMed\, Shanghai\, China.,OrigiMed\, Shanghai\, China.,OrigiMed\, Shanghai\, China.,OrigiMed\, Shanghai\, China.,Department of Clinical Oncology\, The Chinese University of Hong Kong\, Hong Kong SAR\, China.,Department of Thoracic Surgery\, West China Hospital\, Sichuan University\, Chengdu\, China.",,,,,"KRAS G12C,actionable alteration,co-aberration,pathway analysis,smoking status"
32961317,"van 't Erve I,Greuter MJE,Bolhuis K,Vessies DCL,Leal A,Vink GR,van den Broek D,Velculescu VE,Punt CJA,Meijer GA,Coupé VMH,Fijneman RJA",Diagnostic Strategies toward Clinical Implementation of Liquid Biopsy RAS/BRAF Circulating Tumor DNA Analyses in Patients with Metastatic Colorectal Cancer.,"Detection of KRAS, NRAS, and BRAF mutations in tumor tissue is currently used to predict resistance to treatment with anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). Liquid biopsies are minimally invasive, and cell-free circulating tumor DNA (ctDNA) mutation analyses may better represent tumor heterogeneity. This study examined the incorporation of liquid biopsy RAS/BRAF ctDNA analyses into diagnostic strategies to determine mCRC patient eligibility for anti-EGFR therapy. Tumor tissue and liquid biopsies were collected from 100 mCRC patients with liver-only metastases in a multicenter prospective clinical trial. Three diagnostic strategies incorporating droplet digital PCR ctDNA analyses were compared with routine tumor tissue RAS/BRAF mutation profiling using decision tree analyses. Tissue DNA mutations in KRAS, NRAS, and BRAF were present in 54%, 0%, and 3% of mCRC patients, respectively. A 93% concordance was observed between tissue DNA and liquid biopsy ctDNA mutations. The proportion of patients with RAS/BRAF alterations increased from 57% to 60% for diagnostic strategies that combined tissue and liquid biopsy mutation analyses. Consecutive RAS/BRAF ctDNA analysis followed by tissue DNA analysis in case of a liquid biopsy-negative result appeared to be the most optimal diagnostic strategy to comprehensively determine eligibility for anti-EGFR therapy in a cost-saving manner. These results highlight the potential clinical utility of liquid biopsies for detecting primary resistance to anti-EGFR-targeted therapies.",The Journal of molecular diagnostics : JMD,vol.22:12:1430-1437,2020,Journal Article,,,"Department of Pathology\, the Netherlands Cancer Institute\, Amsterdam\, the Netherlands.,Department of Epidemiology and Biostatistics\, Amsterdam University Medical Centers\, Vrije Universiteit Amsterdam\, Amsterdam\, the Netherlands.,Department of Medical Oncology\, Amsterdam University Medical Centers\, University of Amsterdam\, Amsterdam\, the Netherlands.,Department of Laboratory Medicine\, the Netherlands Cancer Institute\, Amsterdam\, the Netherlands.,Sidney Kimmel Comprehensive Cancer Center\, Johns Hopkins University School of Medicine\, Baltimore\, Maryland.,Department of Medical Oncology\, University Medical Center Utrecht\, Utrecht University\, the Netherlands; Department of Research and Development; Netherlands Comprehensive Cancer Organisation (IKNL)\, Utrecht\, the Netherlands.,Department of Laboratory Medicine\, the Netherlands Cancer Institute\, Amsterdam\, the Netherlands.,Sidney Kimmel Comprehensive Cancer Center\, Johns Hopkins University School of Medicine\, Baltimore\, Maryland.,Department of Medical Oncology\, Amsterdam University Medical Centers\, University of Amsterdam\, Amsterdam\, the Netherlands; Julius Center for Health Sciences and Primary Care\, University Medical Center Utrecht\, Utrecht\, the Netherlands.,Department of Pathology\, the Netherlands Cancer Institute\, Amsterdam\, the Netherlands.,Department of Epidemiology and Biostatistics\, Amsterdam University Medical Centers\, Vrije Universiteit Amsterdam\, Amsterdam\, the Netherlands.,Department of Pathology\, the Netherlands Cancer Institute\, Amsterdam\, the Netherlands. Electronic address: r.fijneman@nki.nl.",,,,,
32961530,"Wu CW,Chen MH,Huang KH,Chang SC,Fang WL,Lin CH,Chao Y,Lo SS,Li AF,Shyr YM",The clinicopathological characteristics and genetic alterations between younger and older gastric cancer patients with curative surgery.,"Few reports have investigated different genetic alterations according to age in various cancers. In total, 1749 GC patients receiving curative surgery were enrolled. The clinicopathological features, and prognoses were compared between younger (<65 years) and older (≥65 years) patients. Genetic mutations were analyzed using mass spectrometric single nucleotide polymorphism genotyping technology, including 68 validated mutations within eight genes (TP53, ARID1A, BRAF, and the PI3K/AKT pathway) previously reported in relation to age. Younger patients were more likely to be female and have poor cell differentiation, diffuse-type tumors, less lymphovascular invasion, fewer liver metastases, and better 5-year overall survival (OS) (68.0% vs. 54.6%, P<0.001) and disease-free survival (DFS) (65.4% vs. 53.0%, P<0.001) rates than older patients. Regarding the genetic alterations, older patients had more microsatellite instability-high (MSI-H) tumors and more ARID1A mutations than younger patients. Younger patients had significantly better OS and DFS rates than older patients for each pathological Tumor, Node, Metastasis (TNM) stage. Older patients had a significantly higher non-cancer related death rate than younger patients (36.2% vs. 12.3%, P<0.001). Age was an independent prognostic factor in GC. In conclusion, age was associated with different clinicopathological features and genetic alterations in GC with curative surgery.",Aging,vol.12:18:18137-18150,2020,Journal Article,,,"Division of General Surgery\, Department of Surgery\, Taipei Veterans General Hospital\, Taipei\, Taiwan.,School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan.,Division of General Surgery\, Department of Surgery\, Taipei Veterans General Hospital\, Taipei\, Taiwan.,School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan.,Division of General Surgery\, Department of Surgery\, Taipei Veterans General Hospital\, Taipei\, Taiwan.,Genome Research Center\, National Yang-Ming University\, Taipei\, Taiwan.,School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan.,School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan.,School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan.,Division of General Surgery\, Department of Surgery\, Taipei Veterans General Hospital\, Taipei\, Taiwan.",,,,,"age,clinicopathological feature,gastric cancer,genetic alteration,prognosis"
32965665,"Armstrong SA,Malley R,Weinberg BA",Molecular Profiling in Metastatic Colorectal Cancer.,"Colorectal cancer (CRC) is a commonly diagnosed malignancy. Although chemotherapy remains the backbone of treatment, the landscape of treating metastatic CRC (mCRC) is changing with the understanding of its heterogeneity and molecular blueprint. Colon cancer sidedness has proven to hold prognostic implications, with right-sided tumors having higher incidence of BRAF and KRAS mutations and being microsatellite instability-high (MSI-H); overall, they have a worse prognosis compared with left sided-tumors. Results of molecular research have demonstrated the need to profile each mCRC patient for RAS and BRAF mutations, MSI-H status, HER2 amplifications, and NTRK fusions. Ongoing clinical trials using targeted agents aim to further improve survival outcomes. We emphasize the epidemiology, knowledge of primary tumor location, and mutational landscape of mCRC, as well as novel treatment options for patients harboring unique subtypes of these characteristics.","Oncology (Williston Park, N.Y.)",vol.34:9:352-355,2020,Journal Article,,,"Ruesch Center for the Cure of Gastrointestinal Cancers\, Lombardi Comprehensive Cancer Center\, Washington\, DC.,Ruesch Center for the Cure of Gastrointestinal Cancers\, Lombardi Comprehensive Cancer Center\, Washington\, DC.,Ruesch Center for the Cure of Gastrointestinal Cancers\, Lombardi Comprehensive Cancer Center\, Washington\, DC.",,,,,
32966238,"Xie Z,Lun Y,Li X,He Y,Wu S,Wang S,Sun J,He Y,Zhang J",Bioinformatics analysis of the clinical value and potential mechanisms of AHNAK2 in papillary thyroid carcinoma.,"AHNAK2 has been recently reported as a biomarker in many cancers. However\, a systematic investigation of AHNAK2 in papillary thyroid carcinoma (PTC) has not been conducted.,AHNAK2 is overexpressed in PTC tissues and could be an independent prognostic factor. AHNAK2 expression was significantly high in patients with advanced stage\, advanced T classification\, lymph node metastasis\, increased BRAF mutations and decreased RAS mutations. Cell adhesion-\, cell junction-\, and immune-related pathways were the most frequently noted in gene set enrichment analysis. AHNAK2 expression in PTC was positively correlated with immune infiltration and negatively correlated with AHNAK2 methylation. AHNAK2 expression was significantly positively correlated with tumor progression and poor overall survival (OS) in pan-cancer patients.,AHNAK2 is a good biomarker for the diagnosis and prognosis of PTC. AHNAK2 may promote thyroid cancer progression through cell adhesion-\, cell junction-\, and immune-related pathways. Methylation may act as an upstream regulator to inhibit the expression and biological function of AHNAK2. Additionally\, AHNAK2 has broad prognostic value in pan-cancer.,Based on The Cancer Genome Atlas (TCGA) data\, we screened AHNAK2-related genes through weighted gene coexpression network analysis and explored the clinical value and the potential mechanism of AHNAK2 in PTC by multiomics analysis.",Aging,vol.12:18:18163-18180,2020,Journal Article,,,"Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.,Department of Vascular and Thyroid Surgery\, The First Hospital\, China Medical University\, Shenyang\, China.",,,,,"AHNAK2,diagnostic biomarker,immune infiltration,papillary thyroid carcinoma,prognostic biomarker"
32966885,"Coura BP,Bernardes VF,de Sousa SF,Diniz MG,Moreira RG,de Andrade BAB,Romañach MJ,Pontes HAR,Gomez RS,Odell EW,Gomes CC",Targeted Next-Generation Sequencing and Allele-Specific Quantitative PCR of Laser Capture Microdissected Samples Uncover Molecular Differences in Mixed Odontogenic Tumors.,"The molecular pathogenesis of mixed odontogenic tumors has not been established, and understanding their genetic basis could refine their classification and help define molecular markers for diagnostic purposes. Potentially pathogenic mutations in the component tissues of 28 cases of mixed odontogenic tumors were assessed. Laser capture microdissected tissue from 10 ameloblastic fibromas (AF), 4 ameloblastic fibrodentinomas (AFD), 6 ameloblastic fibro-odontomas (AFO), 3 ameloblastic fibrosarcomas (AFS), and 5 odontomas (OD) were screened by next-generation sequencing and results confirmed by TaqMan allele-specific quantitative PCR. BRAF p.V600E mutation in the mesenchymal component was shown in 4 of 10 AF (40%), 2 of 4 AFD (50%), 2 of 6 AFO (33%), and 2 of 3 AFS (67%), whereas all 5 OD were wild type for BRAF p.V600E. Mutation in the epithelial component was only observed in one AF and one AFO. One AFS contained an area of benign AF, and the mesenchymal component of both (AFS and AF) contained BRAF p.V600E, supporting the concept of malignant progression from a benign AF precursor. KDR, TP53, KIT, and PIK3CA single-nucleotide polymorphisms are reported. In conclusion, AF, AFD, AFO, and AFS show BRAF p.V600E in their mesenchymal component, unlike OD, which are BRAF wild type, suggesting that at least a subset of AF, AFD, and AFO are molecularly distinct from OD, and may represent distinct entities and be neoplastic.",The Journal of molecular diagnostics : JMD,vol.22:12:1393-1399,2020,Journal Article,,,"Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Center of Multi-Users Laboratories-Genomics Laboratory\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Diagnosis and Pathology\, Dental School\, Universidade Federal do Rio de Janeiro (UFRJ)\, Rio de Janeiro\, Brazil.,Department of Oral Diagnosis and Pathology\, Dental School\, Universidade Federal do Rio de Janeiro (UFRJ)\, Rio de Janeiro\, Brazil.,Service of Oral Pathology\, João de Barros Barreto University Hospital\, Universidade Federal do Pará (UFPA)\, Belém\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Head and Neck Pathology\, King's College London\, Guy's Hospital\, London\, United Kingdom. Electronic address: edward.odell@kcl.au.uk.,Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil. Electronic address: carolinacgomes@ufmg.br.",,,,,
32970929,"Usman RM,Razzaq F,Akbar A,Farooqui AA,Iftikhar A,Latif A,Hassan H,Zhao J,Carew JS,Nawrocki ST,Anwer F",Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance.,"A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy-induced tumorigenesis and drug resistance including Beclin-1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF-2, MEG3, LAPTM4B, mTOR, BRAF and c-MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.",Asia-Pacific journal of clinical oncology,vol.::,2020,Review,,,"Department of Medicine\, The University of Tennessee Health Sciences Center\, Memphis\, TN\, USA.,Foundation University Medical College\, Islamabad\, Pakistan.,Department of Medical Intensive Care\, Holy Family Hospital\, Rawalpindi\, Pakistan.,Department of Medicine\, King Edward Medical University\, Lahore\, Pakistan.,https://orcid.org/0000-0002-2358-7057Department of Medicine\, The University of Arizona\, Tucson\, AZ\, USA.,Department of Medicine\, Crieghton University\, Omaha\, NE\, USA.,Department of Hematology & Medical Oncology\, Boston University Medical Center\, Boston\, MA\, USA.,Taussig Cancer Center\, Cleveland Clinic\, Cleveland\, OH\, USA.,Department of Medicine\, The University of Arizona\, Tucson\, AZ\, USA.,Department of Medicine\, The University of Arizona\, Tucson\, AZ\, USA.,Taussig Cancer Center\, Cleveland Clinic\, Cleveland\, OH\, USA.",,,,,"Autophagy-related genes,autophagy,drug resistance,hydroxychloroquine,tumorigenesis"
32972866,"Barreno LRQ,Mello JBH,Barros-Filho MC,Francisco AL,Chulam TC,Pinto CAL,Gonçalves-Filho J,Kowalski LP",Characterization of BRAF mutation in patients older than 45 years with well-differentiated thyroid carcinoma.,"Papillary thyroid carcinoma is the most frequent endocrine neoplasia and its incidence has tripled over the past 35 years. Although papillary thyroid carcinoma carries a good prognosis\, 10%-30% of patients still develop recurrence and metastasis. Some clinical and genetic features are associated with worse prognosis. The most frequent mutation is the BRAF p.V600E\, which has been associated with many clinical features of poor prognosis. However\, many studies have produced controversial results without any association between BRAF mutation and clinicopathological features of poor prognosis.,Since the prognostic value of BRAF mutations remains controversial\, this study aims to investigate the importance of this mutation in therapeutic decisions for papillary thyroid carcinoma.,Therefore\, we evaluated whether the presence of BRAF mutation is associated with features of poor prognosis in 85 patients with papillary thyroid carcinoma older than 45 years treated at A.C. Camargo Cancer Center\, from 1980 to 2007. BRAF mutation was evaluated by pyrosequencing. Statistical analysis was performed using SPSS.,The mean age of patients was 54 years (range: 45 - 77 years)\, 73 were women (85.8%) and 12 were men (14.2%). Among them\, 39 cases (45.9%) presented extrathyroidal extension and 11 cases had recurrent disease. BRAF mutation was detected in 57 (67%) patients. No significant association was observed between BRAF mutation and gender (p  = 0.743)\, age (p  = 0.236)\, N-stage (p  = 0.423)\, vascular and perineural infiltration (p  = 0.085 or multifocality (p  = 1.0). Although not statistically significant\, the majority of patients with recurrent disease were BRAF positive (9 out of 11) (p  = 0.325). Patients affected by BRAF mutation are associated with tumors larger than 1 cm (p  = 0.034) and with extrathyroidal extension (p  = 0.033).,Although BRAF testing is widely available\, there are no consistent data to support improvement in outcomes from incorporating it into therapeutic decision for thyroid cancer.",Brazilian journal of otorhinolaryngology,vol.::,2020,Journal Article,,,"A.C. Camargo Cancer Center\, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia\, Sao Paulo\, SP\, Brazil.,Instituto Nacional do Câncer (INCA)\, Programa de Carcinogênese Molecular\, Rio de Janeiro\, RJ\, Brazil.,A.C. Camargo Cancer Center\, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia\, Sao Paulo\, SP\, Brazil.,A.C. Camargo Cancer Center\, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia\, Sao Paulo\, SP\, Brazil.,A.C. Camargo Cancer Center\, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia\, Sao Paulo\, SP\, Brazil.,A.C. Camargo Cancer Center\, Departamento de Patologia\, Sao Paulo\, SP\, Brazil.,A.C. Camargo Cancer Center\, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia\, Sao Paulo\, SP\, Brazil.,A.C. Camargo Cancer Center\, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia\, Sao Paulo\, SP\, Brazil; Faculdade de Medicina da USP\, São Paulo\, SP\, Brazil. Electronic address: lp_kowalski@uol.com.br.",,,,,"BRAF mutation,Carcinoma papilífero,Câncer de tireoide,Mutação em BRAF,Papillary carcinoma,Prognosis,Prognóstico,Recorrência,Recurrence,Sobrevida,Survival,Thyroid cancer"
32973641,"Liang J,Zhao W,Lu C,Liu D,Li P,Ye X,Zhao Y,Zhang J,Yang D",Next-Generation Sequencing Analysis of ctDNA for the Detection of Glioma and Metastatic Brain Tumors in Adults.,"Background and aims: The next-generation sequencing technologies and their related assessments of circulating tumor DNA in both glioma and metastatic brain tumors remain largely limited. Methods: Based largely on a protocol approved by the institutional review board at Peking University International Hospital, the current retrospective, single-center study was conducted. Genomic DNA was extracted from blood samples or tumor tissues. With the application of NextSeq 500 instrument (Illumina), Sequencing was performed with an average coverage of 550-fold. Paired-end sequencing was employed utilized with an attempt to achieve improved sensitivity of duplicate detection and therefore to increase the detection reliability of possible fusions. Results: A total of 28 patients (21 men and 7 women) with brain tumors in the present study were involved in the study. The patients enrolled were assigned into two groups, including glioma group (n = 21) and metastatic brain tumor group (n = 7). The mean age of metastatic brain tumor group (59.86 ± 8.85 y), (43.65 ± 13.05 y) reported significantly higher results in comparison to that of glioma group (45.3 ± 12.3 years) (P < 0.05). The mutant genes in metastatic brain tumor group included ALK, MDM2, ATM, BRCA1, FGFR1, MDM4 and KRAS; however, there were no glioma-related mutant genes including MGMT, IDH1, IDH2, 1p/19q, and BRAF et al. Interesteringly, only two patient (28.3%) was detected blood ctDNA in metastatic brain tumor group; In contrast, blood ctDNA was found in ten glioma patients (47.6%) including 1p/19q, MDM2, ERBB2, IDH1, CDKN2A, CDK4, PDGFRA, CCNE1, MET. The characterizations of IDH mutations in the glioma included IDH1 mutation (p.R132H) and IDH2 mutation (p.R172K). The mutation rate of IDH in tumor tissues was 37.06 ± 8.32%, which was significantly higher than blood samples (P < 0.05). Conclusion: The present study demonstrated that the mutant genes among glioma and metastatic brain tumors are shown to be different. Moreover, the ctDNAs in the metastatic brain tumors included ALK and MDM2, and glioma-related ctDNAs included 1p/19q and MDM2 followed by frequencies of ERBB2, IDH1, CDKN2A, CDK4, PDGFRA, CCNE1, MET. These ctDNAs might be biomarkers and therapeutic responders in brain tumor.",Frontiers in neurology,vol.11::544,2020,Journal Article,,,"Department of Neurosurgery\, Peking University International Hospital\, Beijing\, China.,Department of General Surgery\, Beijing Hospital\, National Center of Gerontology\, Beijing\, China.,Department of Neurosurgery\, Peking University International Hospital\, Beijing\, China.,HaploX Biotechnology\, Shenzhen\, China.,Department of Hematology\, Tongji Hospital of Tongji University\, Shanghai\, China.,Department of Neurosurgery\, Peking University International Hospital\, Beijing\, China.,Department of Neurosurgery\, Peking University International Hospital\, Beijing\, China.,HaploX Biotechnology\, Shenzhen\, China.,Department of Neurosurgery\, China-Japan Friendship Hospital\, Beijing\, China.",,,,,"IDH1/2,MGMT,NGS,brain tumors,ctDNA"
32978227,,Trametinib Promotes MEK Binding to the RAF-Family Pseudokinase KSR.,The MEK inhibitor trametinib caused MEK to engage KSR more efficiently than MEK engaged BRAF.,Cancer discovery,vol.10:11:1624,2020,Journal Article,,,,,,,,
32539314,"Gozzetti A,Sammartano V,Bacchiarri F,Raspadori D,Bocchia M",A -Negative Classic Hairy Cell Leukemia Patient with Long-Lasting Complete Remission after Rituximab and Pentostatin,,Turkish journal of haematology : official journal of Turkish Society of Haematology,vol.37:4:286-287,2020,Journal Article,,,"0000-0003-0769-6891University of Siena\, Hematology\, Siena\, Italy,0000-0003-4383-282XAzienda Ospedaliera Universitaria\, Siena\, Italy,0000-0001-6186-3895Azienda Ospedaliera Universitaria\, Siena\, Italy,0000-0002-2597-6312Azienda Ospedaliera Universitaria\, Siena\, Italy,0000-0003-3538-3913University of Siena\, Hematology\, Siena\, Italy",,,,,"BRAF,Hairy cell leukemia"
32540454,"Subbiah V,Baik C,Kirkwood JM",Clinical Development of BRAF plus MEK Inhibitor Combinations.,"Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.",Trends in cancer,vol.6:9:797-810,2020,"Research Support, Non-U.S. Gov't",,,"Department of Investigational Cancer Therapeutics\, Division of Cancer Medicine\, University of Texas MD Anderson Cancer Center\, Houston\, TX 77030\, USA. Electronic address: vsubbiah@mdanderson.org.,Department of Thoracic\, Head and Neck Medical Oncology\, University of Washington School of Medicine\, Seattle Cancer Care Alliance\, Fred Hutchinson Cancer Research Center\, Seattle\, WA 98109\, USA.,Department of Medicine\, Division of Medical Oncology University of Pittsburgh\, and Melanoma Program\, University of Pittsburgh Cancer Institute\, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center\, Pittsburgh\, PA 15232\, USA.",,,,,"BRAF V600 mutation,BRAF inhibitor,MEK inhibitor,anaplastic thyroid cancer,melanoma,non-small cell lung cancer"
32541157,Nagasaka T,"[A New Era of Colorectal Cancer Treatment Being Led by a Precise Analysis of Somatic Mutational Profiles Including RAS, BRAF Mutation and Microsatellite Instability Status].","In Japan, clinically, a decade has passed since KRAS exon 2 hotspot mutations could be measured as a companion diagnostic agent of an anti-epidermal growth factor receptor antibody to treat unresectable advanced colorectal cancer. Till now, not only KRAS exon 2, but also KRAS exon 3, 4 and NRAS exon 2-4 mutation, and BRAF mutation(V600E)are approved as insurance as a companion diagnostics tool. In addition to those somatic mutations observed in Ras-Raf signal cascade, the measurement of microsatellite instability status is also approved as a companion diagnostic to anti-programmed death-1 receptor antibodies. Since these somatic mutational profiles in colorectal cancer cells are measured to determine the propriety of administration of a particular medicine, the results must be appropriately reflected in therapy for each patient. In this review, I will summarize the feature of clinical characteristics belonging to each somatic mutational profile commonly observed in colorectal cancer, and discuss howsuch somatic mutational profiles including RAS, BRAF mutation, and microsatellite instability status bring us to a newera of colorectal cancer.",Gan to kagaku ryoho. Cancer & chemotherapy,vol.47:6:861-869,2020,Review,"|Colorectal Neoplasms|genetics|,|Humans|,|Japan|,|Microsatellite Instability|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|",,"Dept. of Clinical Oncology, Kawasaki Medical School.","BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)",,,,
32544965,"Noepel-Duennebacke S,Juette H,Feder IS,Kluxen L,Basara N,Hiller W,Herzog T,Klaassen-Mielke R,Mueller L,Senkal M,Engel L,Teschendorf C,Trenn G,Verdoodt B,Wolters H,Uhl W,Reinacher-Schick A,Tannapfel A",High microsatellite instability (MSI-H) is associated with distinct clinical and molecular characteristics and an improved survival in early Colon cancer (CC); real world data from the AIO molecular registry Colopredict Plus.,"Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.",Zeitschrift fur Gastroenterologie,vol.58:6:533-541,2020,Journal Article,"|Aged|,|Aged\, 80 and over|,|Colonic Neoplasms|genetics|mortality|pathology|,|Colorectal Neoplasms|genetics|mortality|pathology|,|Female|,|Germany|,|Humans|,|Microsatellite Instability|,|Microsatellite Repeats|genetics|,|Middle Aged|,|Neoplasm Recurrence\, Local|,|Neoplasm Staging|,|Prognosis|,|Registries|,|Survival Rate|",,"Abteilung für Hämatologie\, Onkologie und Palliativmedizin\, St. Josef-Hospital Bochum\, Ruhr Universität Bochum.,Institut für Pathologie\, Ruhr Universität Bochum.,Institut für Pathologie\, Ruhr Universität Bochum.,Institut für Pathologie\, Ruhr Universität Bochum.,Medizinische Klinik 1\, Malteser Krankenhaus St. Franziskus-Hospital\, Flensburg.,Klinik für Allgemein-\, Viszeral- und Thoraxchirurgie\, Klinikum Lippe GmbH\, Detmold.,Klinik für Allgemein- und Viszeralchirurgie\, St.-Josef Hospital Bochum\, Ruhr Universität Bochum\, Bochum.,Abteilung für medizinische Informatik\, Biometrie und Epidemiologie\, Ruhr-Universität Bochum.,Onkologie UnterEms\, Leer.,Klinik für Allgemein- und Viszeralchirurgie\, Marien Hospital Witten\, Witten.,Paracelsus Medizinische Universität\, Klinikum Nürnberg\, Klinik für Viszeralchirurgie\, Nürnberg.,Klinik für Innere Medizin I\, St. Josef-Hospital Dortmund\, Dortmund.,Klinik für Innere Medizin I\, Knappschaftskrankenhaus Bottrop\, Bottrop.,Institut für Pathologie\, Ruhr Universität Bochum.,Klinik für Allgemein- und Viszeralchirurgie\, St. Josef-Hospital Dortmund\, Dortmund.,Klinik für Allgemein- und Viszeralchirurgie\, St.-Josef Hospital Bochum\, Ruhr Universität Bochum\, Bochum.,Abteilung für Hämatologie\, Onkologie und Palliativmedizin\, St. Josef-Hospital Bochum\, Ruhr Universität Bochum.,Institut für Pathologie\, Ruhr Universität Bochum.",,,,,
32545884,"Molina-Cerrillo J,San Román M,Pozas J,Alonso-Gordoa T,Pozas M,Conde E,Rosas M,Grande E,García-Bermejo ML,Carrato A",BRAF Mutated Colorectal Cancer: New Treatment Approaches.,"Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.",Cancers,vol.12:6:,2020,Review,,,"0000-0003-4616-0598Medical Oncology Department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.,Medical Oncology Department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.,Medical Oncology Department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.,0000-0002-8966-7236Medical Oncology Department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.,Medical Oncology Department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.,0000-0002-3751-9602Biomarkers and Therapeutic Targets Group and Core Facility\, The Ramón y Cajal Health Research Institute (IRYCIS)\, CIBERONC\, 28034 Madrid\, Spain.,Pathology department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.,Department of Medical Oncology\, MD Anderson Cancer Center\, 28033 Madrid\, Spain.,Biomarkers and Therapeutic Targets Group and Core Facility\, The Ramón y Cajal Health Research Institute (IRYCIS)\, CIBERONC\, 28034 Madrid\, Spain.,0000-0001-7749-8140Medical Oncology Department\, University Hospital Ramon y Cajal\, 28034 Madrid\, Spain.",,,,,"BRAF,CXCR4,colorectal cancer,immunotherapy,tyrosine kinases"
32547066,"Bai H,Chen B",A 5-Gene Stemness Score for Rapid Determination of Risk in Multiple Myeloma.,"Risk stratification in patients with multiple myeloma (MM) remains a challenge. As clinicopathological characteristics have been demonstrated insufficient for exactly defining MM risk\, and molecular biomarkers have become the focuses of interests. Prognostic predictions based on gene expression profiles (GEPs) have been the most accurate to this day. The purpose of our study was to construct a risk score based on stemness genes to evaluate the prognosis in MM.,Bioinformatics studies by ingenuity pathway analyses in side population (SP) and non-SP (MP) cells of MM patients were performed. Firstly\, co-expression network was built to confirm hub genes associated with the top five Kyoto Encyclopedia of Genes and Genomes pathways. Functional analyses of hub genes were used to confirm the biologic functions. Next\, these selective genes were utilized for construction of prognostic model\, and this model was validated in independent testing sets. Finally\, five stemness genes (ROCK1\, GSK3B\, BRAF\, MAPK1 and MAPK14) were used to build a MM side population 5 (MMSP5) gene model\, which was demonstrated to be forcefully prognostic compared to usual clinical prognostic parameters by multivariate cox analysis. MM patients in MMSP5 low-risk group were significantly related to better prognosis than those in high-risk group in independent testing sets.,Our study provided proof-of-concept that MMSP5 model can be adopted to evaluate recurrence risk and clinical outcome for MM. The MMSP5 model evaluated in different databases clearly indicated novel risk stratification for personalized anti-MM treatments.",OncoTargets and therapy,vol.13::4339-4348,2020,Journal Article,,,"Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, Nanjing 210008\, People's Republic of China.,Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, Nanjing 210008\, People's Republic of China.",,,,,"gene expression profiling,multiple myeloma,prognosis,risk score,side population"
32547201,"Zhou L,Gao C,Li H,Liang W,Zeng Q,Chen B",Isthmic Papillary Thyroid Carcinoma Presents a Unique Pattern of Central Lymph Node Metastasis.,"Treatment protocols for occult central lymph node metastasis (LNM) associated with papillary thyroid cancer (PTC) located in the isthmus are debatable. We aimed to analyze the pattern of occult central LNM in isthmic PTC\, including risk factors for bilateral paratracheal LNM.,Consecutive patients with PTC were recruited to this study. All patients underwent total thyroidectomy and prophylactic bilateral central neck dissection. The clinicopathologic features and distribution of central LNM were compared between the two groups\, and risk factors for bilateral paratracheal LNM were analyzed.,A total of 174 patients with PTC were enrolled in this study\, of whom 87 patients had isthmic PTC (study group) and 87 patients had lobe-originating PTC (control group). The two groups had comparable demographics and tumor features. There were higher frequencies of pretracheal LNM (P =0.001) and bilateral paratracheal LNM (P = 0.002) in the isthmic PTC group. Bilateral paratracheal LNM was significantly associated with age <55 years (P = 0.037)\, capsular invasion (P = 0.034)\, tumor location (isthmus) (P < 0.001)\, BRAF gene mutation (P = 0.013)\, and pretracheal LNM (P < 0.001). Isthmus location (odds ratio [OR]: 4.116\, 95% confidence interval [CI]: 1.264-13.433\, P = 0.019) and pretracheal LNM (OR: 3.422\, 95% CI: 1.214-9.642\, P = 0.020) were independent risk factors for bilateral paratracheal LNM.,Because of its unique anatomic location\, isthmic PTC differs from PTC in the lobe with respect to pretracheal and bilateral paratracheal LNM\, even in patients of comparable age\, sex\, tumor size\, extrathyroidal extension\, BRAF mutation\, and pathologic TNM staging. The isthmus location was found to be an independent risk factor for bilateral paratracheal LNM. This information may contribute to the development of an appropriate surgical protocol for isthmic PTC.",Cancer management and research,vol.12::3643-3650,2020,Journal Article,,,"Department of Ultrasound\, Shandong Provincial Hospital Affiliated to Shandong University\, Jinan\, People's Republic of China.,Department of Thyroid Surgery\, General Surgery\, Qilu Hospital\, Shandong University\, Jinan 250012\, People's Republic of China.,Department of General Surgery\, Cao County People's Hospital\, Heze\, People's Republic of China.,0000-0002-8991-7071Department of Thyroid Surgery\, General Surgery\, Qilu Hospital\, Shandong University\, Jinan 250012\, People's Republic of China.,Department of Thyroid Surgery\, General Surgery\, Qilu Hospital\, Shandong University\, Jinan 250012\, People's Republic of China.,Department of Thyroid Surgery\, General Surgery\, Qilu Hospital\, Shandong University\, Jinan 250012\, People's Republic of China.",,,,,"bilateral paratracheal sub-compartments,risk factors,tumor location"
32553555,"Liu Y,Zeng H,Wang K,Li Y,Tian P,Li W",Acquired BRAF N581S mutation mediated resistance to gefitinib and responded to dabrafenib plus trametinib.,"BRAFG469A and V600E were reported as the mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer patients. Here\, we described a rare case of BRAF N581S after gefitinib resistance and response to BRAF inhibitor plus MEK inhibitor.,Next-generation sequencing (NGS) was performed on the tumor tissue and plasma samples of a patient with metastatic lung adenocarcinoma harboring EGFR exon 19 deletion (EGFR 19del).,EGFR 19del and MET amplification was detected after resistance to the initial gefitinib therapy. After 9 months of treatment with gefitinib plus crizotinib\, the disease progressed again. NGS revealed the known EGFR 19del and a BRAF N581S missense mutation after progression. The patient obtained durable clinical benefit upon treatment with dabrafenib plus trametinib\, achieving a progression-free survival (PFS) of more than 33 months.,BRAF N581S mutation could be explored as one kind of mechanism of acquired resistance to EGFR-TKIs. Combined inhibition of BRAF and MEK is a potential therapeutic strategy.","Lung cancer (Amsterdam, Netherlands)",vol.146::355-357,2020,"Research Support, Non-U.S. Gov't",,,"Department of Respiratory and Critical Care Medicine\, West China Hospital\, West China School of Medicine\, Sichuan University\, Chengdu\, 610041\, Sichuan\, China.,Department of Respiratory and Critical Care Medicine\, West China Hospital\, West China School of Medicine\, Sichuan University\, Chengdu\, 610041\, Sichuan\, China.,Department of Respiratory and Critical Care Medicine\, Lung Cancer Treatment Center\, West China Hospital\, Sichuan University\, Chengdu\, 610041\, Sichuan\, China.,Department of Respiratory and Critical Care Medicine\, West China Hospital\, Sichuan University\, Chengdu\, 610041\, Sichuan\, China. Electronic address: 59968642@qq.com.,Department of Respiratory and Critical Care Medicine\, Lung Cancer Treatment Center\, West China Hospital\, Sichuan University\, Chengdu\, 610041\, Sichuan\, China. Electronic address: mrascend@163.com.,Department of Respiratory and Critical Care Medicine\, West China Hospital\, Sichuan University\, Chengdu\, 610041\, Sichuan\, China.",,,,,"BRAF N581S,Dabrafenib,Gefitinib,Trametinib"
32553612,"Rubio-Rivas M,Moreira C,Marcoval J",Sarcoidosis related to checkpoint and BRAF/MEK inhibitors in melanoma.,"Therapy for advanced melanoma has deeply changed in the last decade with the introduction of checkpoint and BRAF/MEK inhibitors. Granulomatous reactions have been reported related to these drugs. We performed a systematic review of all the cases described in the medical literature by the search ((""Melanoma""[Mesh]) AND (""Sarcoidosis""[Mesh] OR ""Granuloma""[Mesh])). Ninety-one patients under immunotherapy were included in the analyses. The time from the initiation of the immunotherapy until the onset of sarcoidosis or sarcoid-like reaction (SLR) was 7.1 months (SD 9). Peripheral lymph nodes as the mode of onset were seen more frequently in patients under CTLA-4 inhibitors (p = .016) whereas in patients under BRAF/MEK inhibitors used to be in the form of specific skin lesions (p = .006). Chest X-ray stage I-II was the rule in the CTLA-4 and PD-1 groups. On the contrary, stage 0 accounted for 80% of the patients in the BRAF/MEK group examined for pulmonary involvement. Specific skin involvement was the most common manifestation apart from pulmonary involvement. It was more frequent in patients under BRAF/MEK inhibitors and especially in the form of papules. Splenic involvement was found also more frequently in patients under CTLA-4 inhibitors. Specific treatment for sarcoidosis/SLR was prescribed in 50 patients (58.8%), without differences among groups. Almost all patients presented a good prognosis independently of the decision made regarding their previous immunotherapy. CONCLUSION: Physicians should bear in mind the possibility of sarcoidosis/SLR after the initiation of checkpoint or BRAF/MEK inhibitors in patients diagnosed with advanced melanoma, especially in the form of skin involvement and mediastinal and peripheral lymph nodes. It is important to achieve an accurate diagnosis to rule out the possibility of cancer involvement. What to do with these drugs is yet to be clarified. It seems reasonable to prioritize cancer treatment so it is not mandatory to stop these drugs.",Autoimmunity reviews,vol.19:8:102587,2020,Systematic Review,"|Antineoplastic Agents|adverse effects|therapeutic use|,|Humans|,|Immunotherapy|adverse effects|,|MAP Kinase Kinase 1|antagonists & inhibitors|,|Melanoma|drug therapy|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|,|Sarcoidosis|chemically induced|",,"Autoimmune Diseases Unit\, Department of Internal Medicine\, Bellvitge University Hospital\, Bellvitge Biomedical Research Institute-IDIBELL\, University of Barcelona\, Barcelona\, Spain. Electronic address: mrubio@bellvitgehospital.cat.,Department of Internal Medicine\, Igualada Hospital\, Barcelona\, Spain.,Department of Dermatology\, Bellvitge University Hospital\, Bellvitge Biomedical Research Institute-IDIBELL\, University of Barcelona\, Barcelona\, Spain.","Antineoplastic Agents,BRAF protein\, human,Proto-Oncogene Proteins B-raf,MAP Kinase Kinase 1",,,,"BRAF/MEK inhibitors,Checkpoint inhibitors,Immunotherapy,Melanoma,Sarcoidosis"
32554313,"Cybulska-Stopa B,Rogala P,Czarnecka AM,Ługowska I,Teterycz P,Galus Ł,Rajczykowski M,Dawidowska A,Piejko K,Suwiński R,Mackiewicz J,Rutkowski P",Efficacy of ipilimumab after anti-PD-1 therapy in sequential treatment of metastatic melanoma patients - Real world evidence.,"Immunotherapy has become a standard treatment option for patients with metastatic melanoma\, and the use of checkpoint inhibitors significantly improves the treatment outcomes in this group.,A total of 116 patients with metastatic melanoma were enrolled in the study. In the first line\, they were treated with an anti-PD-1 inhibitor (nivolumab or pembrolizumab)\, following which ipilimumab was used as the second-line therapy.,BRAF mutation was detected in 12 patients (10%). The median progression-free survival (PFS) of ipilimumab treatment was 2.8 months\, the overall survival (OS) was 5.1 months. The rate of 6-month survival was 45%\, 1-year survival was 24%\, and 2-year survival was 3%. The responses to treatment were: complete response in 2 cases (2%)\, partial response in 7 cases (6%)\, stable disease in 39 cases (34%). In multivariate analysis\, normal levels of lactate dehydrogenase (LDH) were associated with a longer median OS and PFS (p = 0.02 and p = 0.009\, respectively)\, while 2 or less number of metastatic locations and the presence of BRAF mutations were correlated with a longer OS (p = 0.041 and p = 0.024\, respectively).,Ipilimumab could be considered after anti-PD-1 treatment. Treatment with ipilimumab following anti-PD-1 therapy showed beneficial effects in patients with normal levels of LDH\, 2 or less number of metastatic locations\, and BRAF-mutated melanoma. However\, further studies are required to confirm our results as the study included a low number of patients with BRAF mutation-positive melanoma. No significant increase in toxicity was detected with the use of ipilimumab after anti-PD-1 therapy.",Advances in medical sciences,vol.65:2:316-323,2020,Journal Article,,,"Clinical Oncology Clinic\, Maria Sklodowska-Curie National Research Institute of Oncology\, Cracow Branch\, Cracow\, Poland. Electronic address: bcybulskatopa@vp.pl.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland; Department of Experimental Pharmacology\, Mossakowski Medical Research Centre\, Polish Academy of Sciences\, Warsaw\, Poland.,Early Phase Clinical Trials Unit\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland.,Department of Medical and Experimental Oncology\, Heliodor Swiecicki Clinical Hospital\, University of Medical Sciences\, Poznan\, Poland; Chemotherapy Department\, Greater Poland Cancer Centre\, Poznan\, Poland.,II Radiotherapy and Chemotherapy Clinic\, Maria Sklodowska-Curie National Research Institute of Oncology\, Gliwice Branch\, Gliwice\, Poland.,Early Phase Clinical Trials Unit\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland.,Clinical Oncology Clinic\, Maria Sklodowska-Curie National Research Institute of Oncology\, Cracow Branch\, Cracow\, Poland.,II Radiotherapy and Chemotherapy Clinic\, Maria Sklodowska-Curie National Research Institute of Oncology\, Gliwice Branch\, Gliwice\, Poland.,Department of Medical and Experimental Oncology\, Heliodor Swiecicki Clinical Hospital\, University of Medical Sciences\, Poznan\, Poland; Department of Biology and Environmental Studies\, University of Medical Sciences\, Poznan\, Poland; Department of Diagnostics and Cancer Immunology\, Greater Poland Cancer Centre\, Poznan\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland.",,,,,"Anti-PD-1,Immunotherapy,Ipilimumab,Metastatic melanoma,Sequential treatment"
32528881,"Ziemys A,Kim M,Menzies AM,Wilmott JS,Long GV,Scolyer RA,Kwong L,Holder A,Boland G",Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors.,"Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify ""hot"" areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.",Frontiers in oncology,vol.10::757,2020,Journal Article,,,"Department of Nanomedicine\, Houston Methodist Research Institute\, Houston\, TX\, United States.,Department of Surgery\, Massachusetts General Hospital\, Boston\, MA\, United States.,Department of Medical Oncology\, Westmead Hospital\, Westmead\, NSW\, Australia.,Melanoma Institute of Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Department of Medical Oncology\, Westmead Hospital\, Westmead\, NSW\, Australia.,Melanoma Institute of Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,University of Texas MD Anderson Cancer Center\, Houston\, TX\, United States.,Department of Nanomedicine\, Houston Methodist Research Institute\, Houston\, TX\, United States.,Department of Surgery\, Massachusetts General Hospital\, Boston\, MA\, United States.",,,,,"RNAseq,immune infiltrate,melanoma,spatial analysis,targeted therapy (TT)"
32528879,"Avagliano A,Fiume G,Pelagalli A,Sanità G,Ruocco MR,Montagnani S,Arcucci A",Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment.,"Cutaneous melanoma (CM) is a highly aggressive and drug resistant solid tumor, showing an impressive metabolic plasticity modulated by oncogenic activation. In particular, melanoma cells can generate adenosine triphosphate (ATP) during cancer progression by both cytosolic and mitochondrial compartments, although CM energetic request mostly relies on glycolysis. The upregulation of glycolysis is associated with constitutive activation of BRAF/MAPK signaling sustained by BRAFV600E kinase mutant. In this scenario, the growth and progression of CM are strongly affected by melanoma metabolic changes and interplay with tumor microenvironment (TME) that sustain tumor development and immune escape. Furthermore, CM metabolic plasticity can induce a metabolic adaptive response to BRAF/MEK inhibitors (BRAFi/MEKi), associated with the shift from glycolysis toward oxidative phosphorylation (OXPHOS). Therefore, in this review article we survey the metabolic alterations and plasticity of CM, its crosstalk with TME that regulates melanoma progression, drug resistance and immunosurveillance. Finally, we describe hallmarks of melanoma therapeutic strategies targeting the shift from glycolysis toward OXPHOS.",Frontiers in oncology,vol.10::722,2020,Review,,,"Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Experimental and Clinical Medicine\, University ""Magna Graecia"" of Catanzaro\, Catanzaro\, Italy.,Department of Advanced Biomedical Sciences\, University of Naples Federico II\, Naples\, Italy.,Department of Molecular Medicine and Medical Biotechnology\, University of Naples Federico II\, Naples\, Italy.,Department of Molecular Medicine and Medical Biotechnology\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.",,,,,"OXPHOS,cutaneous melanoma,metabolic alterations,therapeutic strategies,tumor microenvironment"
32529280,"Ishi Y,Takamiya S,Seki T,Yamazaki K,Hida K,Hatanaka KC,Ishida Y,Oda Y,Tanaka S,Yamaguchi S","Prognostic role of H3K27M mutation, histone H3K27 methylation status, and EZH2 expression in diffuse spinal cord gliomas.","The objective of this study is to clarify clinical significance of the H3F3A K27M mutation (H3K27M) and analyze the correlation between H3K27M, H3K27me3 status, and EZH2 expression and prognosis in spinal cord gliomas. Patients with spinal cord diffuse glioma regardless of World Health Organization (WHO) grade underwent genetic analysis for H3F3A, HIST1H3B, TERT promoter, IDH1/2, and BRAF. H3K27me3 status and EZH2 expression were analyzed through immunohistochemistry. Thereafter, the association between H3K27M, H3K27me3 status, and EZH2 expression and prognosis was retrospectively analyzed using the log-rank test. A total of 26 cases, 5 with WHO grade 4, 9 with grade 3, and 12 with grade 2 glioma, were analyzed. Although WHO grade 2 cases tended to present favorable overall survival, the difference was not statistically significant. H3K27M, which was detected in four grade 4 cases (80%) and three grade 3 cases (33%), was not associated with prognosis among grade 3 and 4 cases. Among WHO grade 2-4 cases, the combination of retained H3K27me3 and negative EZH2 expression was correlated with favorable overall survival (p = 0.03). The combination of H3K27me3 status and EZH2 expression was considered as a potential prognostic marker in WHO grade 2-4 diffuse spinal cord gliomas.",Brain tumor pathology,vol.37:3:81-88,2020,Journal Article,"|Enhancer of Zeste Homolog 2 Protein|genetics|metabolism|,|Gene Expression|,|Glioma|genetics|therapy|,|Histones|genetics|metabolism|,|Humans|,|Methylation|,|Mutation\, Missense|,|Prognosis|,|Retrospective Studies|,|Spinal Cord Neoplasms|genetics|therapy|",,"Department of Neurosurgery\, Hokkaido University School of Medicine\, North 15 West 7\, Kita-ku\, Sapporo\, 060-8638\, Japan.,Department of Neurosurgery\, Hokkaido University School of Medicine\, North 15 West 7\, Kita-ku\, Sapporo\, 060-8638\, Japan.,Department of Neurosurgery\, Hokkaido University School of Medicine\, North 15 West 7\, Kita-ku\, Sapporo\, 060-8638\, Japan.,Department of Neurosurgery\, Hokkaido University School of Medicine\, North 15 West 7\, Kita-ku\, Sapporo\, 060-8638\, Japan.,Department of Neurosurgery\, Sapporo Azabu Neurosurgical Hospital\, Sapporo\, Japan.,Department of Surgical Pathology\, Hokkaido University Hospital\, Sapporo\, Japan.,Department of Cancer Pathology\, Hokkaido University School of Medicine\, Sapporo\, Japan.,Department of Cancer Pathology\, Hokkaido University School of Medicine\, Sapporo\, Japan.,Department of Cancer Pathology\, Hokkaido University School of Medicine\, Sapporo\, Japan.,Department of Neurosurgery\, Hokkaido University School of Medicine\, North 15 West 7\, Kita-ku\, Sapporo\, 060-8638\, Japan. yama-shu@med.hokudai.ac.jp.","H3 histone family member 3A\, human,Histones,EZH2 protein\, human,Enhancer of Zeste Homolog 2 Protein",,,,"EZH2,Glioma,H3F3A,H3K27me3,Spinal cord"
32531927,"Palušová V,Renzová T,Verlande A,Vaclová T,Medková M,Cetlová L,Sedláčková M,Hříbková H,Slaninová I,Krutá M,Rotrekl V,Uhlířová H,Křížová A,Chmelík R,Veselý P,Krafčíková M,Trantírek L,Schink KO,Uldrijan S",Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds.,"BRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, SB203580, and SB590885 as dual inhibitors of critical proliferative pathways in human melanoma cells bearing the V600E activating mutation of BRAF kinase. We found that the drugs simultaneously disrupt the BRAF V600E-driven extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly inhibit BRAF V600E kinase. Moreover, they interfere with the endolysosomal compartment, promoting the accumulation of large acidic vacuole-like vesicles and dynamic changes in mTOR signaling. A transient increase in mTORC1 activity is followed by the enrichment of the Ragulator complex protein p18/LAMTOR1 at contact sites of large vesicles and delocalization of mTOR from the lysosomes. The induced disruption of the endolysosomal pathway not only disrupts mTORC1 signaling, but also renders melanoma cells sensitive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and provide a biological rationale for the development of anti-melanoma therapeutics based on the pyridinyl imidazole core.",Cancers,vol.12:6:,2020,Journal Article,,,"0000-0003-0790-4726Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,0000-0001-6794-4119Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,0000-0001-8906-0891Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,0000-0002-1298-0849Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,0000-0002-0704-3148Institute of Physical Engineering\, Faculty of Mechanical Engineering\, Brno University of Technology\, Technická 2896/2\, 616 69 Brno\, Czech Republic.,CEITEC-Central European Institute of Technology\, Brno University of Technology\, Purkyňova 656/123\, 612 00 Brno\, Czech Republic.,0000-0001-5410-4794Institute of Physical Engineering\, Faculty of Mechanical Engineering\, Brno University of Technology\, Technická 2896/2\, 616 69 Brno\, Czech Republic.,CEITEC-Central European Institute of Technology\, Brno University of Technology\, Purkyňova 656/123\, 612 00 Brno\, Czech Republic.,National Centre for Biomolecular Research\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,CEITEC-Central European Institute of Technology\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.,Centre for Cancer Cell Reprogramming\, Faculty of Medicine\, University of Oslo\, Montebello\, N-0379 Oslo\, Norway.,0000-0001-8316-2539Faculty of Medicine\, Masaryk University\, Kamenice 753/5\, 625 00 Brno\, Czech Republic.",,"European Regional Development Fund,Masarykova Univerzita,Grantová Agentura České Republiky,Ministerstvo Zdravotnictví Ceské Republiky,Ministerstvo Školství\, Mládeže a Tělovýchovy,Ministerstvo Školství\, Mládeže a Tělovýchovy",",,,,,","CZ.02.1.01/0.0/0.0/16_019/0000868,MUNI/A/1087/2018,18-01396S,NV19-08-00450,CIISB - LM2018127,LM2015062","BRAF V600E,BRAF inhibitor,ER stress,endosome,lysosome,mTORC1,melanoma,pyridinyl imidazole,small molecule drug"
32532044,"Larribère L,Utikal J",Update on Alterations in Cancer: Implications for Uveal Melanoma Treatment.,"Tumorigenesis is correlated with abnormal expression and activity of G protein-coupled receptors (GPCRs) and associated G proteins. Oncogenic mutations in both GPCRs and G proteins (GNAS, GNAQ or GNA11) encoding genes have been identified in a significant number of tumors. Interestingly, uveal melanoma driver mutations in GNAQ/GNA11 were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for BRAF mutations in cutaneous melanoma which saw enormous success. Moreover, new immunotherapies strategies such as immune checkpoint inhibitors have given underwhelming results. In this review, we summarize the current knowledge on cancer-associated alterations of GPCRs and G proteins and we focus on the case of uveal melanoma. Finally, we discuss the possibilities that this signaling might represent in regard to novel drug development for cancer prevention and treatment.",Cancers,vol.12:6:,2020,Review,,,"Skin Cancer Unit\, German Cancer Research Center (DKFZ)\, 69120 Heidelberg\, Germany.,0000-0001-5316-0241Skin Cancer Unit\, German Cancer Research Center (DKFZ)\, 69120 Heidelberg\, Germany.",,Deutsche Forschungsgemeinschaft,,259332240/RTG 2099,"G proteins,GNA mutations,GPCR,therapy,uveal melanoma"
32534646,"Gutzmer R,Stroyakovskiy D,Gogas H,Robert C,Lewis K,Protsenko S,Pereira RP,Eigentler T,Rutkowski P,Demidov L,Manikhas GM,Yan Y,Huang KC,Uyei A,McNally V,McArthur GA,Ascierto PA","Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial.","IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma.,IMspire150 was a randomised\, double-blind\, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV\, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab\, vemurafenib\, and cobimetinib (atezolizumab group) or atezolizumab placebo\, vemurafenib\, and cobimetinib (control group). In cycle 1\, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo\, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov\, NCT02908672) is ongoing but no longer recruiting patients.,Between Jan 13\, 2017\, and April 26\, 2018\, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8)\, progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%)\, diarrhoea (42·2% vs 46·6%)\, rash (40·9%\, both groups)\, arthralgia (39·1% vs 28·1%)\, pyrexia (38·7% vs 26·0%)\, alanine aminotransferase increased (33·9% vs 22·8%)\, and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events.,The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma.,F Hoffmann-La Roche and Genentech.","Lancet (London, England)",vol.395:10240:1835-1844,2020,"Research Support, Non-U.S. Gov't","|Adult|,|Aged|,|Antibodies\, Monoclonal\, Humanized|adverse effects|therapeutic use|,|Antineoplastic Combined Chemotherapy Protocols|adverse effects|therapeutic use|,|Azetidines|adverse effects|therapeutic use|,|Double-Blind Method|,|Drug Administration Schedule|,|Female|,|Humans|,|Kaplan-Meier Estimate|,|Male|,|Melanoma|drug therapy|genetics|pathology|,|Middle Aged|,|Mutation|,|Neoplasm Metastasis|,|Neoplasm Staging|,|Piperidines|adverse effects|therapeutic use|,|Progression-Free Survival|,|Proto-Oncogene Proteins B-raf|genetics|,|Vemurafenib|adverse effects|therapeutic use|",,"Haut-Tumor-Zentrum Hannover\, Klinik für Dermatologie\, Allergologie und Venerologie\, Medizinische Hochschule Hannover\, Hannover\, Germany. Electronic address: gutzmer.ralf@mh-hannover.de.,Moscow City Oncology Hospital Number 62 of Moscow Healthcare Department\, Moscow\, Russia.,First Department of Medicine\, Laiko General Hospital\, National and Kapodistrian University of Athens\, Greece.,Gustave Roussy and Université Paris-Saclay\, Villejuif-Paris\, France.,University of Colorado Comprehensive Cancer Center\, Aurora\, CO\, USA.,Department of Chemotherapy and Innovative Technologies\, NN Petrov National Medical Research Center of Oncology\, St Petersburg\, Russia.,Hospital de Clínicas de Porto Alegre\, Porto Alegre\, Brazil.,University Hospital Tübingen\, Tübingen\, Germany.,Department of Soft Tissue-Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie National Research Institute of Oncology\, Warsaw\, Poland.,NN Blokhin Russian Cancer Research Center\, Ministry of Health\, Moscow\, Russia.,St Petersburg Oncology Hospital\, St Petersburg\, Russia.,Genentech\, South San Francisco\, CA\, USA.,Genentech\, South San Francisco\, CA\, USA.,Genentech\, South San Francisco\, CA\, USA.,Roche Products\, Welwyn Garden City\, UK.,Melanoma and Skin Service and Cancer Therapeutics Program\, Peter MacCallum Cancer Centre\, Melbourne\, VIC\, Australia.,Istituto Nazionale Tumori IRCCS Fondazione G Pascale\, Naples\, Italy.","Antibodies\, Monoclonal\, Humanized,Azetidines,Piperidines,Vemurafenib,atezolizumab,BRAF protein\, human,Proto-Oncogene Proteins B-raf,cobimetinib",,,,
32534795,"Meng P,Koopman B,Kok K,Ter Elst A,Schuuring E,van Kempen LC,Timens W,Hiltermann TJN,Groen HJM,van den Berg A,van der Wekken AJ","Combined osimertinib, dabrafenib and trametinib treatment for advanced non-small-cell lung cancer patients with an osimertinib-induced BRAF V600E mutation.","Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However\, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations.,Two patients with anEGFR exon 19 deletion and a T790 M mutation\, both treated with osimertinib\, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board\, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered.,Because of toxicity\, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient\, treated with full doses of the combined therapy\, had progression with metastases in lung and brain one month after starting therapy.,BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation.","Lung cancer (Amsterdam, Netherlands)",vol.146::358-361,2020,"Research Support, Non-U.S. Gov't",,,"Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Genetics\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pulmonary Diseases\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pulmonary Diseases\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pathology and Medical Biology\, University of Groningen\, University Medical Center Groningen\, the Netherlands.,Department of Pulmonary Diseases\, University of Groningen\, University Medical Center Groningen\, the Netherlands. Electronic address: a.j.van.der.wekken@umcg.nl.",,,,,"BRAF V600E,Dabrafenib,EGFR,NSCLC,Osimertinib,Trametinib"
32535222,"Sandri S,Watanabe LRM,Oliveira EA,Faião-Flores F,Migliorini S,Tiago M,Felipe-Silva A,Vazquez VL,da Costa Souza P,Consolaro MEL,Campa A,Maria-Engler SS","Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance.","Indoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFNγ) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant.",Pharmacological research,vol.159::104998,2020,"Research Support, Non-U.S. Gov't",,,"Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Department of Pathology\, Faculdade de Medicina (FMUSP)\, Universidade de São Paulo\, São Paulo\, Brazil.,Institute of Research and Education and Melanoma/Sarcoma Surgery\, Barretos Cancer Hospital\, Barretos\, SP\, Brazil.,Laboratório Souza de Patologia\, Maringá\, Paraná\, Brazil.,Department of Clinical Analysis and Biomedicine\, State University of Maringá\, Maringá\, Paraná\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil.,Skin Biology Group\, Department of Clinical Chemistry and Toxicological Analysis\, School of Pharmaceutical Sciences\, University of Sao Paulo\, São Paulo\, Brazil. Electronic address: silvya@usp.br.",,,,,"1-Methyl tryptophan (1-MT),Antiproliferative effects,BRAFi,Immune effects,Indoleamine 2\,3 dioxygenase activity,Kynurenine,Melanoma resistance"
32555626,"Grzywa TM,Klicka K,Paskal W,Dudkiewicz J,Wejman J,Pyzlak M,Włodarski PK",miR-410-3p is induced by vemurafenib via ER stress and contributes to resistance to BRAF inhibitor in melanoma.,"Despite significant development of melanoma therapies, death rates remain high. MicroRNAs, controlling posttranscriptionally gene expression, play role in development of resistance to BRAF inhibitors. The aim of the study was to assess the role of miR-410-3p in response to vemurafenib-BRAF inhibitor. FFPE tissue samples of 12 primary nodular melanomas were analyzed. With the use of Laser Capture Microdissection, parts of tumor, transient tissue, and adjacent healthy tissue were separated. In vitro experiments were conducted on human melanoma cell lines A375, G361, and SK-MEL1. IC50s of vemurafenib were determined using MTT method. Cells were transfected with miR-410-3p mimic, anti-miR-410-3p and their non-targeting controls. ER stress was induced by thapsigargin. Expression of isolated RNA was determined using qRT-PCR. We have found miR-410-3p is downregulated in melanoma tissues. Its expression is induced by vemurafenib in melanoma cells. Upregulation of miR-410-3p level increased melanoma cells resistance to vemurafenib, while its inhibition led to the decrease of resistance. Induction of ER stress increased the level of miR-410-3p. miR-410-3p upregulated the expression of AXL in vitro and correlated with markers of invasive phenotype in starBase. The study shows a novel mechanism of melanoma resistance. miR-410-3p is induced by vemurafenib in melanoma cells via ER stress. It drives switching to the invasive phenotype that leads to the response and resistance to BRAF inhibition.",PloS one,vol.15:6:e0234707,2020,"Research Support, Non-U.S. Gov't","|Cell Line\, Tumor|,|Down-Regulation|drug effects|,|Drug Resistance\, Neoplasm|genetics|,|Endoplasmic Reticulum Stress|drug effects|,|Humans|,|Melanoma|drug therapy|genetics|pathology|,|MicroRNAs|genetics|,|Protein Kinase Inhibitors|pharmacology|therapeutic use|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|,|Vemurafenib|pharmacology|therapeutic use|",,"0000-0002-1809-248XDepartment of Methodology\, Laboratory of Centre for Preclinical Research\, Medical University of Warsaw\, Warsaw\, Poland.,Department of Methodology\, Laboratory of Centre for Preclinical Research\, Medical University of Warsaw\, Warsaw\, Poland.,0000-0003-3051-5446Department of Methodology\, Laboratory of Centre for Preclinical Research\, Medical University of Warsaw\, Warsaw\, Poland.,Department of Methodology\, Laboratory of Centre for Preclinical Research\, Medical University of Warsaw\, Warsaw\, Poland.,Department of Pathology\, Medical Center of Postgraduate Education\, Warsaw\, Poland.,Department of Pathology\, Medical Center of Postgraduate Education\, Warsaw\, Poland.,Department of Methodology\, Laboratory of Centre for Preclinical Research\, Medical University of Warsaw\, Warsaw\, Poland.","MIRN410 microRNA\, human,MicroRNAs,Protein Kinase Inhibitors,Vemurafenib,Proto-Oncogene Proteins B-raf",,,,
31819973,"Martin AM,Bell WR,Yuan M,Harris L,Poore B,Arnold A,Engle EL,Asnaghi L,Lim M,Raabe EH,Eberhart CG",PD-L1 Expression in Pediatric Low-Grade Gliomas Is Independent of BRAF V600E Mutational Status.,"To evaluate a potential relationship between BRAF V600E mutation and PD-L1 expression, we examined the expression of PD-L1 in pediatric high- and low-grade glioma cell lines as well as a cohort of pediatric low-grade glioma patient samples. Half of the tumors in our patient cohort were V600-wildtype and half were V600E mutant. All tumors expressed PD-L1. In most tumors, PD-L1 expression was low (<5%), but in some cases over 50% of cells were positive. Extent of PD-L1 expression and immune cell infiltration was independent of BRAF V600E mutational status. All cell lines evaluated, including a BRAF V600E mutant xenograft, expressed PD-L1. Transient transfection of cell lines with a plasmid expressing mutant BRAF V600E had minimal effect on PD-L1 expression. These findings suggest that the PD-1 pathway is active in subsets of pediatric low-grade glioma as a mechanism of immune evasion independent of BRAF V600E mutational status. Low-grade gliomas that are unresectable and refractory to traditional therapy are associated with significant morbidity and continue to pose a treatment challenge. PD-1 pathway inhibitors may offer an alternative treatment approach. Clinical trials will be critical in determining whether PD-L1 expression indicates likely therapeutic benefit with immune checkpoint inhibitors.",Journal of neuropathology and experimental neurology,vol.79:1:74-85,2020,Journal Article,"|Adolescent|,|B7-H1 Antigen|biosynthesis|genetics|,|Brain Neoplasms|genetics|immunology|pathology|,|Cell Line\, Tumor|,|Child|,|Child\, Preschool|,|Cohort Studies|,|Female|,|Glioma|genetics|immunology|pathology|,|Humans|,|Immunohistochemistry|,|Male|,|Microglia|pathology|,|Mutation|genetics|,|Plasmids|genetics|,|Proto-Oncogene Proteins B-raf|genetics|,|Transfection|,|Xenograft Model Antitumor Assays|,|Young Adult|",,"Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.,Division of Pediatric Oncology\, Johns Hopkins School of Medicine\, Sidney Kimmel Cancer Center\, Baltimore\, Maryland (AMM\, EHR); Department of Laboratory Medicine and Pathology\, University of Minnesota Medical School\, Minneapolis\, Minnesota (WRB); Department of Pathology\, Division of Neuropathology\, Johns Hopkins School of Medicine\, Baltimore\, Maryland (MY\, BP\, AA\, LA\, EHR\, CGE); Department of Molecular and Cell Biology\, The Johns Hopkins University\, Krieger School of Arts and Sciences\, Baltimore\, Maryland (LH); Department of Oncology\, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery\, Division of Neurosurgical Oncology (ML)\, Johns Hopkins School of Medicine\, Baltimore\, Maryland.","B7-H1 Antigen,CD274 protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF,Immune response,Low-grade glioma,PD-1,PD-L1,Tumor infiltrating immune cells"
31820133,"Tan CL,Lian DWQ,Kuick CH,Chan YH,Chang KTE",Cells with ganglionic differentiation frequently stain for VE1 antibody: a potential pitfall.,"Mitogen-activated protein kinase (MAPK) pathway plays a major role in pediatric low-grade gliomas (pLGGs). Immunohistochemistry with mutant-specific antibody, VE1, has appeared to be the most affordable and rapidly deployable method to identify tumors with aberrant MAPK signaling pathway, by highlighting tumor with BRAFV600E mutation. Nonetheless, positive staining cases but not associated with BRAFV600E mutation are also seen. We analyzed 62 pLGGs for the two commonest genetic aberrations in MAPK pathway: KIAA1549-BRAF fusion, using reverse-transcriptase polymerase chain reaction, and BRAFV600E mutation, using VE1 antibody and Sanger sequencing. We recorded a specificity and accuracy rate of 68.75% and 75%, respectively, for VE1, when strong cytoplasmic staining is observed. Interestingly, we observed that cells with ganglionic features frequently bind VE1 but not associated with BRAFV600E mutation. Such observation was also confirmed in four cases of differentiating neuroblastoma. This false positive staining may serve as an important confounder in the interpretation of VE1 immunoreactivity with major therapeutic implication. It is important to confirm the presence of BRAFV600E mutation by DNA-based method, especially in tumor entities not known to, or rarely harbor such mutations.",Brain tumor pathology,vol.37:1:14-21,2020,Journal Article,"|Antibodies\, Monoclonal|,|Brain Neoplasms|genetics|pathology|,|Gene Fusion|,|Glioma|genetics|pathology|,|Humans|,|MAP Kinase Signaling System|,|Membrane Proteins|genetics|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Staining and Labeling|methods|",,"http://orcid.org/0000-0002-1470-3175Department of Pathology\, National University Health System\, Singapore\, Singapore. char_loo_tan@nuhs.edu.sg.,Department of Pathology\, National University Health System\, Singapore\, Singapore.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore\, Singapore.,Biostatistics Unit\, Yong Loo Lin School of Medicine\, National University of Singapore\, Singapore\, Singapore.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore\, Singapore.","Antibodies\, Monoclonal,KIAA1549 protein\, human,Membrane Proteins,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAFV600E,Ganglioglioma,Ganglions,Immunohistochemistry,MAPK,Neuroblastoma"
31821518,"Sakaizawa K,Ashida A,Kiniwa Y,Okuyama R",BRAF Mutation Heterogeneity in Melanoma Lesions.,,Acta dermato-venereologica,vol.100:1:adv00045,2020,Journal Article,"|Adult|,|Aged|,|Biomarkers\, Tumor|genetics|,|DNA Mutational Analysis|,|Female|,|Genetic Heterogeneity|,|Genetic Predisposition to Disease|,|Humans|,|Male|,|Melanoma|genetics|secondary|,|Middle Aged|,|Mutation|,|Phenotype|,|Proto-Oncogene Proteins B-raf|genetics|,|Skin Neoplasms|genetics|pathology|,|Young Adult|",,"Department of Dermatology\, Shinshu University School of Medicine\, 3-1-1 Asahi\, Matsumoto 390-8621\, Japan.,,,","Biomarkers\, Tumor,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF,droplet digital PCR,heterogeneity,melanoma,targeted therapy"
31821746,"Bellevicine C,Migliatico I,Sgariglia R,Nacchio M,Vigliar E,Pisapia P,Iaccarino A,Bruzzese D,Fonderico F,Salvatore D,Biondi B,Masone S,Novizio V,Scavuzzo F,Serino D,De Palma M,Chiofalo MG,Botti G,Pezzullo L,Nuzzo V,Spiezia S,De Chiara G,Iorio S,Conzo G,Docimo G,Faggiano A,Bongiovanni M,Malapelle U,Colao A,Triassi M,Troncone G","Evaluation of BRAF, RAS, RET/PTC, and PAX8/PPARg alterations in different Bethesda diagnostic categories: A multicentric prospective study on the validity of the 7-gene panel test in 1172 thyroid FNAs deriving from different hospitals in South Italy.","Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules\, although up to 30% of FNAs are still classified as ""indeterminate."" Molecular testing of FNAs could improve preoperative diagnosis\, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated\, using a 7-gene assay\, the distribution and diagnostic impact of BRAF\, RAS\, RET/PTC\, and PAX8/PPARg\, the most frequent genomic alterations occurring during thyroid oncogenesis.,In total\, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested\, and molecular data were compared with available histology or cytologic follow-up.,In particular\, for atypia of undetermined significance/follicular lesion of undetermined significance cases\, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%)\, suggesting different surgical management\, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class\, supporting the identification of prognostically relevant diagnostic categories.,The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs\, especially when considering the biologic significance of the different types of mutations. Moreover\, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class.",Cancer cytopathology,vol.128:2:107-118,2020,Validation Study,"|Adolescent|,|Adult|,|Aged|,|Aged\, 80 and over|,|Biomarkers\, Tumor|analysis|genetics|,|Biopsy\, Fine-Needle|,|Carcinogenesis|genetics|,|Child|,|Clinical Decision-Making|methods|,|Diagnosis\, Differential|,|Female|,|Genetic Testing|methods|,|Humans|,|Male|,|Middle Aged|,|Mutation|,|Patient Selection|,|Preoperative Care|methods|,|Prognosis|,|Prospective Studies|,|Risk Assessment|methods|,|Thyroid Gland|pathology|,|Thyroid Nodule|diagnosis|genetics|pathology|surgery|,|Thyroidectomy|,|Young Adult|",,"0000-0002-7479-6457Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,0000-0002-6429-0620Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Clinical Medicine and Surgery\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Clinical Medicine and Surgery\, University of Naples Federico II\, Naples\, Italy.,Department of Clinical Medicine and Surgery\, University of Naples Federico II\, Naples\, Italy.,Department of Endocrinology\, Aziena Ospedaliera di Rilievo Nazionale A. Cardarelli\, Naples\, Italy.,Department of Endocrinology\, Aziena Ospedaliera di Rilievo Nazionale A. Cardarelli\, Naples\, Italy.,Department of Endocrinology\, Aziena Ospedaliera di Rilievo Nazionale A. Cardarelli\, Naples\, Italy.,Department of Surgery\, Aziena Ospedaliera di Rilievo Nazionale A. Cardarelli\, Naples\, Italy.,Thyroid and Parathyroid Surgery Unit\, IRCCS G. Pascale\, Naples\, Italy.,IRCCS G. Pascale\, Naples\, Italy.,Thyroid and Parathyroid Surgery Unit\, IRCCS G. Pascale\, Naples\, Italy.,Department of Endocrinology\, Hospital of the Sea-Azienda Sanitaria Locale Naples 1 Center\, Naples\, Italy.,Department of Endocrine Surgery\, Hospital of the Sea-Azienda Sanitaria Locale Naples 1 Center\, Naples\, Italy.,Department of Pathology\, Aziena Ospedaliera di Rilievo Nazionale San Giuseppe Moscati\, Avellino\, Italy.,Department of Medical\, Surgical\, Neurological\, Metabolic\, and Aging Sciences\, University of Campania Luigi Vanvitelli\, Caserta\, Italy.,Department of Cardiothoracic and Respiratory Sciences\, University of Campania Luigi Vanvitelli\, Caserta\, Italy.,Department of Medical\, Surgical\, Neurological\, Metabolic\, and Aging Sciences\, University of Campania Luigi Vanvitelli\, Caserta\, Italy.,Department of Experimental Medicine\, University of Rome Sapienza\, Rome\, Italy.,0000-0001-9846-6682Cytopathology\, Synlab SA\, Lausanne\, Switzerland.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,Department of Clinical Medicine and Surgery\, University of Naples Federico II\, Naples\, Italy.,Department of Public Health\, University of Naples Federico II\, Naples\, Italy.,0000-0003-1630-5805Department of Public Health\, University of Naples Federico II\, Naples\, Italy.","Biomarkers, Tumor",,,,"7-gene test,cancer,cytopathology,fine-needle aspiration,molecular diagnostics,thyroid"
31821747,"Dell'Aquila M,Granitto A,Martini M,Capodimonti S,Cocomazzi A,Musarra T,Fiorentino V,Pontecorvi A,Lombardi CP,Fadda G,Pantanowitz L,Larocca LM,Rossi ED",PD-L1 and thyroid cytology: A possible diagnostic and prognostic marker.,"Programmed death-ligand 1 (PD-L1) expression is emerging as an important predictive biomarker in anti-PD-L1 cancer immunotherapy. Its role has been clearly defined in various human cancers and is linked to a poor prognosis and resistance to anticancer therapies. The role of PD-L1 in thyroid cancers has not been well defined in fine-needle aspiration cytology (FNAC). The authors examined the performance of PD-L1 immunostaining in liquid-based cytology (LBC) to determine whether it could be a biomarker of malignancy or aggressive disease.,From January 2018 to March 2019\, 236 thyroid lesions\, which had been diagnosed by FNAC as indeterminate lesions\, suspicious for malignancy (SFM)\, and malignant\, were enrolled. PD-L1 immunostaining was performed on both LBC and corresponding histology samples.,The FNAC cohort included 50 benign negative controls\, 42 samples of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)\, 33 samples of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)\, 53 samples that were suspicious for malignancy (SFM)\, and 58 malignant samples. AUS/FLUS samples included 3 goiters\, 32 follicular adenomas (FAs)\, 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)\, 5 invasive follicular variants of papillary thyroid carcinoma (I-FVPTCs)\, and 1 follicular carcinoma; whereas FN/SFN samples included 24 FAs and 9 malignancies (4 I-FVPTCs\, 1 NIFTP\, 3 papillary thyroid carcinomas [PTCs]\, and 1 oncocytic follicular carcinoma). The 53 SFM samples were diagnosed on histopathology as 2 FAs\, 5 NIFTPs\, 15 I-FVPTCs\, and 31 PTCs; whereas the 58 malignant specimens included 5 NIFTPs\, 5 I-FVPTCs\, and 48 PTCs. Increased plasma membrane and cytoplasmic PD-L1 expression was found in 79 cases (38.5%)\, including 61 PTCs (conventional and variants). Negative PD-L1 expression was found in NIFTPs and FAs. A BRAF V600E mutation was identified in 15% of PD-L1-positive malignancies.,The current data suggest that PD-L1 expression in the thyroid gland might represent a marker of malignancy that correlates with PTC\, but not with NIFTP. Thyroid neoplasms with PD-L1 expression also ae enriched with BRAF V600E mutations\, suggesting that they are associated with more aggressive behavior.",Cancer cytopathology,vol.128:3:177-189,2020,Journal Article,"|Adenocarcinoma\, Follicular|genetics|metabolism|pathology|,|Adolescent|,|Adult|,|Aged|,|B7-H1 Antigen|biosynthesis|,|Biomarkers\, Tumor|biosynthesis|,|Biopsy\, Fine-Needle|methods|,|Female|,|Humans|,|Immunohistochemistry|methods|,|Male|,|Middle Aged|,|Mutation\, Missense|,|Proto-Oncogene Proteins B-raf|genetics|,|Reproducibility of Results|,|Thyroid Cancer\, Papillary|genetics|metabolism|pathology|,|Thyroid Gland|metabolism|pathology|,|Thyroid Neoplasms|genetics|metabolism|pathology|,|Young Adult|",,"Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Endocrinology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Endocrine Surgery\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,0000-0001-8182-5503Department of Pathology\, University of Pittsburgh Medical Center\, Pittsburgh\, Pennsylvania.,Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.,0000-0003-3819-4229Division of Anatomic Pathology and Histology\, Fondazione Policlinico Universitario ""Agostino Gemelli"" IRCCS\, Rome\, Italy.","B7-H1 Antigen,Biomarkers\, Tumor,CD274 protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF mutation,fine-needle aspiration cytology,personalized medicine,programmed death-ligand 1 (PD-L1),thyroid cancer"
31833094,"Chino A,Kawachi H,Takamatsu M,Hatamori H,Ide D,Saito S,Igarashi M,Fujisaki J,Nagayama S",Macroscopic and microscopic morphology and molecular profiling to distinguish heterogeneous traditional serrated adenomas of the colorectum.,"Serrated lesions of the colorectum often have complex histological morphology\, and some groups include subtypes with different molecular biology. This study aimed to characterize serrated lesions with heterogeneous histology that was dominated by a traditional serrated adenoma (TSA) component.,Representative lesions were selected based on both endoscopic and histological features. If a lesion had more than one component\, each of the different structural parts was considered as a separate sample. DNA was extracted from 177 samples of 60 lesions and amplified to screen for BRAF and K/NRAS mutations.,Heterogeneous TSA samples were classified into four categories: sessile serrated lesion with TSA (SA-1); TSAs with microvesicular hyperplastic polyp (SA-2); TSAs with unclassified adenoma\, characterized by tubulo-serrated histology (SA-3); and TSAs with conventional adenomas (SA-4). On endoscopy\, SA-1 lesions had sessile-elevated morphology with the small reddish elevations; SA-2 lesions had a pedunculated appearance with a whitish mucosal component at the stalk; SA-3 lesions had a sessile-elevated component surrounded by flat spreading margins; and SA-4 lesions had mixed adenomatous morphology. Eighteen of the 19 category SA-1 and -2 lesions (95%) had BRAF mutations\, and all of the SA-3 and -4 lesions had K/NRAS mutations.,Traditional serrated adenomas were classified into two phenotypes according to their molecular characteristics: microvesicular serrated subtypes with BRAF mutations (SA-1 and -2 lesions) and subtypes containing tubulo-serrated/conventional adenoma with K/NRAS mutations (SA-3 and -4 lesions). Each subtype had characteristic macroscopic and microscopic morphologies and was distinct on endoscopy.",Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society,vol.32:6:921-931,2020,Journal Article,,,"https://orcid.org/0000-0001-7412-4397Department of Gastroenterology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Pathology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Pathology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Gastroenterology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Gastroenterology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Gastroenterology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Gastroenterology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Gastroenterology\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.,Department of Digestive Surgery\, The Cancer Institute Hospital of Japanese for Cancer Research\, Tokyo\, Japan.",,,,,"BRAF mutation,KRAS mutation,mixed polyp,serrated pathway,traditional serrated adenoma"
31532537,"Ramondetta A,Ribero S,Conti L,Fava P,Marra E,Broganelli P,Caliendo V,Picciotto F,Guida M,Fierro MT,Quaglino P",Clinical and Pathological Relevance of Drug-induced Vitiligo in Patients Treated for Metastatic Melanoma with Anti-PD1 or BRAF/MEK Inhibitors.,"Current therapies for metastatic melanoma (anti-PD1 and BRAF/MEK inhibitors) can cause drug-induced vitiligo. The aim of this study is to dermatologically define and histologically characterize this new type of vitiligo, and assess the clinical course of the disease. Fourteen patients with metastatic melanoma treated with immune or targeted therapy were included in a dataset evaluating clinical data, vitiligo description and histopathological features. Vitiligo-like lesions occurred after a mean of 7.5 months from the start of the therapies (range 1-42 months), with a prevalence of the non-segmental variant (71.4%). Fifty percent of patients showed a clinical response (4 complete response and 3 partial response), 35.7% had stable disease, and one patient died after disease progression. Median survival from the start of the therapies was 32.5 months. Drug-induced vitiligo can be related to both immune and targeted therapies, is associated with a favourable prognosis, and has clinical characteristics different from the classical form.",Acta dermato-venereologica,vol.100:1:adv00001,2020,Journal Article,"|Adult|,|Female|,|Humans|,|Immunotherapy|methods|,|Male|,|Melanoma|complications|mortality|pathology|,|Middle Aged|,|Programmed Cell Death 1 Receptor|antagonists & inhibitors|,|Protein Kinase Inhibitors|pharmacology|therapeutic use|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|,|Retrospective Studies|,|Skin Neoplasms|complications|,|Survival Rate|,|Vitiligo|chemically induced|pathology|",,"Department of Medical Sciences\, Dermatologic Clinic\, Turin\, Italy.,,,,,,,,,,","Programmed Cell Death 1 Receptor,Protein Kinase Inhibitors,Proto-Oncogene Proteins B-raf",,,,"immunotherapy,melanoma,survival,targeted therapy,vitiligo"
32130701,"Luís R,Brito C,Pojo M",Melanoma Metabolism: Cell Survival and Resistance to Therapy.,"Cutaneous melanoma is one of the most aggressive types of cancer, presenting the highest potential to form metastases, both locally and distally, which are associated with high death rates of melanoma patients. A high somatic mutation burden is characteristic of these tumours, with most common oncogenic mutations occurring in the BRAF, NRAS and NF1 genes. These intrinsic oncogenic pathways contribute to the metabolic switch between glycolysis and oxidative phosphorylation metabolisms of melanoma, facilitating tumour progression and resulting in a high plasticity and adaptability to unfavourable conditions. Moreover, melanoma microenvironment can influence its own metabolism and reprogram several immune cell subset functions, enabling melanoma to evade the immune system. The knowledge of the biology, molecular alterations and microenvironment of melanoma has led to the development of new targeted therapies and the improvement of patient care. In this work, we reviewed the impact of melanoma metabolism in the resistance to BRAF and MEK inhibitors and immunotherapies, emphasizing the requirement to evaluate metabolic alterations upon development of novel therapeutic approaches. Here we summarized the current understanding of the impact of metabolic processes in melanomagenesis, metastasis and microenvironment, as well as the involvement of metabolic pathways in the immune modulation and resistance to targeted and immunocheckpoint therapies.",Advances in experimental medicine and biology,vol.1219::203-223,2020,Review,"|Cell Survival|drug effects|,|Drug Resistance\, Neoplasm|drug effects|,|Humans|,|Immunotherapy|,|Melanoma|metabolism|pathology|,|Molecular Targeted Therapy|,|Protein Kinase Inhibitors|therapeutic use|,|Skin Neoplasms|metabolism|pathology|,|Tumor Microenvironment|drug effects|",,"Unidade de Investigação em Patobiologia Molecular (UIPM)\, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E\, Lisbon\, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM)\, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E\, Lisbon\, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM)\, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E\, Lisbon\, Portugal. martapojo@gmail.com.",Protein Kinase Inhibitors,,,,"Immunotherapy,Melanoma,Metabolic profile,Microenvironment,Oncogenic mutations,Targeted therapy"
32131760,"Dimou A,Barron G,Merrick DT,Kolfenbach J,Doebele RC",Granulomatosis with polyangiitis in a patient treated with dabrafenib and trametinib for BRAF V600E positive lung adenocarcinoma.,"Dabrafenib and trametinib combination therapy is approved for the treatment of patients with BRAF V600E positive tumors including melanoma and lung cancer. The effect of BRAF and MEK inhibitors on the immune system is not fully understood although a number of case reports indicate autoimmune side effects related to the use of these drugs. Here\, we discuss a case of a patient diagnosed with granulomatosis with polyangiitis (GPA) shortly after starting treatment with dabrafenib and trametinib for BRAF V600E positive metastatic lung adenocarcinoma.,A 57 years old female patient was diagnosed with recurrent lung adenocarcinoma following initial lobectomy for early stage disease. A BRAF V600E mutation was identified at the time of recurrence and she received combination dabrafenib and trametinib therapy. Shortly after commencement of treatment\, she developed persistent fevers necessitating withholding both drugs. Pyrexia continued and was followed by left vision loss and acute kidney injury. Further rheumatological workup led to the unifying diagnosis of GPA. The patient was then treated with rituximab for GPA to the present date while all antineoplastic drugs were held. Lung cancer oligoprogression was addressed with radiation therapy and has not required further systemic treatment whereas GPA has been controlled to-date with rituximab.,This case report raises awareness among clinicians treating patients with lung cancer for the possibility of triggering a flare of autoimmune diseases like GPA in patients with BRAF V600E positive lung cancer receiving treatment with BRAF directed therapy.",BMC cancer,vol.20:1:177,2020,Journal Article,"|Adenocarcinoma of Lung|drug therapy|genetics|radiotherapy|,|Amino Acid Substitution|,|Antineoplastic Combined Chemotherapy Protocols|administration & dosage|adverse effects|,|Female|,|Granulomatosis with Polyangiitis|chemically induced|drug therapy|,|Humans|,|Imidazoles|administration & dosage|adverse effects|,|Lung Neoplasms|drug therapy|genetics|radiotherapy|,|Middle Aged|,|Oximes|administration & dosage|adverse effects|,|Proto-Oncogene Proteins B-raf|genetics|,|Pyridones|administration & dosage|adverse effects|,|Pyrimidinones|administration & dosage|adverse effects|,|Rituximab|therapeutic use|,|Treatment Outcome|",,"http://orcid.org/0000-0002-3950-3305Division of Medical Oncology\, University of Colorado\, Anschutz Medical Campus\, 13001 E 1 Pl\, Aurora\, CO\, 80045\, USA. Anastasios.dimou@ucdenver.edu.,Division of Rheumatology\, University of Colorado\, Anschutz Medical Campus\, 13001 E 1 Pl\, Aurora\, CO\, 80045\, USA.,Department of Pathology\, University of Colorado\, School of Medicine\, 13001 E 1 Pl\, Aurora\, CO\, 80045\, USA.,Division of Rheumatology\, University of Colorado\, Anschutz Medical Campus\, 13001 E 1 Pl\, Aurora\, CO\, 80045\, USA.,Thoracic Oncology Research Initiative\, Division of Medical Oncology\, University of Colorado\, School of Medicine\, 12801 E. 1 Ave.\, MS 8117\, Aurora\, CO\, 80045\, USA.","Imidazoles,Oximes,Pyridones,Pyrimidinones,trametinib,Rituximab,BRAF protein\, human,Proto-Oncogene Proteins B-raf,dabrafenib",,,,"Autoimmune side effects,MAPK,MEK inhibitor,P-ANCA,Pyrexia"
32132121,"Arnold L,Alexiadis V,Watanaskul T,Zarrabi V,Poole J,Singh V",Clinical validation of qPCR Target Selector™ assays using highly specific switch-blockers for rare mutation detection.,"The identification of actionable DNA mutations associated with a patient's tumour is critical for devising a targeted\, personalised cancer treatment strategy. However\, these molecular analyses are typically performed using tissue obtained via biopsy\, which involves substantial risk and is often not feasible. In addition\, biopsied tissue does not always reflect tumour heterogeneity\, and sequential biopsies to track disease progression (eg\, emergence of drug resistance mutations) are not well tolerated. To overcome these and other biopsy-associated limitations\, we have developed non-invasive 'liquid biopsy' technologies to enable the molecular characterisation of a patient's cancer using peripheral blood samples.,The Target Selector ctDNA platform uses a real-time PCR-based approach\, coupled with DNA sequencing\, to identify cancer-associated genetic mutations within circulating tumour DNA. This is accomplished via a patented blocking approach suppressing wild-type DNA amplification\, while allowing specific amplification of mutant alleles.,To promote the clinical uptake of liquid biopsy technologies\, it is first critical to demonstrate concordance between results obtained via liquid and traditional biopsy procedures. Here\, we focused on three genes frequently mutated in cancer: EGFR (Del19\, L858\, and T790)\, BRAF (V600) and KRAS (G12/G13). For each Target Selector assay\, we demonstrated extremely high accuracy\, sensitivity and specificity compared with results obtained from tissue biopsies. Overall\, we found between 93% and 96% concordance to blinded tissue samples across 127 clinical assays.,The switch-blocker technology reported here offers a highly effective method for non-invasively determining the molecular signatures of patients with cancer.",Journal of clinical pathology,vol.73:10:648-655,2020,Validation Study,"|Biomarkers\, Tumor|blood|genetics|,|Circulating Tumor DNA|analysis|,|DNA Mutational Analysis|methods|,|Humans|,|Real-Time Polymerase Chain Reaction|methods|",,"Research and Development\, Biocept Inc\, San Diego\, California\, USA.,Research and Development\, Biocept Inc\, San Diego\, California\, USA.,Research and Development\, Biocept Inc\, San Diego\, California\, USA.,Department of Molecular Pathology\, UCLA\, Los Angeles\, California\, USA.,Research and Development\, Biocept Inc\, San Diego\, California\, USA.,http://orcid.org/0000-0002-6300-7811Clinical Laboratory\, Biocept Inc\, San Diego\, California\, USA vsingh@biocept.com.","Biomarkers\, Tumor,Circulating Tumor DNA",,,,"cancer genetics,genetics,laboratory tests,lung cancer,oncology"
32132305,"Liu G,Liu T,Shen C,Zhou L,Ouyang R",A case report.,"Langerhans cell histiocytosis (LCH) is a rare and unexplained disease that can involve in any organ or system in the body and displays a variety of clinical manifestations. A 31-year-old man, who had a more than 10-year smoke history, initially presented dry cough, polydipsia and diuresis, with recurrent spontaneous pneumothorax. Pulmonary high-resolution computed tomography showed diffuse cystic and nodular lesions. Langerhans cell histiocytosis was confirmed by a transbronchial cryobiopsy. The disease is involved in the lung, pituitary, thyroid, liver, lymph node, and skin. Glucocorticoid or systemic chemotherapy is commonly used in the treatment for this disease. BRAF gene mutation inhibitor is a new direction for the treatment.",Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences,vol.45:1:96-101,2020,Journal Article,"|Adult|,|Histiocytosis\, Langerhans-Cell|,|Humans|,|Lung|,|Male|,|Skin|,|Thyroid Gland|,|Tomography\, X-Ray Computed|",,"Department of Respiratory and Critical Care Medicine\, Second Xiangya Hospital\, Central South University\, Changsha 410011\, China.,Department of Respiratory and Critical Care Medicine\, Second Xiangya Hospital\, Central South University\, Changsha 410011\, China.,Department of Respiratory and Critical Care Medicine\, Second Xiangya Hospital\, Central South University\, Changsha 410011\, China.,Department of Respiratory and Critical Care Medicine\, Second Xiangya Hospital\, Central South University\, Changsha 410011\, China.,Department of Respiratory and Critical Care Medicine\, Second Xiangya Hospital\, Central South University\, Changsha 410011\, China.",,"United States,United States,United States,the National Key Research and Development Program,Industrial Research and Development Project from Hunan Provincial Department of Finance","United States,United States,United States,,","2012-650,2016YFC0901502,2015-83┫。This work was supported by the National Key Clinical Specialty Construction Project┣2012-650,2016YFC0901502,2015-83","Langerhans cell histiocytosis,diagnosis,multisystem,treatment"
32150778,"Zaidi A,Gautam U,Srinivasan R,Bal A,Prakash G,Sood A","Challenging diagnosis of two neoplasms, Langerhans cell histiocytosis and papillary thyroid carcinoma, from fine needle aspiration of the thyroid by cell-block immunocytochemistry and molecular testing for BRAF V600E mutation.",,Cytopathology : official journal of the British Society for Clinical Cytology,vol.31:6:598-601,2020,Journal Article,,,"0000-0003-4816-3960Department of Cytology & Gynecological Pathology\, Post Graduate Institute of Medical Education and Research\, Chandigarh\, India.,Department of Cytology & Gynecological Pathology\, Post Graduate Institute of Medical Education and Research\, Chandigarh\, India.,0000-0002-1771-091XDepartment of Cytology & Gynecological Pathology\, Post Graduate Institute of Medical Education and Research\, Chandigarh\, India.,Department of Histopathology\, Post Graduate Institute of Medical Education and Research\, Chandigarh\, India.,Department of Internal Medicine (Hematology-Oncology Division)\, Post Graduate Institute of Medical Education and Research\, Chandigarh\, India.,Department of Nuclear Medicine\, Post Graduate Institute of Medical Education and Research\, Chandigarh\, India.",,,,,
32150939,"Choden S,Keelawat S,Jung CK,Bychkov A",VE1 Immunohistochemistry Improves the Limit of Genotyping for Detecting Mutation in Papillary Thyroid Cancer.,"Detection of BRAFV600E is useful for making diagnosis and risk stratification of papillary thyroid carcinoma (PTC). Molecular testing, however, is not always available for routine clinical use. To assess the clinical utility and reliability of VE1 immunohistochemistry (IHC) for detecting BRAFV600E mutation in PTC, VE1 IHC was performed on the tissue microarrays of 514 patients with PTC and was compared with Sanger sequencing results. Of 514 PTC cases, 433 (84.2%) were positive for VE1 expression. Among 6 discordant cases between VE1 IHC and Sanger sequencing, 3 initial VE1-false negative cases turned out to be true false negative on repeat testing, and 3 VE1-false positive cases showed BRAFV600E mutation using digital PCR analysis. PTCs with low variant allele fraction were positive for VE1 IHC but were not detected using sequencing. VE1 IHC showed 99.3% sensitivity, 100% specificity, 100% positive predictive value, and 96.4% negative predictive value. The BRAFV600E mutation was significantly associated with older age, multifocality, extrathyroidal extension, lymph node metastasis, and advanced tumor stage. In conclusion, VE1 IHC is a reliable method for detecting BRAFV600E mutation in PTC specimens.",Cancers,vol.12:3:,2020,Journal Article,,,"Department of Pathology\, Faculty of Medicine\, Chulalongkorn University\, Bangkok 10330\, Thailand.,Department of Pathology\, Faculty of Medicine\, Chulalongkorn University\, Bangkok 10330\, Thailand.,Department of Hospital Pathology\, College of Medicine\, The Catholic University of Korea\, Seoul 06591\, Korea.,Department of Pathology\, Faculty of Medicine\, Chulalongkorn University\, Bangkok 10330\, Thailand.",,"National Research Foundation of Korea,Ractchadapiseksompotch Fund",",","2017R1D1A1B03029597,RA62/076\, 2019-2020\, Chulalongkorn University","BRAF,VE1,diagnostic performance,immunohistochemistry,papillary thyroid carcinoma"
32155032,"Avila C,Hoffman K,Milani-Nejad N,Pootrakul L",Apparent darkening of scalp hair related to pili multigemini Following dabrafenib and trametinib.,"The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.",Dermatology online journal,vol.26:1:,2020,Journal Article,"|Antineoplastic Combined Chemotherapy Protocols|adverse effects|,|Hair|,|Hair Diseases|chemically induced|,|Hair Follicle|abnormalities|,|Humans|,|Imidazoles|adverse effects|therapeutic use|,|Male|,|Melanoma|drug therapy|secondary|,|Middle Aged|,|Oximes|adverse effects|therapeutic use|,|Pigmentation Disorders|chemically induced|,|Protein Kinase Inhibitors|adverse effects|,|Pyridones|adverse effects|therapeutic use|,|Pyrimidinones|adverse effects|therapeutic use|,|Skin Neoplasms|drug therapy|",,",,,Division of Dermatology\, The Ohio State University Department of Internal Medicine\, Columbus\, OH. llana.pootrakul@osumc.edu.","Imidazoles,Oximes,Protein Kinase Inhibitors,Pyridones,Pyrimidinones,trametinib,dabrafenib",,,,
30618001,"González-Colunga KJ,Lino-Silva LS,Salcedo-Hernández RA,Ruiz-García EB,Zepeda-Najar C",BRAF V600E Expression by Immunohistochemistry in Colon Cancer and Clinico-pathologic Features Associated with BRAF-Mutated Colonic Cancers in Mexican Patients.,"BRAF evaluation is currently limited to molecular techniques\, which are expensive and not widely available to practicing pathologists. Our objective was to determine the diagnostic performance of immunohistochemistry (IHC) against BRAF V600E for BRAF mutation and the secondary objective was determining histopathological characteristics of colon carcinomas with BRAF mutated.,Cases of adenocarcinoma of the colon with a known BRAF mutation status were identified from the pathological files of our institution.,We analyzed 135 cases\, 13 cases had the BRAF mutation (9.6%) and 122 were non-mutated. The mutated cases expressed intense and diffusely the anti-antibody against BRAF V600E\, and 119 (97.5%) of the 122 cases without mutation were negative and the remaining 3 were focal and weakly positive. The IHC demonstrated a sensitivity of 100%\, specificity of 97.5%\, positive predictive value of 81.3% (95% CI = 56.9 to 93.4%)\, negative predictive value of 100% (95% CI = 89 to 100%)\, and an overall accuracy of 97.8%. The only significant clinicopathological differences between cancers with BRAF mutated compared with BRAF non-mutated were that mutated had less lymph node metastases (23% vs. 68.1%) and the tumor size was greater (median 90 mm vs. 60 mm). The survival between groups was not statistically significant.,IHC against BRAF V600E showed an excellent performance\, making it feasible as an alternative for molecular examination. Tumors with BRAF mutated did not show distinctive clinico-pathological characteristics\, except for a larger tumor size.",Journal of gastrointestinal cancer,vol.51:1:35-40,2020,Journal Article,"|Adenocarcinoma|diagnosis|genetics|pathology|,|Aged|,|Biomarkers\, Tumor|genetics|,|Colonic Neoplasms|diagnosis|genetics|pathology|,|Female|,|Humans|,|Immunohistochemistry|,|Lymphatic Metastasis|,|Male|,|Mexico|,|Middle Aged|,|Mutation|,|Predictive Value of Tests|,|Proto-Oncogene Proteins B-raf|genetics|,|Sensitivity and Specificity|",,"Surgical Pathology\, Instituto Nacional de Cancerología\, Mexico City\, Mexico.,http://orcid.org/0000-0002-7394-5123Surgical Pathology\, Instituto Nacional de Cancerología\, Mexico City\, Mexico. saul.lino.sil@gmail.com.,Surgical Oncology\, Instituto Nacional de Cancerología\, Mexico City\, Mexico.,Medical Oncology\, Instituto Nacional de Cancerología\, Mexico City\, Mexico.,Surgical Oncology\, Hospital Ángeles Tijuana\, Tijuana\, Baja California Norte\, Mexico.","Biomarkers\, Tumor,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF,Colon cancer,Diagnostic test,Immunohistochemistry,Molecular pathology"
31836141,"Tong X,Wang Q,Wu D,Bao L,Yin T,Chen H",MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo.,"Hepatocellular carcinoma which is featured with the extensive vascularization is the third most frequent cause of cancer-related deaths with limited therapeutic options, particularly for advanced disease. Cobimetinib, a MEK inhibitor, has been approved for the treatment of melanomas with a BRAF mutation. In this work, we investigated the efficacy of cobimetinib in sensitive and resistant HCC cells. Using a panel of HCC cell lines and normal hepatocellular cells as control, we showed that cobimetinib is active against HCC cells and spare normal hepatocellular cells. Cobimetinib at nanomolar concentration inhibited proliferation and induced apoptosis in sorafenib-resistant HCC cells (Hep3B-r), suggesting its ability to overcome HCC resistance to standard of care. This was further demonstrated by our results that cobimetinib significantly augmented the inhibitory effects of sorafenib and doxorubicin in HCC cells. Notably, cobimetinib dose-dependently inhibited tumor angiogenesis by inhibiting HCC endothelial cell (HCCEC) growth, survival and capillary network work formation. Cobimetinib suppressed ERK/RSK without affecting JNK or p38 signaling pathways in Hep3B-r and HCCEC cells. In addition, cobimetinib negatively influenced the apoptosis pathways by increasing pro-apoptotic protein Bim and decreasing anti-apoptotic proteins Mcl-1 and Bcl-2. In addition, we validated the in vitro findings in HCC xenograft mouse model and demonstrated that cobimetinib inhibited ERK signaling, promoted apoptosis, and was active against resistant HCC growth and angiogenesis in vivo, without causing significant toxicity in mice. Our findings support the clinical trials of cobimetinib for HCC treatment and highlight the therapeutic value of inhibiting MEK/ERK/RSK to overcome HCC resistance.",Biochemical and biophysical research communications,vol.523:1:147-152,2020,"Research Support, Non-U.S. Gov't","|Antineoplastic Agents|chemistry|pharmacology|,|Apoptosis|drug effects|,|Azetidines|chemistry|pharmacology|,|Carcinoma\, Hepatocellular|drug therapy|metabolism|pathology|,|Cell Proliferation|drug effects|,|Cells\, Cultured|,|Dose-Response Relationship\, Drug|,|Drug Screening Assays\, Antitumor|,|Humans|,|Liver Neoplasms|drug therapy|metabolism|pathology|,|Mitogen-Activated Protein Kinases|antagonists & inhibitors|metabolism|,|Neovascularization\, Pathologic|drug therapy|metabolism|pathology|,|Piperidines|chemistry|pharmacology|,|Protein Kinase Inhibitors|chemistry|pharmacology|,|Structure-Activity Relationship|",,"Department of Medical Laboratory\, Hubei Cancer Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Hepatobiliary and Pancreatic Surgery\, Hubei Cancer Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Hepatobiliary and Pancreatic Surgery\, Hubei Cancer Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Hepatobiliary and Pancreatic Surgery\, Hubei Cancer Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Hepatobiliary and Pancreatic Surgery\, Hubei Cancer Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Hepatobiliary and Pancreatic Surgery\, Hubei Cancer Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China. Electronic address: ahu89@163.com.","Antineoplastic Agents,Azetidines,Piperidines,Protein Kinase Inhibitors,Mitogen-Activated Protein Kinases,cobimetinib",,,,"Angiogenesis,Cobimetinib,HCC,MEK/ERK/RSK"
31836957,"Martins F,Schiappacasse L,Levivier M,Tuleasca C,Cuendet MA,Aedo-Lopez V,Gautron Moura B,Homicsko K,Bettini A,Berthod G,Gérard CL,Wicky A,Bourhis J,Michielin O",The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.,"Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.,We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.,We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18)\, ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11)\, during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32\, 95% 0.12-0.83\, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months\, respectively; HR 0.11\, 95% 0.04-0.34\, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65\, synchronous BM\, > 2 metastatic sites\, > 4 BM\, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60\, 95% CI 1.03-2.50; p = 0.04).,The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden\, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.",Journal of neuro-oncology,vol.146:1:181-193,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Antineoplastic Agents\, Immunological|therapeutic use|,|Brain Neoplasms|immunology|metabolism|pathology|therapy|,|Combined Modality Therapy|,|Female|,|Follow-Up Studies|,|Humans|,|Immunotherapy|mortality|,|Ipilimumab|therapeutic use|,|Male|,|Melanoma|immunology|metabolism|pathology|therapy|,|Middle Aged|,|Molecular Targeted Therapy|mortality|,|Prognosis|,|Protein Kinase Inhibitors|therapeutic use|,|Radiosurgery|mortality|,|Retrospective Studies|,|Survival Rate|",,"http://orcid.org/0000-0002-3096-8907Centre Hospitalier Universitaire Vaudois (CHUV)\, Hematology Service and Central Laboratory\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland. filipe.martins@epfl.ch.,http://orcid.org/0000-0001-7621-1662Centre Hospitalier Universitaire Vaudois (CHUV)\, Radio-Oncology Service\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Neurosurgery Service and Gamma Knife Center\, Clinical Neurosciences Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Neurosurgery Service and Gamma Knife Center\, Clinical Neurosciences Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,http://orcid.org/0000-0002-0754-3425Centre Hospitalier Universitaire Vaudois (CHUV)\, Precision Oncology Center\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Oncology Service\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Oncology Service\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Oncology Service\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Fribourg Cantonal Hospital (HFR)\, Internal Medicine Department\, Oncology Service\, CH-1708\, Fribourg\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Oncology Service\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Precision Oncology Center\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Precision Oncology Center\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Radio-Oncology Service\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland. jean.bourhis@chuv.ch.,Centre Hospitalier Universitaire Vaudois (CHUV)\, Oncology Service\, Precision Oncology Center\, Oncology Department\, Rue du Bugnon 46\, CH-1011\, Lausanne\, Switzerland. olivier.michielin@chuv.ch.","Antineoplastic Agents\, Immunological,Ipilimumab,Protein Kinase Inhibitors",,,,"BRAF,CTLA-4,CyberKnife,Gamma knife,Immune-checkpoint inhibitors,Immunotherapy,MEK,PD-1,PD-L1,Stereotactic radiation surgery"
31839532,"Byeon S,Lee B,Park WY,Choi YL,Jung HA,Sun JM,Ahn JS,Ahn MJ,Park K,Lee SH",Benefit of Targeted DNA Sequencing in Advanced Non-Small-Cell Lung Cancer Patients Without EGFR and ALK Alterations on Conventional Tests.,"Genetic sequencing testing has become widely used to inform treatment decisions for advanced non-small-cell lung cancer (NSCLC) patients. We analyzed benefits of genetic sequencing testing in real practice.,We retrospectively reviewed 209 NSCLC patients who had no EGFR and ALK alterations on routine molecular tests and underwent next-generation targeted DNA sequencing of 380 cancer-related genes between November 2013 and October 2016. Median patient age was 59 years. A total of 96 patients (46%) were never smokers\, and 195 patients (93%) had adenocarcinoma.,Among 209 total patients\, 64 (31%) demonstrated actionable genetic alterations; 20 had EGFR mutations (6 L858R\, 8 exon 19 deletions\, 1 L861Q\, 1 G719S\, 4 exon 20 duplications)\, 4 ALK fusions\, 9 ROS1 fusions\, 6 BRAF V600E mutations\, 15 RET fusions\, 1 MET high-level amplification\, 6 MET exon 14 skipping mutations\, and 3 ERBB2 exon 20 insertion mutations. Of the 64 patients harboring actionable alterations\, 28 patients received therapy targeted to their own actionable alterations (15 EGFR\, 3 ALK\, 1 ROS1\, 8 RET\, 1 BRAF). There were significant differences in overall survival between individuals with no actionable alterations\, those with actionable alterations but no targeted therapy\, and those with actionable alterations and targeted therapy (20.1 vs. 17.1 vs. 66.2 months\, P < .001).,The results of targeted DNA sequencing testing could provide improved treatment options for some NSCLC patients and result in a survival benefit to NSCLC patients with no EGFR and ALK alterations on routine tests who are treated with targeted therapy.",Clinical lung cancer,vol.21:3:e182-e190,2020,"Research Support, Non-U.S. Gov't",,,"Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Department of Health Sciences and Technology\, Samsung Advanced Institute of Health Sciences and Technology\, Sungkyunkwan University\, Seoul\, Korea; Samsung Genome Institute\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Department of Health Sciences and Technology\, Samsung Advanced Institute of Health Sciences and Technology\, Sungkyunkwan University\, Seoul\, Korea; Samsung Genome Institute\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Department of Health Sciences and Technology\, Samsung Advanced Institute of Health Sciences and Technology\, Sungkyunkwan University\, Seoul\, Korea; Department of Pathology and Translational Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea.,Division of Hematology-Oncology\, Department of Medicine\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul\, Korea; Department of Health Sciences and Technology\, Samsung Advanced Institute of Health Sciences and Technology\, Sungkyunkwan University\, Seoul\, Korea. Electronic address: shlee119@skku.edu.",,,,,"Anaplastic lymphoma kinase (ALK),DNA sequencing,Epidermal growth factor receptor (EGFR),Non–small-cell lung cancer (NSCLC),Targeted therapy"
32143442,"Ito T,Kaku-Ito Y,Murata M,Furue K,Shen CH,Oda Y,Furue M",Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival.,"Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan-Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.",Journal of clinical medicine,vol.9:3:,2020,Journal Article,,,"Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,National Institute of Cancer Research\, National Health Research Institutes\, Tainan 70456\, Taiwan.,Department of Anatomic Pathology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.",,,,,"BRAF,VE1,acral lentiginous melanoma,acral melanoma,heterogeneity,immunohistochemistry,mutation,outcome,prognosis,survival"
32143579,"Zhou D,Xie T,Chen S,Ling Y,Xu Y,Chen B,Ouyang J,Yang Y",An unusual hematopoietic stem cell transplantation for donor acute lymphoblastic leukemia: a case report.,"Donor acute lymphoblastic leukemia with recipient intact is a rare condition. We report a case of donor developing acute lymphoblastic leukemia 8 yrs after donating both bone marrow and peripheral blood hematopoietic stem cells.,This case report describes a 51-year old female diagnosed with acute lymphoblastic leukemia who donated both bone marrow and peripheral blood stem cells 8 yrs ago for her brother with severe aplastic anemia. Whole exome sequencing revealed leukemic genetic lesions (SF3B1 and BRAF mutation) only appeared in the donor sister\, not the recipient\, and an unusual type of hematopoietic stem cell transplantation with the recipient's peripheral blood stem cells was done. The patient remained in remission for 3 months before disease relapsed. CD19 CAR-T therapy followed by HLA-identical unrelated hematopoietic stem cell transplantation was applied and the patient remains in remission for 7 months till now.,This donor leukemia report supports the hypothesis that genetic lesions happen randomly in leukemogenesis. SF3B1 combined with BRAF mutation might contribute to the development of acute lymphoblastic leukemia.",BMC cancer,vol.20:1:195,2020,Journal Article,"|Anemia\, Aplastic|therapy|,|Bone Marrow Transplantation|,|Female|,|Hematopoietic Stem Cell Transplantation|,|Humans|,|Male|,|Middle Aged|,|Mutation|,|Phosphoproteins|genetics|,|Precursor Cell Lymphoblastic Leukemia-Lymphoma|diagnosis|genetics|,|Proto-Oncogene Proteins B-raf|genetics|,|RNA Splicing Factors|genetics|,|Tissue Donors|,|Transplantation\, Homologous|,|Whole Exome Sequencing|",,",,Jiangsu Institute of Hematology\, First Affiliated Hospital of Soochow University\, Suzhou\, People's Republic of China.,Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, 321 Zhongshan Road\, Nanjing\, 210008\, People's Republic of China.,Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, 321 Zhongshan Road\, Nanjing\, 210008\, People's Republic of China.,Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, 321 Zhongshan Road\, Nanjing\, 210008\, People's Republic of China.,Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, 321 Zhongshan Road\, Nanjing\, 210008\, People's Republic of China.,Department of Hematology\, The Affiliated Drum Tower Hospital of Nanjing University Medical School\, 321 Zhongshan Road\, Nanjing\, 210008\, People's Republic of China. 915834491@qq.com.","Phosphoproteins,RNA Splicing Factors,SF3B1 protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"Acute lymphoblastic leukemia,BRAF,Donor leukemia,Hematopoietic stem cell transplantation,SF3B1"
32146654,"Kim K,Zheng X,Kim JK,Lee CR,Kang SW,Lee J,Jeong JJ,Nam KH,Chung WY",The contributing factors for lateral neck lymph node metastasis in papillary thyroid microcarcinoma (PTMC).,"Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis due to its indolent features. Only few studies have assessed the clinical factors that can predict lateral neck lymph node metastasis (LLNM) in patients with PTMC. This study aimed to examine the clinicopathological factors associated with LLNM in patients with PTMC.,We reviewed medical records of 3578 patients with PTMC that was ≤1 cm in diameter on final pathology at Yonsei University Hospital between January 2015 and December 2017. The patients were divided into two groups (metastasis group [n = 157] and no metastasis group [n = 3421]).,The proportion of patients with multifocality\, extrathyroidal extension (ETE)\, and central node metastasis was significantly higher in metastasis group (p < 0.001\, p < 0.001 and p < 0.001\, respectively)\, and the mean tumor size was relatively larger in metastasis group than in no metastasis group (0.7 ± 0.2 vs. 0.6 ± 0.2 cm\, p < 0.001). However\, no statistically significant differences were observed in the tumors harboring BRAF mutation between the two groups (84.8% vs. 80.6%\, p = 0.199). Multivariate analysis indicated that the significant risk factors of LLNM include ETE (odds ratio [OR]: 1.904\, 95% confidence interval [CI]: 1.267-2.861)\, multifocality (OR: 2.255\, 95% CI: 1.544-3.293)\, and central node metastasis (OR: 7.768\, 95% CI: 4.869-12.395)\, but not BRAF mutation (OR: 0.542\, 95% CI: 0.337-0.874).,Approximately 4.4% of patients with PTMC presented with LLNM at the time of diagnosis. Moreover\, the significant risk factors of LLNM include central node metastasis\, ETE\, and multifocal disease but not BRAF mutation.",Endocrine,vol.69:1:149-156,2020,"Research Support, Non-U.S. Gov't",,,"Department of Surgery\, College of Medicine\, The Catholic University of Korea\, Seoul\, Republic of Korea.,Department of Surgery\, Singapore University College of Medicine\, Singapore\, Singapore.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea. ORALVANCO@yuhs.ac.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.,Department of Surgery\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.",,This study was supported by a faculty research grant of Yonsei University College of Medicine,International,6-2018-0044,"BRAF,Lateral neck lymph node metastasis,Papillary thyroid carcinoma,Papillary thyroid microcarcinoma"
32146818,"Iyer P,Chen MH,Goyal L,Denlinger CS",Targets for therapy in biliary tract cancers: the new horizon of personalized medicine.,"Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repair, and HER2 pathways have demonstrated promising new therapeutic avenues, among others, and various studies have demonstrated clinical activity with targeted tyrosine kinase inhibitors and/or antibodies. In this review, we will discuss the currently identified targets for therapy in BTCs and review currently available data regarding clinical development of treatment options in these molecularly distinct subsets.",Chinese clinical oncology,vol.9:1:7,2020,Review,"|Biliary Tract Neoplasms|therapy|,|Humans|,|Precision Medicine|methods|",,"Fox Chase Cancer Center\, Temple University Health System\, Philadelphia\, PA\, USA.,Department of Oncology\, Taipei Veteran's General Hospital\, Taipei.,Massachusetts General Hospital Cancer Center\, Harvard Medical School\, Boston\, MA\, USA.,Fox Chase Cancer Center\, Temple University Health System\, Philadelphia\, PA\, USA. crystal.denlinger@fccc.edu.",,,,,"Biliary tract cancer (BTC),cholangiocarcinoma,targeted therapy"
33216826,"Clark ME,Rizos H,Pereira MR,McEvoy AC,Marsavela G,Calapre L,Meehan K,Ruhen O,Khattak MA,Meniawy TM,Long GV,Carlino MS,Menzies AM,Millward M,Ziman M,Gray ES",Detection of splicing variants in plasma-derived cell-free nucleic acids and extracellular vesicles of melanoma patients failing targeted therapy therapies.,"The analysis of plasma circulating tumour nucleic acids provides a non-invasive approach to assess disease burden and the genetic evolution of tumours in response to therapy. BRAF splicing variants are known to confer melanoma resistance to BRAF inhibitors. We developed a test to screen cell-free RNA (cfRNA) for the presence of BRAF splicing variants. Custom droplet digital PCR assays were designed for the detection of BRAF splicing variants p61, p55, p48 and p41 and then validated using RNA from cell lines carrying these variants. Evaluation of plasma from patients with reported objective response to BRAF/MEK inhibition followed by disease progression was revealed by increased circulating tumour DNA (ctDNA) in 24 of 38 cases at the time of relapse. Circulating BRAF splicing variants were detected in cfRNA from 3 of these 38 patients; two patients carried the BRAF p61 variant and one the p55 variant. In all three cases the presence of the splicing variant was apparent only at the time of progressive disease. BRAF p61 was also detectable in plasma of one of four patients with confirmed BRAF splicing variants in their progressing tumours. Isolation and analysis of RNA from extracellular vesicles (EV) from resistant cell lines and patient plasma demonstrated that BRAF splicing variants are associated with EVs. These findings indicate that in addition to plasma ctDNA, RNA carried by EVs can provide important tumour specific information.",Oncotarget,vol.11:44:4016-4027,2020,Journal Article,,,"School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,Faculty of Medicine\, Health and Human Sciences\, Macquarie University\, Sydney\, New South Wales\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,Department of Otorhinolaryngology\, Head and Neck Surgery\, Chinese University of Hong Kong\, Hong Kong.,School of Biomedical Science\, University of Western Australia\, Crawley\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,Melanoma Institute Australia\, Sydney\, New South Wales\, Australia.,Westmead Institute for Cancer Research\, The University of Sydney\, Sydney\, New South Wales\, Australia.,Melanoma Institute Australia\, Sydney\, New South Wales\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.,School of Medical and Health Sciences\, Edith Cowan University\, Joondalup\, Western Australia\, Australia.",,,,,"BRAF splicing ,drug resistance,extracellular vesicles,melanoma,targeted therapy"
33214457,"Datta J,Narayan RR,Goldman DA,Chatila WK,Gonen M,Strong J,Balachandran VP,Drebin JA,Kingham TP,Jarnagin WR,Schultz N,Kemeny NE,D'Angelica MI",Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.,"To examine genomic correlates of CTR and overall survival (OS) in patients with IU-CRLM treated with combination systemic and hepatic artery infusion (HAI) chemotherapy.,In patients presenting with IU-CRLM\, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored.,Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR\, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation.,Of 128 IU-CRLM patients\, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure\, node-positive primary status\, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23\, 95% CI: 0.12-0.46\, P < 0.001). The most frequently altered genes were APC (81%)\, TP53 (77%)\, and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations\, any RAS pathway alterations\, and co-altered RAS/RAF-TP53 mutations were associated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52\, 95% CI: 1.37-4.64\, P = 0.003) after controlling for CTR\, number of liver metastases\, and preoperative extrahepatic disease.,Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9\, BRAF\, and co-altered RAS/RAF-TP53 mutations are promising biomarkers that\, when validated in larger datasets\, may impact treatment of IU-CRLM patients.",Annals of surgery,vol.::,2020,Journal Article,,,",,Department of Epidemiology and Biostatistics\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,,Department of Epidemiology and Biostatistics\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,Hepatopancreatobiliary Service\, Department of Surgery\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,Hepatopancreatobiliary Service\, Department of Surgery\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,Hepatopancreatobiliary Service\, Department of Surgery\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,Hepatopancreatobiliary Service\, Department of Surgery\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,Hepatopancreatobiliary Service\, Department of Surgery\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,,Department of Medicine\, Memorial Sloan Kettering Cancer Center\, New York\, New York.,Hepatopancreatobiliary Service\, Department of Surgery\, Memorial Sloan Kettering Cancer Center\, New York\, New York.",,NCI NIH HHS,United States,P30 CA008748,
31852719,"Botton T,Passeron T,Rocchi S",Comment on 'Testing for BRAF fusions in patients with advanced BRAF/NRAS/KIT wild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy'.,,Journal of clinical pathology,vol.73:8:524-525,2020,Comment,"|GTP Phosphohydrolases|,|Humans|,|Melanoma|,|Membrane Proteins|,|Proto-Oncogene Proteins B-raf|",,"0000-0001-9079-7014INSERM U1065\, Team 12\, Centre Méditerranéen de Médecine Moléculaire\, Université Côte d'Azur\, Nice\, France thomas.botton@unice.fr.,INSERM U1065\, Team 12\, Centre Méditerranéen de Médecine Moléculaire\, Université Côte d'Azur\, Nice\, France.,INSERM U1065\, Team 12\, Centre Méditerranéen de Médecine Moléculaire\, Université Côte d'Azur\, Nice\, France.","Membrane Proteins,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human",,,,"fish,melanoma,oncogenes"
32722188,"Chakrabarti S,Kamgar M,Mahipal A",Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm.,"Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.",Cancers,vol.12:8:,2020,Review,,,"0000-0002-1582-098XDepartment of Hematology-Oncology\, Medical College of Wisconsin\, 8701 Watertown Plank Road\, Milwaukee\, WI 53226\, USA.,0000-0001-9364-2712Department of Hematology-Oncology\, Medical College of Wisconsin\, 8701 Watertown Plank Road\, Milwaukee\, WI 53226\, USA.,0000-0002-1111-8333Department of Medical Oncology\, Mayo Clinic\, 200 First Street SW\, Rochester\, MN 55905\, USA.",,,,,"biliary tract cancer,cholangiocarcinoma,circulating tumor DNA (ctDNA),gallbladder cancer,ivosidenib,molecular profiling,next-generation sequencing,pemigatinib,targeted therapy"
32722429,"Li X,Kwon H",The Impact of BRAF Mutation on the Recurrence of Papillary Thyroid Carcinoma: A Meta-Analysis.,"Previous meta-analyses indicated that the BRAF V600E mutation was associated with an increased recurrence rate of papillary thyroid carcinoma (PTC). However, with recent publications of large cohort studies, the need for an updated meta-analysis increases. Therefore, we conducted a comprehensive meta-analysis to assess the impact of the BRAF V600E mutation on PTC recurrences. We performed a literature search using PubMed, SCOPUS, the Cochrane Database of Systematic Reviews, and the Web of Science Core Collection, from their inception to May 31, 2020. The relevant studies compared recurrence rates using the hazard ratio (HR) of BRAF mutations; 11 studies comprising 4674 patients were identified and included. Recurrence rates in patients with the BRAF V600E mutation were comparable with BRAF wild-type patients (HR 1.16, 95% CI 0.78-1.71), after adjustment for possible confounders. In subgroup analysis, both geographical region (HRs for America, Asia, and Europe were 2.16, 1.31 and 0.66, respectively) and tumor stage (HRs for stage I and II were 1.51 and 4.45, respectively) can affect the HRs of the BRAF mutation for recurrence. In conclusion, the BRAF mutation does not increase the risk of recurrences in patients with PTC. Differences in the geographical region or tumor stage should be considered when interpreting the impact of a BRAF mutation on recurrence.",Cancers,vol.12:8:,2020,Journal Article,,,"Department of Surgery\, Ewha Womans University Medical Center\, 1071 Anyangcheon-ro\, Yangcheon-Gu\, Seoul 07985\, Korea.,0000-0003-4979-8749Department of Surgery\, Ewha Womans University Medical Center\, 1071 Anyangcheon-ro\, Yangcheon-Gu\, Seoul 07985\, Korea.",,National Research Foundation of Korea,,2017R1C1B5076977,"BRAF mutation,papillary thyroid carcinoma,recurrence"
32722474,"Sfakianaki M,Papadaki C,Tzardi M,Trypaki M,Manolakou S,Messaritakis I,Saridaki Z,Athanasakis E,Mavroudis D,Tsiaoussis J,Gouvas N,Souglakos J",PKM2 Expression as Biomarker for Resistance to Oxaliplatin-Based Chemotherapy in Colorectal Cancer.,"The purpose of the current study is to investigate the prognostic significance of M2 isoform of pyruvate kinase (PKM2) mRNA expression loss in patients with operable colon cancer (CC). Two hundred sixty-two specimens from patients with stage-III or high-risk stage-II CC (group-A) treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy (FOLFOX), 118 specimens from metastatic CC patients (group-B) treated with FOLFOX, and 104 metastatic CC patients (group-C) treated with irinotecan-based chemotherapy were analyzed for PKM2, TS, ERCC1, MYC, and NEDD9 mRNA expression, as well as KRAS exon2 and BRAFV600E mutations. High PKM2 mRNA expression was correlated with left-sided located primaries (p = 0.001, group-A; p = 0.003, group-B; p = 0.001, group-C), high-grade tumors (p = 0.001, group-A; p = 0.017, group-B; p = 0.021, group-C), microsatellite-stable tumors (p < 0.001, group-A), pericolic lymph nodes involvement (p = 0.018, group-A), and cMYC mRNA expression (p = 0.002, group-A; p = 0.008, group-B; p = 0.006, group-C). High PKM2 mRNA expression was correlated with significantly lower disease free survival (DFS) (p = 0.002) and overall survival (OS) (p = 0.001) in the group-A. Similarly, PKM2 mRNA expression was associated with significantly decreased progression free survival (PFS) (p = 0.001) and OS (p = 0.001) in group-B. On the contrary, no significant association for the PKM2 mRNA expression has been observed with either PFS (p = 0.612) or OS (p = 0.517) in group-C. To conclude, the current study provides evidence for the prediction of PKM2 mRNA expression oxaliplatin-based treatment resistance.",Cancers,vol.12:8:,2020,Journal Article,,,"Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,0000-0002-4591-3757Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,Department of Pathology\, University General Hospital of Heraklion\, 71110 Heraklion\, Greece.,Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,0000-0003-1877-500XLaboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,Department of Surgery\, University General Hospital of Heraklion\, 71110 Heraklion\, Greece.,0000-0002-6363-7258Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,Laboratory of Anatomy\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.,0000-0002-6541-4226School of Medicine\, University of Cyprus\, Nicosia 1678\, Cyprus.,Laboratory of Translational Oncology\, School of Medicine\, University of Crete\, 71003 Heraklion\, Greece.",,,,,"BRAF,MSI,PKM2,colon cancer,prediction,ΚRAS"
32726988,"van der Kooij MK,Wetzels MJAL,Aarts MJB,van den Berkmortel FWPJ,Blank CU,Boers-Sonderen MJ,Dierselhuis MP,de Groot JWB,Hospers GAP,Piersma D,van Rijn RS,Suijkerbuijk KPM,Ten Tije AJ,van der Veldt AAM,Vreugdenhil G,Wouters MWJM,Haanen JBAG,van den Eertwegh AJM,Bastiaannet E,Kapiteijn E","Age Does Matter in Adolescents and Young Adults versus Older Adults with Advanced Melanoma; A National Cohort Study Comparing Tumor Characteristics, Treatment Pattern, Toxicity and Response.","Cutaneous melanoma is a common type of cancer in Adolescents and Young Adults (AYAs, 15-39 years of age). However, AYAs are underrepresented in clinical trials investigating new therapies and the outcomes from these therapies for AYAs are therefore unclear. Using prospectively collected nation-wide data from the Dutch Melanoma Treatment Registry (DMTR), we compared baseline characteristics, mutational profiles, treatment strategies, grade 3-4 adverse events (AEs), responses and outcomes in AYAs (n = 210) and older adults (n = 3775) who were diagnosed with advanced melanoma between July 2013 and July 2018. Compared to older adults, AYAs were more frequently female (51% versus 40%, p = 0.001), and had a better Eastern Cooperative Oncology Group performance status (ECOG 0 in 54% versus 45%, p = 0.004). BRAF and NRAS mutations were age dependent, with more BRAF V600 mutations in AYAs (68% versus 46%) and more NRAS mutations in older adults (13% versus 21%), p < 0.001. This finding translated in distinct first-line treatment patterns, where AYAs received more initial targeted therapy. Overall, grade 3-4 AE percentages following first-line systemic treatment were similar for AYAs and older adults; anti-PD-1 (7% versus 14%, p = 0.25), anti-CTLA-4 (16% versus 33%, p = 0.12), anti-PD-1 + anti-CTLA-4 (67% versus 56%, p = 0.34) and BRAF/MEK-inhibition (14% versus 23%, p = 0.06). Following anti-CTLA-4 treatment, no AYAs experienced a grade 3-4 colitis, while 17% of the older adults did (p = 0.046). There was no difference in response to treatment between AYAs and older adults. The longer overall survival observed in AYAs (hazard ratio (HR) 0.7; 95% CI 0.6-0.8) was explained by the increased cumulative incidence of non-melanoma related deaths in older adults (sub-distribution HR 2.8; 95% CI 1.5-4.9), calculated by competing risk analysis. The results of our national cohort study show that baseline characteristics and mutational profiles differ between AYAs and older adults with advanced melanoma, leading to different treatment choices made in daily practice. Once treatment is initiated, AYAs and older adults show similar tumor responses and melanoma-specific survival.",Cancers,vol.12:8:,2020,Journal Article,,,"0000-0002-9764-5467Department of Medical Oncology\, Leiden University Medical Center\, Albinusdreef 2\, PO box 9600\, 2300 RC Leiden\, The Netherlands.,Department of Medical Oncology\, Leiden University Medical Center\, Albinusdreef 2\, PO box 9600\, 2300 RC Leiden\, The Netherlands.,Department of Medical Oncology\, Maastricht University Medical Center\, P. Debyelaan 25\, 6202 AZ Maastricht\, The Netherlands.,Department of Medical Oncology\, Zuyderland Medical Center\, 6130 MB Sittard-Geleen\, The Netherlands.,Department of Medical Oncology\, Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital\, Plesmanlaan 121\, 1066 CX Amsterdam\, The Netherlands.,Department of Medical Oncology\, Radboud University Medical Center\, Geert Grooteplein Zuid 10\, 6500 HB Nijmegen\, The Netherlands.,Department of Pediatric Oncology\, Princess Máxima Center\, Heidelberglaan 25\, 3584 CS Utrecht\, The Netherlands.,Isala Oncology Center\, Isala\, 8000 GK Zwolle\, The Netherlands.,Department of Medical Oncology\, University Medical Center Groningen\, Hanzeplein 1\, 9713 GZ Groningen\, The Netherlands.,Department of Medical Oncology\, Medisch Spectrum Twente\, Koningsplein 1\, 7512 KZ Enschede\, The Netherlands.,Department of Medical Oncology\, Medical Center Leeuwarden\, Henri Dunantweg 2\, 8934 AD Leeuwarden\, The Netherlands.,0000-0003-3604-5430Department of Medical Oncology\, University Medical Center Utrecht\, Heidelberglaan 100\, 3584 CX Utrecht\, The Netherlands.,Department of Medical Oncology\, Amphia Ziekenhuis\, Langendijk 175\, 4819 EV Breda\, The Netherlands.,Department of Medical Oncology\, Erasmus MC Cancer Institute\, Dr. Molewaterplein 40\, 3000 CA Rotterdam\, The Netherlands.,Department of Medical Oncology\, Maxima Medical Center\, de Run 4600\, 5500 MB Veldhoven\, The Netherlands.,0000-0001-6173-0662Department of Surgical Oncology\, Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital\, Plesmanlaan 121\, 1066 CX Amsterdam\, The Netherlands.,Department of Medical Oncology\, Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital\, Plesmanlaan 121\, 1066 CX Amsterdam\, The Netherlands.,Department of Medical Oncology\, Cancer Center Amsterdam\, Amsterdam UMC\, Vrije Universiteit Amsterdam\, de Boelelaan 1117\, 1081 HZ Amsterdam\, The Netherlands.,Department of Surgery\, Leiden University Medical Centre\, Albinusdreef 2\, PO box 9600\, 2300 RC Leiden\, The Netherlands.,0000-0002-4814-6426Department of Medical Oncology\, Leiden University Medical Center\, Albinusdreef 2\, PO box 9600\, 2300 RC Leiden\, The Netherlands.",,The Netherlands Organization for Health Research and Development,,836002002,"AYA,BRAF mutation,adolescents,advanced melanoma,checkpoint inhibitors,clinical audit,outcome research,prospective nation-wide data,targeted therapy,young adults"
32731406,"Monti M,Vescovi R,Consoli F,Farina D,Moratto D,Berruti A,Specchia C,Vermi W",Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis.,"The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAFV600+ subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment.",Cancers,vol.12:8:,2020,Journal Article,,,"Department of Molecular and Translational Medicine\, University of Brescia\, 25123 Brescia\, Italy.,Department of Molecular and Translational Medicine\, University of Brescia\, 25123 Brescia\, Italy.,0000-0003-0933-8334Oncology Unit\, ASST Spedali Civili di Brescia\, 25123 Brescia\, Italy.,Radiology Unit\, Department of Medical and Surgical Specialties\, Radiological Sciences and Public Health\, University of Brescia\, 25123 Brescia\, Italy.,Laboratory of Genetic Disorders of Childhood\, Angelo Nocivelli Institute for Molecular Medicine\, ASST Spedali Civili di Brescia\, 25123 Brescia\, Italy.,Oncology Unit\, ASST Spedali Civili di Brescia\, 25123 Brescia\, Italy.,Department of Molecular and Translational Medicine\, University of Brescia\, 25123 Brescia\, Italy.,0000-0002-2291-2997Department of Molecular and Translational Medicine\, University of Brescia\, 25123 Brescia\, Italy.",,Associazione Italiana per la Ricerca sul Cancro,,IG23179,"CXCL10,TLR,interferon,lactate dehydrogenase,melanoma,plasmacytoid dendritic cells"
32734128,"Ko E,Baek S,Kim J,Park D,Lee Y",Antitumor Activity of Combination Therapy with Metformin and Trametinib in Non-Small Cell Lung Cancer Cells.,"Metformin has been widely used as an antidiabetic drug, and reported to inhibit cell proliferation in many cancers including non-small cell lung cancer (NSCLC). In NSCLC cells, metformin suppresses PI3K/AKT/mTOR signaling pathway, but effect of metformin on RAS/ RAF/MEK/ERK signaling pathway is controversial; several studies showed the inhibition of ERK activity, while others demonstrated the activation of ERK in response to metformin exposure. Metformin-induced activation of ERK is therapeutically important, since metformin could enhance cell proliferation through RAS/RAF/MEK/ERK pathway and lead to impairment of its anticancer activity suppressing PI3K/AKT/mTOR pathway, requiring blockade of both signaling pathways for more efficient antitumor effect. The present study tested the combination therapy of metformin and trametinib by monitoring the alterations of regulatory effector proteins of cell signaling pathways and the effect of the combination on cell viability in NCI-H2087 NSCLC cells with NRAS and BRAF mutations. We show that metformin alone blocks PI3K/AKT/mTOR signaling pathway but induces the activation and phosphorylation of ERK. The combination therapy synergistically decreased cell viability in treatment with low doses of two drugs, while it gave antagonistic effect with high doses. These findings suggest that the efficacy of metformin and trametinib combination therapy may depend on the alteration of ERK activity induced by metformin and specific cellular context of cancer cells.",Development & reproduction,vol.24:2:113-123,2020,Journal Article,,,"https://orcid.org/0000-0003-4631-4331Dept. of Medicine\, Jeju National University School of Medicine\, Jeju 63243\, Korea.,https://orcid.org/0000-0002-0871-4353Dept. of Medicine\, Jeju National University School of Medicine\, Jeju 63243\, Korea.,https://orcid.org/0000-0002-5984-3219Histology\, Jeju National University School of Medicine\, Jeju 63243\, Korea.,https://orcid.org/0000-0002-0387-8279Histology\, Jeju National University School of Medicine\, Jeju 63243\, Korea.,https://orcid.org/0000-0001-6710-3352Histology\, Jeju National University School of Medicine\, Jeju 63243\, Korea.",,,,,"Cell viability,ERK,Metformin,Non-small cell lung cancer (NSCLC) Cell,Trametinib"
32736279,"Trisolini R,Cancellieri A,Livi V,Annema JT,Ferrari M,Natali F,Paioli D,Conci N,Altimari A,Fiorentino M,Ardizzoni A",Pulmonary adenocarcinoma with psammoma bodies is associated with a specific endobronchial ultrasound pattern and a high prevalence of actionable driver mutations.,"Pulmonary adenocarcinoma with psammoma bodies (PAPBs) is a rare histological variant whose association with a high prevalence of targetable mutations has been suggested by scant literature reports describing small series. We aim to describe the endobronchial ultrasound (EBUS) pattern and the molecular profile by next-generation sequencing of an Italian series of patients with PAPBs.,Over a 8-year period (2012-2019)\, we identified 15 patients with a very uncommon endobronchial ultrasound (EBUS) heterogeneity pattern characterized by the presence of multiple to countless\, punctate non-shadowing foci (""starry sky"" sign) which were not evident at CT and corresponded to psammoma bodies at pathological examination. The clinical\, radiological\, pathological and molecular findings of these patients were retrieved and analyzed.,Pathological examination of the EBUS-TBNA specimens revealed malignancy (12 pulmonary adenocarcinoma\, 2 breast carcinoma\, 1 colonic carcinoma) and showed the presence of psammoma bodies in all of the 15 patients with the starry sky sign. Among the 12 patients with pulmonary adenocarcinoma with psammoma bodies\, female sex (8/12\, 66.7 %) and never-smoking habit (6/12\, 50 %) were prevalent. Molecular tumor profiling using the Oncomine™ Focus DNA and RNA fusion panels was successfully performed in 11/12 patients and revealed 10 genetic alterations (BRAF mutation\, 4; EGFR mutation\, 2; ALK rearrangement\, RET rearrangement\, PIK3CA mutation\, CDK4 amplification 1) in 7 patients (63.6 %).,The present series suggests that pulmonary adenocarcinoma with psammoma bodies is associated with a readily identifiable EBUS pattern and with a high prevalence of different\, often uncommon and actionable\, driver mutations.","Lung cancer (Amsterdam, Netherlands)",vol.147::204-208,2020,Journal Article,,,"Interventional Pulmonology Unit\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Bologna\, Italy; Interventional Pulmonology Unit\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, Roma\, Italy. Electronic address: rocco.trisolini@policlinicogemelli.it.,Pathology Unit\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Bologna\, Italy; Pathology Unit\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, Roma\, Italy.,Interventional Pulmonology Unit\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Bologna\, Italy; Interventional Pulmonology Unit\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, Roma\, Italy.,Department of Respiratory Medicine\, Academic Medical Center\, University of Amsterdam\, Amsterdam\, The Netherlands.,Interventional Pulmonology Unit\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, Roma\, Italy.,Interventional Pulmonology Unit\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, Roma\, Italy.,Interventional Pulmonology Unit\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Bologna\, Italy; Interventional Pulmonology Unit\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, Roma\, Italy.,Medical Oncology Unit\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Università di Bologna\, Bologna\, Italy.,Laboratory of Oncologic Molecular Pathology\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Università di Bologna\, Bologna\, Italy.,Department of Experimental\, Diagnostic and Specialty Medicine\, Università di Bologna\, Bologna\, Italy.,Medical Oncology Unit\, Azienda Ospedaliero Universitaria Policlinico S. Orsola\, Università di Bologna\, Bologna\, Italy.",,,,,"BRAF mutation,Endobronchial ultrasound,Molecular profiling,Next generation sequencing,Psammoma body,Pulmonary adenocarcinoma"
33081201,"Salzmann M,Benesova K,Buder-Bakhaya K,Papamichail D,Dimitrakopoulou-Strauss A,Lorenz HM,Enk AH,Hassel JC",Arthralgia Induced by BRAF Inhibitor Therapy in Melanoma Patients.,"BRAF inhibitors (BRAFi)\, commonly used in BRAF-mutated metastatic melanoma (MM) treatment\, frequently cause arthralgia. Although this is one of the most common side effects\, it has not been characterized yet.,We retrospectively included all patients treated with BRAFi +/- MEK inhibitors (MEKi) for MM at the National Center for Tumor Diseases (Heidelberg) between 2010 and 2018 and reviewed patient charts for the occurrence and management of arthralgia. The evaluation was supplemented by an analysis of frozen sera.,We included 154 patients (63% males); 31% (48/154) of them reported arthralgia with a median onset of 21 days after the start of the therapy. Arthralgia mostly affected small joints (27/36\, 75%) and less frequently large joints (19/36\, 53%). The most commonly affected joints were in fingers (19/36\, 53%)\, wrists (16/36\, 44%)\, and knees (12/36\, 33%). In 67% (24/36) of the patients\, arthralgia occurred with a symmetrical polyarthritis\, mainly of small joints\, resembling the pattern typically observed in patients affected by rheumatoid arthritis (RA)\, for which a role of the MAPK signaling pathway was previously described. Patients were negative for antinuclear antibodies\, anti-citrullinated protein antibodies\, and rheumatoid factor; arthritis was visible in 10 of 13 available PET-CT scans. The development of arthralgia was linked to better progression-free survival and overall survival.,Arthralgia is a common side effect in patients receiving BRAFi +/- MEKi therapy and often presents a clinical pattern similar to that observed in RA patients. Its occurrence was associated with longer-lasting tumor control.",Cancers,vol.12:10:,2020,Journal Article,,,"0000-0003-4310-4822Department of Dermatology and National Center for Tumor Diseases\, University Hospital Heidelberg\, Im Neuenheimer Feld 460\, 69120 Heidelberg\, Germany.,Division of Rheumatology\, Department of Medicine V\, University Hospital Heidelberg\, Im Neuenheimer Feld 410\, 69120 Heidelberg\, Germany.,Department of Dermatology and National Center for Tumor Diseases\, University Hospital Heidelberg\, Im Neuenheimer Feld 460\, 69120 Heidelberg\, Germany.,Clinical Cooperation Unit Nuclear Medicine\, German Cancer Research Center\, Im Neuenheimer Feld 280\, 69120 Heidelberg\, Germany.,Clinical Cooperation Unit Nuclear Medicine\, German Cancer Research Center\, Im Neuenheimer Feld 280\, 69120 Heidelberg\, Germany.,Division of Rheumatology\, Department of Medicine V\, University Hospital Heidelberg\, Im Neuenheimer Feld 410\, 69120 Heidelberg\, Germany.,Department of Dermatology and National Center for Tumor Diseases\, University Hospital Heidelberg\, Im Neuenheimer Feld 460\, 69120 Heidelberg\, Germany.,Department of Dermatology and National Center for Tumor Diseases\, University Hospital Heidelberg\, Im Neuenheimer Feld 460\, 69120 Heidelberg\, Germany.",,,,,"BRAF,BRAF inhibitor,arthralgia,melanoma,rheumatoid arthritis"
33084582,"Kang H,Li J,Wu M,Shen L,Hou L",Building a Pharmacogenomics Knowledge Model Toward Precision Medicine: Case Study in Melanoma.,"Many drugs do not work the same way for everyone owing to distinctions in their genes. Pharmacogenomics (PGx) aims to understand how genetic variants influence drug efficacy and toxicity. It is often considered one of the most actionable areas of the personalized medicine paradigm. However\, little prior work has included in-depth explorations and descriptions of drug usage\, dosage adjustment\, and so on.,We present a pharmacogenomics knowledge model to discover the hidden relationships between PGx entities such as drugs\, genes\, and diseases\, especially details in precise medication.,PGx open data such as DrugBank and RxNorm were integrated in this study\, as well as drug labels published by the US Food and Drug Administration. We annotated 190 drug labels manually for entities and relationships. Based on the annotation results\, we trained 3 different natural language processing models to complete entity recognition. Finally\, the pharmacogenomics knowledge model was described in detail.,In entity recognition tasks\, the Bidirectional Encoder Representations from Transformers-conditional random field model achieved better performance with micro-F1 score of 85.12%. The pharmacogenomics knowledge model in our study included 5 semantic types: drug\, gene\, disease\, precise medication (population\, daily dose\, dose form\, frequency\, etc)\, and adverse reaction. Meanwhile\, 26 semantic relationships were defined in detail. Taking melanoma caused by a BRAF gene mutation into consideration\, the pharmacogenomics knowledge model covered 7 related drugs and 4846 triples were established in this case. All the corpora\, relationship definitions\, and triples were made publically available.,We highlighted the pharmacogenomics knowledge model as a scalable framework for clinicians and clinical pharmacists to adjust drug dosage according to patient-specific genetic variation\, and for pharmaceutical researchers to develop new drugs. In the future\, a series of other antitumor drugs and automatic relation extractions will be taken into consideration to further enhance our framework with more PGx linked data.",JMIR medical informatics,vol.8:10:e20291,2020,Journal Article,,,"https://orcid.org/0000-0001-9647-0645Institute of Medical Information &Library\, Chinese Academy of Medical Sciences/Peking Union Medical College\, Beijing\, China.,https://orcid.org/0000-0001-6391-8343Institute of Medical Information &Library\, Chinese Academy of Medical Sciences/Peking Union Medical College\, Beijing\, China.,https://orcid.org/0000-0003-4308-6660Institute of Medical Information &Library\, Chinese Academy of Medical Sciences/Peking Union Medical College\, Beijing\, China.,https://orcid.org/0000-0003-1144-0178Institute of Medical Information &Library\, Chinese Academy of Medical Sciences/Peking Union Medical College\, Beijing\, China.,https://orcid.org/0000-0001-9226-2216Institute of Medical Information &Library\, Chinese Academy of Medical Sciences/Peking Union Medical College\, Beijing\, China.",,,,,"BERT–CRF model,knowledge model,melanoma,named entity recognition,pharmacogenomics"
33088346,"Diamantopoulos PT,Ziogas D,Viniou NA,Anastasopoulou A,Kyriakakis G,Frangia K,Gogas H","Clinical considerations about the coexistence of melanoma and chronic lymphocytic leukemia in the era of targeted therapies, triggered by rare clinical scenarios. A case series and review of the literature.","The epidemiologic correlation of melanoma and chronic lymphocytic leukemia (CLL) has been the subject of several population studies. In the present article, through the presentation of five illustrative cases of patients with melanoma and CLL, several aspects of this complex relationship are highlighted, with a focus on the increased incidence of melanoma in patients with CLL, its speculated etiology, and the impact of CLL stage and disease duration on the incidence and prognosis of melanoma. Furthermore, the rare entity of the synchronous diagnosis of melanoma and CLL in biopsied lymph nodes is discussed, along with its implications on the diagnostic and therapeutic procedures. In addition, the available data on the treatment choices in patients with melanoma and CLL are presented and the efficacy and safety of fludarabine, anti-CD20 monoclonal antibodies, new targeted therapies for CLL, and checkpoint inhibitors are further discussed. Finally, since no formal guidelines are available for the management of this group of patients, guidelines are proposed for skin-cancer screening in patients with CLL, for the correct interpretation of BRAF mutation analysis in lymph-node specimens with 'collision of tumors,' and for the optimal use of imaging studies in the diagnosis of metastatic disease in patients with CLL and melanoma, while a treatment approach for such patients is also suggested. The information and proposed guidelines provided in the present article comprise a useful guide for physicians managing such patients, focusing on diagnostic challenges and therapeutic dilemmas posed by the coexistence of the two disease entities.",Therapeutic advances in medical oncology,vol.12::1758835920962369,2020,Case Reports,,,"https://orcid.org/0000-0003-2692-5944First Department of Internal Medicine\, Laikon General Hospital\, National and Kapodistrian University of Athens\, Athens 11527\, Greece.,https://orcid.org/0000-0003-2620-4004First Department of Internal Medicine\, National and Kapodistrian University of Athens\, Athens\, Greece.,First Department of Internal Medicine\, National and Kapodistrian University of Athens\, Athens\, Greece.,First Department of Internal Medicine\, National and Kapodistrian University of Athens\, Athens\, Greece.,First Department of Internal Medicine\, National and Kapodistrian University of Athens\, Athens\, Greece.,Histo-Bio Diagnosis\, Athens\, Greece.,First Department of Internal Medicine\, National and Kapodistrian University of Athens\, Athens\, Greece.",,,,,"BRAF mutation,chronic lymphocytic leukemia,immunotherapy,melanoma,targeted therapy"
33088794,"Kuo CY,Yang PS,Chien MN,Cheng SP",Preoperative Factors Associated with Extrathyroidal Extension in Papillary Thyroid Cancer.,"Extrathyroidal extension may not be accurately recognized during thyroidectomy and can increase the risk of positive margins and even recurrence. This study aimed to investigate the preoperative factors associated with extrathyroidal extension.,We analyzed 887 patients with papillary thyroid cancer (PTC) who underwent surgery in the period of 2005-2017. Binary logistic regression analyses and generalized additive models were used to identify associations.,Minimal extrathyroidal extension was present in 233 (26%) patients and advanced extrathyroidal extension was found in 60 (7%) patients. Age\, BMI\, and tumor size were independent predictors of all or advanced extrathyroidal extension. Among the 493 patients whose BRAF mutation status was available\, age (OR = 1.025)\, BMI (OR = 1.091)\, tumor size (OR = 1.544)\, and BRAF V600E mutation (OR = 2.311) were independently associated with extrathyroidal extension.,Older age\, a greater BMI\, a larger tumor size\, and presence of the BRAF mutation were predictive of extrathyroidal extension. These factors should be taken into consideration in decision-making before surgery is performed.",European thyroid journal,vol.9:5:256-262,2020,Journal Article,,,"Department of Surgery\, MacKay Memorial Hospital and Mackay Medical College\, Taipei\, Taiwan.,Department of Surgery\, MacKay Memorial Hospital and Mackay Medical College\, Taipei\, Taiwan.,Division of Endocrinology and Metabolism\, Department of Internal Medicine\, MacKay Memorial Hospital and Mackay Medical College\, Taipei\, Taiwan.,Department of Surgery\, MacKay Memorial Hospital and Mackay Medical College\, Taipei\, Taiwan.",,,,,"Age,BRAF,Body mass index,Extrathyroidal extension,Thyroid carcinoma"
33099543,"Gerard L,Garcia J,Gauthier A,Lopez J,Durand A,Hervieu V,Lemelin A,Chardon L,Landel V,Gibert B,Lombard-Bohas C,Payen L,Walter T",ctDNA in neuroendocrine carcinoma of gastroenteropancreatic origin or of unknown primary: the CIRCAN-NEC pilot study.,"Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterised by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations\, to assess their predictive value for response to chemotherapies\, and their change according to disease progression.,The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary\, scheduled to begin first or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation\, at first evaluation\, and during disease progression. ctDNA were sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction (MAF).,All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n=21)\, RB1 (n=2)\, KRAS (n=4)\, BRAF (n=3). Ten (42%) had a ""adenocarcinoma-like"" profile. Five of six patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA-mutation/immunohistochemistry-profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups\, patients with KRAS (HR=3.60\, 95%CI [1.06-12.04]) and BRAF (HR=4.25\, 95%CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide\, while the two patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response)\, which was associated with longer PFS (HR=0.37\, 95%CI [0.15; 0.91]).,This pilot study shows a high sensitivity of ctDNA assessment\, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).",Neuroendocrinology,vol.::,2020,Journal Article,,,",,,,,,,,,,,,",,,,,
33100226,"Vachtenheim J,Kodet R,Fischer O,Kolek V,Strizova Z,Ozaniak A,Simonek J,Stolz A,Pozniak J,Kolarik J,Svorcova M,Vachtenheim J,Lischke R",Giant lung metastasis of NRAS-mutant melanoma in a 24-year-old patient with a history of BRAF-mutant conventional melanoma harboring Spitzoid morphology: a case report.,"Spitzoid melanocytic lesions represent a heterogeneous group of proliferations with ambiguous and overlapping terminology. The exact distinction of a Spitz nevus from a Spitzoid melanoma can be very difficult or\, in some cases\, impossible. Among the Spitzoid lesions\, there is a lesion termed an atypical Spitz tumour (AST) that has intermediate histopathologic features between those of a Spitz nevus and a Spitzoid melanoma and thus uncertain malignant potential. There are several rare cases of patients with a Spitzoid melanoma initially misdiagnosed as a Spitz nevus or an AST with fatal consequences. It is\, therefore\, advised to perform a molecular characterization in cases where uncertain skin lesions are presented\, as it may provide extended set of information with a possible impact on the treatment options. Furthermore\, preventive measures\, such as regular physical and skin examinations\, as well as thorough scheduling of individual follow-up visits\, are essential in patients with potentially malignant skin nevi.,We report a case of a young adult female with a history of AST excision with a negative sentinel lymph node biopsy (SLNB) and insufficient follow-up. Four years after the primary dermatological diagnosis\, she presented with a giant tumour in the right hemithorax. Radical en bloc resection of the tumour with right pneumonectomy and resection of the pericardium with reconstruction of the pericardium using mesh was performed. A definitive histopathological examination revealed a metastatic melanoma. The association of the previously diagnosed AST and subsequent appearance of melanoma metastases led to a retrospective re-evaluation of the initial lesion. The suspected diagnosis of Spitzoid melanoma\, however\, was not confirmed. Moreover\, the molecular examination revealed a major discordance between the initial lesion and the lung tumour\, which most likely excluded the possible association of the lung metastasis with the initial skin lesion. The initial skin lesion was a BRAF-mutant melanoma with Spitzoid features and termed as AST\, while the giant lung metastasis was NRAS-mutant melanoma. The subsequent postoperative course was complicated by the appearance of brain metastases that were stereotactically irradiated. Nevertheless\, despite complex specialised medical care\, the patient's clinical condition rapidly deteriorated. By this time\, no active oncological treatment was possible. The patient was delegated to local hospice for palliative care six months after the surgery and died three weeks later.,Our patient was surgically treated at the age of 20 for AST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin. Molecular characterization\, as well as the close clinical follow-up should be always precisely performed in patients with uncertain skin lesions\, such as AST.",Diagnostic pathology,vol.15:1:132,2020,Journal Article,,,"http://orcid.org/0000-0002-1468-4242Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic. jiri.vachtenheim@fnmotol.cz.,Department of Pathology and Molecular Medicine\, Second Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Department of Respiratory Medicine\, Palacký University Medical School and Teaching Hospital\, Olomouc\, Czech Republic.,Department of Respiratory Medicine\, Palacký University Medical School and Teaching Hospital\, Olomouc\, Czech Republic.,Department of Immunology\, Second Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.,Department of Transcription and Cell Signaling\, Institute of Medical Biochemistry and Laboratory Diagnostics\, First Faculty of Medicine\, Charles University\, Prague\, Czech Republic.,Third Department of Surgery\, First Faculty of Medicine\, Charles University and University Hospital Motol\, Prague\, Czech Republic.",,Univerzita Karlova v Praze,,PROGRESQ25,"Atypical spitz tumour,Case report,Conventional melanoma,Metastasis,Molecular analysis,Spitz nevus,Spitzoid melanoma"
33101670,"Kamada T,Ishiguro H,Okada S,Takeuchi H,Takahashi J,Nakashima K,Nakaseko Y,Suzuki N,Ohdaira H,Suzuki Y",Pembrolizumab plus platinum-based chemotherapy for unfavorable cancer of unknown primary site: Case report.,"We report a case of sustained complete response in unfavorable cancer of unknown primary site (CUP) successfully treated with chemotherapy combining pembrolizumab\, pemetrexed and platinum.,A 66-year-old man was presented with weight loss and cough for 3 months. Contrast-enhanced computed tomography (CT) confirmed a mass in the superior anterior mediastinum and multiple enlarged mediastinal and axillary lymph nodes. Positron emission tomography-CT (PET-CT) showed abnormal uptake in the corresponding lesions. Histopathological analysis of the left axillary nodule revealed poorly differentiated adenocarcinoma. Immunohistochemistry showed the tumor cells were positive for cytokeratin 7 and thyroid transcription factor-1 and negative for cytokeratin 20. Thus\, the patient was diagnosed as poorly differentiated adenocarcinoma of unknown primary\, and treated as non-small-cell lung cancer. Additional genetic testing revealed the patient was negative for EGFR\, ALK fluorescence in situ hybridization\, ROS1\, BRAF\, and PD-L1 22C3 IHC with Tumor Proportion Score (TPS) was less than 1%. The patient received six cycles of pembrolizumab\, platinum\, and pemetrexed intravenously. Cisplatin was switched to carboplatin because of cisplatin nephrotoxicity in one course. PET-CT after six cycles showed all lesions disappeared; complete response was considered to have been achieved. Maintenance therapy of pembrolizumab and pemetrexed has been continued for 6 months after the induction therapies to prevent progressive disease. Complete response has been maintained.,Chemotherapy with pembrolizumab\, platinum and pemetrexed could be valuable for treating unfavorable CUP.,Chemotherapy with pembrolizumab\, platinum\, and pemetrexed helped achieved sustained complete response in a patient with unfavorable CUP.",Annals of medicine and surgery (2012),vol.60::31-35,2020,Case Reports,,,"Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Oncology\, International University of Health and Welfare Narita Hospital\, 852\, Hatakeda\, Narita\, Chiba\, 286-0124\, Japan.,Department of Pathology\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.,Department of Surgery\, International University of Health and Welfare Hospital\, 537-3\, Iguchi\, Nasushiobara\, Tochigi\, 329-2763\, Japan.",,,,,"ALK\, anaplastic lymphoma kinase,CEA\, carcinoembryonic antigen,CK7\, cytokeratin 7,CR\, complete response,CT\, computed tomography,CUP\, cancer of unknown primary site,Cancer of unknown primary,EGFR\, epidermal growth factor receptor,LDH\, lactate dehydrogenase,NCCN\, National Comprehensive Cancer Network,Non-small-cell lung cancer,PD-L1\, programmed death ligand 1,PET\, positron emission tomography,Pembrolizumab,Pemetrexed,Platinum,TTF-1\, thyroid transcription factor-1"
33102215,"Imyanitov EN,Ivantsov AO,Tsimafeyeu IV",Harmonization of Molecular Testing for Non-Small Cell Lung Cancer: Emphasis on PD-L1.,"Comprehensive molecular testing plays a critical role in the choice of treatment for non-small lung cell cancer (NSCLC). The analysis of druggable alterations in EGFR, BRAF, MET, KRAS, ALK, ROS1, RET and NTRK1/2/3 genes is more or less standardized and can be achieved using a single diagnostic platform, e.g., next generation sequencing (NGS) or polymerase chain reaction (PCR). In contrast to above targets, PD-L1 testing requires the use of immunohistochemistry (IHC). There are multiple PD-L1 IHC assays, which utilize distinct antibodies and detection systems. These PD-L1 tests are tailored to distinct drugs, often rely on different thresholds and scoring guidelines, and are characterized by incomplete inter-laboratory and inter-observer reproducibility. Several studies evaluated the performance of PD-L1 RNA expression tests, as PCR-based RNA analysis is compatible with other NSCLC molecular testing platforms, can be performed in a semi-automated manner, and has a potential for proper standardization. These investigations revealed a correlation between PD-L1 protein and RNA expression; however, there were NSCLCs demonstrating decent amounts of PD-L1 transcript in the absence of PD-L1 IHC staining. Clinical studies are required to evaluate, which of the two PD-L1 testing approaches, i.e., RNA or protein expression measurement, has a better predictive value.",Frontiers in oncology,vol.10::549198,2020,Journal Article,,,"Department of Tumor Growth Biology\, N.N. Petrov Institute of Oncology\, St. Petersburg\, Russia.,Department of Tumor Growth Biology\, N.N. Petrov Institute of Oncology\, St. Petersburg\, Russia.,Institute of Oncology\, Hadassah Moscow\, Moscow\, Russia.",,,,,"PCR,PD-L1,molecular testing,non-small cell lung cancer,review"
33102773,"Ishida Y,Takano S,Maekawa S,Yamaguchi T,Yoshida T,Kobayashi S,Iwamoto F,Kuno T,Hayakawa H,Matsuda S,Fukasawa M,Shindo H,Inoue T,Nakayama Y,Ichikawa D,Sato T,Enomoto N",Fractionated small cell-free DNA increases possibility to detect cancer-related gene mutations in advanced colorectal cancer.,"Liquid biopsy is a method that can efficiently detect tumor genetic abnormalities from body fluids such as blood and urine. Detection sensitivity and the available number of mutations in cell-free DNA (cfDNA) are limited. In this study\, we develop a highly sensitive and comprehensive method to detect mutations from cfDNA by concentrating tumor fractions of small cfDNA in advanced colorectal cancers.,Biopsied specimens and 37 serum samples were collected from 27 patients with advanced colorectal carcinoma. A serum-extracted cfDNA was divided into enriched fractionated small cfDNA and unfractionated cfDNA. Both cfDNAs were subjected to digital polymerase chain reaction (PCR) to evaluate their KRAS\, BRAF\, CDKN2A\, and TP53 status. Consequently\, their mutant allele frequencies (MAFs) were compared and analyzed by next-generation sequencing (NGS) in conjunction with tissue-derived DNA.,NGS analyses revealed mutations in TP53 (63%)\, KRAS (63%)\, APC (30%)\, and PIK3CA (22%). Digital PCR could detect mutations in 25 of 27 samples (93%) of unfractionated cfDNA\, a rate that increased to 100% when samples were enriched with fractionated small cfDNA (6.8 vs 10.7%\, P < 0.001). NGS also showed increased MAFs in fractionated small cfDNA compared to unfractionated cfDNA (16.3 vs 18.8%\, P = 0.012) and a tendency to detect a greater number of cancer-related genes in fractionated cfDNA.,Fractionated small cfDNA increased MAFs of gene mutations and increases the possibilities to detect cancer-related genes even in advanced cancer patients from whom it is difficult to obtain tissue samples.",JGH open : an open access journal of gastroenterology and hepatology,vol.4:5:978-986,2020,Journal Article,,,"First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,https://orcid.org/0000-0002-3364-828XFirst Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,https://orcid.org/0000-0002-5643-9472First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,https://orcid.org/0000-0002-8106-5716First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Surgery\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.,First Department of Internal Medicine\, Faculty of Medicine University of Yamanashi Yamanashi Japan.",,,,,"colorectal carcinoma,digital PCR,fractionated small cfDNA,liquid biopsy,next‐generation sequencing"
31442328,"Gouillon L,Perier-Muzet M,Amini-Adle M,Poulalhon N,Debarbieux S,Boespflug A,Balme B,Depaepe L,Harou O,Lopez J,Bringuier PP,Ferraro-Peyret C,Maucort-Boulch D,Robinson P,Thomas L,Dalle S",Dermoscopic features in BRAF and NRAS primary cutaneous melanoma: association with peppering and blue-white veil.,,Journal of the European Academy of Dermatology and Venereology : JEADV,vol.34:2:e57-e59,2020,Letter,"|Dermoscopy|methods|,|GTP Phosphohydrolases|genetics|,|Genetic Testing|,|Humans|,|Melanoma|genetics|pathology|,|Membrane Proteins|genetics|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Skin Neoplasms|genetics|pathology|",,"https://orcid.org/0000-0003-0254-2420Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,https://orcid.org/0000-0003-2366-6238Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service d'anatomie Pathologique\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service d'anatomie Pathologique\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service d'anatomie Pathologique\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Biologie et Biologie Moléculaire\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Biologie Moléculaire\, Hôpital Édouard Herriot\, Lyon\, France.,Hospices Civils de Lyon\, Service de Biologie Moléculaire\, Hôpital Édouard Herriot\, Lyon\, France.,Hospices Civils de Lyon\, Service de Statistiques\, Université Lyon 1\, Lyon\, France.,Hospices Civils de Lyon\, Direction de la Recherche Clinique et Innovation\, Lyon\, France.,https://orcid.org/0000-0003-1995-2434Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.,Hospices Civils de Lyon\, Service de Dermatologie\, Centre Hospitalier Lyon Sud\, Pierre-Bénite\, France.","Membrane Proteins,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human",,,,
32866902,"Nilforoushan N,Moatamed NA",Evaluation of MTAP immunohistochemistry loss of expression in ovarian serous borderline tumors as a potential marker for prognosis and progression.,"Serous borderline tumors (SBT) are the most common subtype of ovarian borderline tumors with excellent clinical course. However\, they can recur or progress to low-grade serous carcinoma (LGSC) in a small proportion of the cases. Beside BRAF and KRAS mutations\, copy number alterations (CNA)\, particularly loss of chromosome 9p21 locus which results in deletion of genes CDKN2A and MTAP\, have been suggested to be involved in disease progression. MTAP immunohistochemistry recently has been introduced for mesothelioma as a reliable surrogate marker for the homozygous deletion of chromosome 9p21 locus. Therefore\, in the current study\, we aimed to evaluate the MTAP loss of expression in serous borderline tumors and low-grade serous carcinomas to identify if it can be used as a marker for prognosis and progression.,Eighty-four total cases of ovarian serous lesions\, including 21 cases of serous cystadenomas\, 21 cases of serous borderline tumors\, 12 cases of low-grade serous carcinomas and 30 cases of high-grade serous carcinomas were selected. MTAP immunohistochemistry was performed on the representative blocks and cytoplasmic staining was used for interpretation. The cases were labeled as positive (retained) if MTAP showed cytoplasmic granular staining and negative (loss of expression) if negative cytoplasmic staining was observed in the presence of positive internal control.,Ten of 21 cases of serous borderline tumors showed loss of MTAP expression (48%). Among those\, 7 cases were bilateral\, 2 cases had micropapillary features\, one case had supraclavicular and cervical lymph node involvement by serous borderline tumor and 2 cases had progression to low-grade serous carcinoma\, including one of micropapillary tumors. Also 8 out of 12 cases of LGSCs showed MTAP loss of expression (66%). Only 4 of 30 cases of high-grade serous carcinomas (13%) and none of the serous cystadenoma cases showed loss of expression of MTAP.,To our knowledge\, this is the first description of MTAP immunohistochemistry in serous borderline tumors and low-grade serous carcinomas. Our study was limited due to small sample size. However\, it showed an association between MTAP loss of expression and adverse clinical behavior in ovarian serous borderline tumors. This supports the role for further investigations in larger series to evaluate the role of MTAP stain as a prognostic marker in these neoplasms.",Annals of diagnostic pathology,vol.48::151582,2020,Journal Article,,,"Pathology & Laboratory Medicine\, David Geffen School of Medicine at UCLA\, Los Angeles\, CA\, United States. Electronic address: nilforoushan.neshat@gmail.com.,Pathology & Laboratory Medicine\, David Geffen School of Medicine at UCLA\, Los Angeles\, CA\, United States.",,,,,"CDKN2A,Chromosome 9p21,Low-grade serous carcinoma,MTAP,Serous borderline tumor"
33045146,"Gilani SM,Ross JA,Prasad ML,Hammers L,Cai G,Adeniran AJ",Molecular alterations in Hürthle cell neoplasms of thyroid: A fine needle aspiration cytology study with cytology-histology correlation.,"Hürthle cell features are frequently observed on the fine-needle aspiration (FNA) cytology of thyroid nodules and often pose a diagnostic challenge because of a significant overlap between cytomorphologic features seen in benign and malignant lesions. Molecular alterations (MAs) associated with these lesions are not well described. The objective of the current study was to evaluate the molecular profile of Hürthle cell lesions classified as Hürthle cell neoplasm (HCN) on cytologic evaluation.,The authors retrospectively reviewed their electronic database for cytologic diagnoses of HCN from January 1\, 2017 to March 31\, 2020.,In total\, 279 cases from 275 patients who had a diagnosis of HCN were included in the study. Molecular testing results were available in 85 cases (51 with MAs and 34 without MAs) and\, of those\, 42 had histologic follow-up available. Eight of 10 malignant cases had MAs\, whereas the remaining 2 cases were negative for MAs. The most frequently encountered predominant genetic alterations or classifier findings were chromosome copy number alterations (n = 15)\, followed by NRAS (n = 8)\, KRAS (n = 7)\, suspicious (n = 6)\, EIF1AX (n = 4)\, TSHR (n = 3)\, gene overexpression (n = 3)\, positive microRNA classifier (n = 2)\, and 1 each of BRAF K601E\, TERT\, and HRAS mutations. One hundred thirty-seven cases had histologic follow-up available; of those\, 28 were classified as malignant\, and 109 were classified as benign (neoplastic and nonneoplastic). The overall risk of malignancy associated with HCN was 20%\, and the risk of HCN with MAs was 25%.,The cytologic diagnosis of HCN includes various MAs without any obvious trend\, and most malignant cases (80%) have some type of MA.",Cancer cytopathology,vol.::,2020,Journal Article,,,"https://orcid.org/0000-0001-6185-6062Department of Pathology\, Yale School of Medicine\, New Haven\, Connecticut.,Department of Pathology\, Yale School of Medicine\, New Haven\, Connecticut.,Department of Pathology\, Yale School of Medicine\, New Haven\, Connecticut.,Department of Pathology\, Yale School of Medicine\, New Haven\, Connecticut.,https://orcid.org/0000-0002-8725-5940Department of Pathology\, Yale School of Medicine\, New Haven\, Connecticut.,https://orcid.org/0000-0001-9820-632XDepartment of Pathology\, Yale School of Medicine\, New Haven\, Connecticut.",,,,,"Hürthle cell lesions,Hürthle cell neoplasm,fine-needle aspiration,molecular alterations,thyroid"
33045465,"Mayenga M,Assié JB,Monnet I,Massiani MA,Tabeze L,Friard S,Fraboulet S,Métivier AC,Chouaïd C,Zemoura L,Longchampt E,Callens C,Melaabi S,Couderc LJ,Doubre H",Durable responses to immunotherapy of non-small cell lung cancers harboring MET exon-14-skipping mutation: A series of 6 cases.,"About 2-3% of non-small-cell lung cancers (NSCLCs) harbor MET exon-14-skipping (METex14) mutations. Efficacy of the MET-inhibitor crizotinib has been reported\, but progression-free survival (PFS) was very short. Immune-checkpoint inhibitors (ICIs) have become a cornerstone of NSCLC treatment but appear to be less effective in non-smokers and against tumors exhibiting oncogenic addiction. We describe 6 remarkable (PFS exceeding 18 months) and durable responses to ICIs of NSCLCs harboring a METex14 mutation.,Each patient's clinical and biological characteristics\, and tumor responses after ICIs were examined. Complete tumor-DNA sequencing was available after starting second-line ICIs\, which followed first-line chemotherapy. Tumor-cell programmed cell-death protein-1 ligand-1 (PD-L1) expression on tumor cells was evaluated using antibody clone E1L3N (Cell Signaling Technology).,Among 25 patients with METex14-mutated NSCLCs\, 13 of whom were ICI-treated\, 6 had prolonged responses: 5 women\, 1 man; 57-80 years old; 3 never-smokers\, 1 ex-smoker and 2 smokers; 5 adenocarcinomas\, 1 sarcomatoid carcinoma; 5 received nivolumab\, 1 pembrolizumab. No EGFR\, BRAF or KRAS mutations (only 1 minority KRAS mutation)\, or ALK or ROS translocations were detected. No concurrent MET amplification was observed. Tumor-mutation burden was low (<10 mutations/Mb) in 3 tested tumors. Four partial and 2 complete responses were obtained during the first 3 months for 5 patients\, while pseudoprogression was initially observed in 1. Tolerance was excellent\, with only 1 grade-3 immune-related adverse event. Response was maintained for 18-49 months.,ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.","Lung cancer (Amsterdam, Netherlands)",vol.150::21-25,2020,"Research Support, Non-U.S. Gov't",,,"Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: mmayenga@hotmail.fr.,Department of Pulmonology\, CHI Creteil\, 40\, avenue de Verdun\, 94010\, Creteil\, France. Electronic address: jbaptiste.assie@gmail.com.,Department of Pulmonology\, CHI Creteil\, 40\, avenue de Verdun\, 94010\, Creteil\, France. Electronic address: isabelle.monnet@chicreteil.fr.,Department of Medical Oncology\, Hôpital René-Huguenin-Institut Curie\, 35\, rue Dailly\, 92210\, Saint-Cloud\, France. Electronic address: marieange.massiani@curie.fr.,Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: laure.tabeze@aphp.fr.,Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: s.friard@hopital-foch.org.,Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: s.fraboulet@hopital-foch.org.,Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: ac.metivier@hopital-foch.org.,Department of Pulmonology\, CHI Creteil\, 40\, avenue de Verdun\, 94010\, Creteil\, France. Electronic address: christos.chouaid@chicreteil.fr.,Department of Anatomical Pathology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: l.zemoura@hopital-foch.org.,Department of Anatomical Pathology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: e.longchampt@hopital-foch.org.,Department of Genetics\, Institut Curie\, 26\, rue d'Ulm\, 75005\, Paris\, France. Electronic address: eline.callens@curie.fr.,Department of Genetics\, Institut Curie\, 26\, rue d'Ulm\, 75005\, Paris\, France. Electronic address: samia.melaabi@curie.fr.,Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: lj.couderc@hopital-foch.org.,Department of Pulmonology\, Hôpital Foch\, 40\, rue Worth\, 92151\, Suresnes\, France. Electronic address: h.doubre@hopital-foch.org.",,,,,"Immune checkpoint,Immunotherapy,MET exon-14–skipping mutation,Non-small–cell lung cancer,PD-L1"
33046021,"Catic A,Kurtovic-Kozaric A,Sophian A,Mazur L,Skenderi F,Hes O,Rohan S,Rakheja D,Kogan J,Pins MR",KANK1-NTRK3 fusions define a subset of BRAF mutation negative renal metanephric adenomas.,"Metanephric adenoma (MA) is a rare benign renal neoplasm. On occasion\, MA can be difficult to differentiate from renal malignancies such as papillary renal cell carcinoma in adults and Wilms̕ tumor in children. Despite recent advancements in tumor genomics\, there is limited data available regarding the genetic alterations characteristic of MA. The purpose of this study is to determine the frequency of metanephric adenoma cases exhibiting cytogenetic aberration t (9;15)(p24;q24)\, and to investigate the association between t (9\,15) and BRAF mutation in metanephric adenoma.,This study was conducted on 28 archival formalin fixed paraffin-embedded (FFPE) specimens from patients with pathologically confirmed MA. Tissue blocks were selected for BRAF sequencing and fluorescent in situ hybridization (FISH) analysis for chromosomal rearrangement between KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3)\, which was previously characterized and described in two MA cases.,BRAFV600E mutation was identified in 62% of our cases\, 9 (38%) cases were BRAFWT\, and 4 cases were uninformative. Of the 20 tumors with FISH results\, two (10%) were positive for KANK1-NTRK3 fusion. Both cases were BRAFWT suggesting mutual exclusivity of BRAFV600E and KANK1-NTRK3 fusion\, the first such observation in the literature.,Our data shows that BRAF mutation in MA may not be as frequent as suggested in the literature and KANK-NTRK3 fusions may account for a subset of BRAFWT cases in younger patients. FISH analysis for KANK1-NTRK3 fusion or conventional cytogenetic analysis may be warranted to establish the diagnosis of MA in morphologically and immunohistochemically ambiguous MA cases lacking BRAF mutations.",BMC medical genetics,vol.21:1:202,2020,Journal Article,"|Adaptor Proteins\, Signal Transducing|genetics|,|Adenoma|genetics|pathology|,|Adolescent|,|Adult|,|Aged|,|Child|,|Chromosomes\, Human\, Pair 15|genetics|,|Chromosomes\, Human\, Pair 9|genetics|,|Cytoskeletal Proteins|genetics|,|Female|,|Humans|,|In Situ Hybridization\, Fluorescence|,|Kidney Neoplasms|genetics|pathology|,|Male|,|Middle Aged|,|Mutation|,|Oncogene Proteins\, Fusion|genetics|,|Proto-Oncogene Proteins B-raf|genetics|,|Receptor\, trkC|genetics|,|Translocation\, Genetic|,|Young Adult|",,"0000-0002-7009-6947Department of Cytogenetics\, ACL Laboratories\, Rosemont\, IL\, USA. aida.catic.00@gmail.com.,Department of Genetics and Bioengineering\, International Burch University\, Francuske revolucije bb\, Ilidza\, 71000\, Sarajevo\, Bosnia and Herzegovina.,Department of Cytogenetics\, ACL Laboratories\, Rosemont\, IL\, USA.,Department of Cytogenetics\, ACL Laboratories\, Rosemont\, IL\, USA.,Department of Clinical Pathology\, Cytology and Human Genetics\, Clinical Center of the University of Sarajevo\, Sarajevo\, Bosnia and Herzegovina.,Department of Pathology\, Charles University Hospital Pilsen\, Pilsen\, Czech Republic.,Department of Pathology\, Saint Joseph Hospital\, Denver\, CO\, USA.,Department of Pathology and Pediatrics\, University of Texas Southwestern Medical Center\, Dallas\, TX\, USA.,Department of Cytogenetics\, ACL Laboratories\, Rosemont\, IL\, USA.,Department of Pathology\, Advocate Lutheran General Hospital\, Park Ridge\, IL\, USA.","Adaptor Proteins\, Signal Transducing,Cytoskeletal Proteins,KANK1 protein\, human,NTRK3 protein\, human,Oncogene Proteins\, Fusion,Receptor\, trkC,Proto-Oncogene Proteins B-raf",,,,"BRAFV600E,Chromosomal translocations,Cytogenetics,KANK1-NTRK3 fusion,Metanephric adenoma"
33046979,"Zhu Z,Wang D,Shen Y",Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma.,"Aim: Malignant melanoma (MM) is a highly aggressive cutaneous cancer with undetermined underlying genetic disposition. We aim to evaluate prognostic and mechanistic role of ACSM3 in MM. Methods: In silico reproduction of TCGA MM dataset, GEO dataset, GDSC dataset and human protein atlas was performed to establish differential expression of ACSM3. In vitro and in vivo validation using A375 and SKMEL1 MM cells were performed to profile tumorigenic role and functional attribution of the gene. Results: ACSM3 expression was significantly downregulated in MM. Lower expression of ACSM3 conferred worsened prognosis of MM. Lower ACSM3 was observed in Asian ethnicity. Knock-down (KD) and overexpression (OE) of ACSM3 resulted in significant increased and decreased proliferation, invasion and colony formation in MM cells, respectively. Pathway annotation revealed significantly active immune response invoked by ACSM3. Lower ACSM3 expression was associated with decreased CD8+, macrophage and dendritic cell infiltration. Cox regression revealed loss of survival contribution of ACSM3 in the presence of immune infiltrates supporting immune regulatory role of ACSM3. Drug sensitivity analysis revealed BRAF inhibitor PLX-4720 was sensitive in both MM cells. ACSM3 expression showed no correlation with immune checkpoint molecules. Combined ACSM3-OE and PLX-4720 in MM cells showed synergistic inhibition in MM cells and xenograft murine models with no significant toxicity. Conclusion: Loss of ACSM3 was associated with poor prognosis in MM. Overexpression of ACSM3 synergistically inhibited MM with PLX-4720. ACSM3 was potentially associated with immune exclusion in MM. Further validation was warranted in future studies.",Journal of Cancer,vol.11:22:6582-6590,2020,Journal Article,,,"Department of Cardiology\, Huashan Hospital\, Fudan University\, PR\, China.,Department of Dermatology\, Huashan Hospital\, Fudan University\, PR\, China.,Department of Dermatology\, Huashan Hospital\, Fudan University\, PR\, China.",,,,,"ACSM3,Cancer immunity,Malignant melanoma"
32739910,"Champaneri H,Banerjee AD",Pediatric Langerhans Cell Histiocytosis with BRAF Mutation Affecting Sacral Vertebra: A Case Report and Disease Review.,"Histiocytoses are rare diseases affecting mainly children and can occur in any organ of the body. They are divided into Langerhans type and non-Langerhans type. Langerhans cell histiocytosis (LCH) mainly affects skin\, bones\, and lymph nodes but can also affect the hematopoietic system. Bone lesions can be critical when they involve skull base\, orbit\, or vertebrae and can cause permanent neurological sequelae or death. Histopathological diagnosis and molecular markers are the mainstay for accurate diagnosis. Sixty percent of LCH cases show mutation in the BRAF oncogene. They are treated with multimodality treatment which includes surgery\, chemotherapy\, and BRAF inhibitor therapy. Owing to the rarity of the disease and paucity of cases\, the understanding and standardization of treatment is still evolving.,A 14-year-old boy presented with backache\, and his imaging showed erosion of first sacral vertebral body with soft tissue component impinging and compressing the spinal canal. Histopathology and molecular diagnosis showed LCH which was positive for BRAF gene mutation. Adequate canal decompression and near-total removal of the disease load with fixation of weight-bearing axis resulted in symptomatic relief and good outcome. Systemic chemotherapy was given for the small residual disease due to fear of recurrence and impending neurological complications. He responded well to first-line therapy with vinblastine and prednisolone with complete resolution of disease on a follow-up scan.,Accurate diagnosis with molecular markers is essential for a good outcome of LCH. Treatment of lesions at critical locations like skull base\, orbit\, or vertebral axis needs to be tailored to prevent permanent neurological deficits. Newer therapies in the form of BRAF inhibitors are on the way\, but the efficacy and benefit need to be tested.",Pediatric neurosurgery,vol.55:3:169-174,2020,Case Reports,,,"Department of Neurosurgery\, Institute of Neurosciences\, Medanta-the Medicity\, Gurugram\, India.,Department of Neurosurgery\, Institute of Neurosciences\, Medanta-the Medicity\, Gurugram\, India\, banerjeeanirbandeep391@gmail.com.",,,,,"BRAF gene mutation,Langerhans cell histiocytosis,Sacral stenosis"
33069191,"Morelli C,Formica V,Riondino S,Russo A,Ferroni P,Guadagni F,Roselli M",Irinotecan or Oxaliplatin: Which is the First Move for the Mate?,"The aim of the present review is to discuss the potential link between RAS\, BRAF and microsatellite instability (MSI) mutational patterns and chemotherapeutic agent efficacy [Irinotecan (IRI) vs. Oxaliplatin (OXA)]\, and how this can potentially influence the choice of the chemotherapy backbone.,Following a review of the research literature\, all pertinent articles published in the core journals were selected for study. The inclusion criteria regarded relevant clinical and pre-clinical studies on the topic of interest (Relationship of OXA and IRI to KRAS/BRAF mutations and MSI).,Excision repair cross complementation group 1 (ERCC1) expression is inhibited by KRAS mutation\, making tumor cells more sensitive to OXA. Results from OPUS\, COIN and PRIME trials support that. No conclusive data are available for BRAF mutant population because of the small number of patients. Enhanced IRI cytotoxicity to MSI cell lines is due to the participation of some of the mismatch repair (MMR) components into various DNA repair processes and their role in maintenance of the pro-apoptotic effect of IRI and G2/M cell arrest.,OXA and IRI are indispensable drugs for mCRC treatment and their selection must be as careful as that of targeted agents. We suggest to take into consideration the interaction between known genomic alterations and OXA and IRI activity to personalize chemotherapy in mCRC patients.",Current medicinal chemistry,vol.::,2020,Journal Article,,,"Department of Systems Medicine\, Medical Oncology Unit\, Tor Vergata Clinical Center\, Tor Vergata University of Rome\, Viale Oxford 81\, 00133\, Rome. Italy.,Department of Systems Medicine\, Medical Oncology Unit\, Tor Vergata Clinical Center\, Tor Vergata University of Rome\, Viale Oxford 81\, 00133\, Rome. Italy.,Department of Systems Medicine\, Medical Oncology Unit\, Tor Vergata Clinical Center\, Tor Vergata University of Rome\, Viale Oxford 81\, 00133\, Rome. Italy.,Department of Surgical\, Oncological and Stomatological Sciences\, University of Palermo\, Via del Vespro 129\, 90127\, Palermo. Italy.,BioBIM (InterInstitutional Multidisciplinary Biobank)\, IRCCS San Raffaele Pisana\, Via di Val Cannuta 247\, 00166\, Rome. Italy.,BioBIM (InterInstitutional Multidisciplinary Biobank)\, IRCCS San Raffaele Pisana\, Via di Val Cannuta 247\, 00166\, Rome. Italy.,Department of Systems Medicine\, Medical Oncology Unit\, Tor Vergata Clinical Center\, Tor Vergata University of Rome\, Viale Oxford 81\, 00133\, Rome. Italy.",,,,,"BRAF,Chemotherapy,Colorectal cancer,Irinotecan,KRAS,MSI,Molecular targets,Oxaliplatin"
33072607,"Kang K,Xie F,Mao J,Bai Y,Wang X",Significance of Tumor Mutation Burden in Immune Infiltration and Prognosis in Cutaneous Melanoma.,"Background: Melanoma is highly immunogenic and therefore suitable for immunotherapy, but the efficacy is limited by response rate. In several types of tumor, tumor mutation burden (TMB) and immune infiltration have been reported to predict the response to immunotherapy, although each has its limitations. In the current study, we aimed to explore the association of TMB with immune infiltration and prognosis in cutaneous melanoma. Methods: The data of cutaneous melanoma used for analyses was downloaded from The Cancer Genome Atlas (TCGA) database. The mutation data was sorted using ""maftools"" R package. TMB was estimated and then patients were divided into two groups based on TMB. The association of TMB with prognosis and clinical characteristics was explored. Differential analysis between two TMB groups was performed using ""DESeq2"" R package to identify differentially expressed genes (DEGs). The function enrichment analyses of DEGs were conducted to screen critical pathways. Besides, DEGs were further filtered to identify two hub genes, based on which a risk score model and nomogram for predicting prognosis were conducted, and the validation was performed using three datasets from Gene Expression Omnibus (GEO) database. Finally, CIBERSORT algorithm and TIMER database were used to assess the effect of TMB and hub genes on immune infiltration. Results: The most common mutation was C > T, and the top three frequently mutated genes were TTN, MUC16, and BRAF. Higher TMB indicated better survival outcomes and lower pathological stages. 735 DEGs were identified and mainly involved in immune-related and adhesion-related pathways. The risk score model and nomogram were validated using receiver operating characteristic (ROC) curves and calibration curves, and exhibited relatively high predictive capability. Decision curve analysis (DCA) was used to assess clinical benefit. As for immune infiltration, the proportion was higher for macrophages M1 and M2 in the high-TMB group, while lower for memory B cells and regulatory T cells. Conclusions: In cutaneous melanoma, TMB was positively correlated with prognosis. The risk score model and nomogram can be conveniently used to predict prognosis. The association of TMB with immune infiltration can help improve the predicting methods for the response to immunotherapy.",Frontiers in oncology,vol.10::573141,2020,Journal Article,,,"Department of Medical Oncology\, Peking Union Medical College Hospital\, Chinese Academy of Medical Sciences\, Beijing\, China.,Department of Medical Oncology\, Peking Union Medical College Hospital\, Chinese Academy of Medical Sciences\, Beijing\, China.,Department of Medical Oncology\, Peking Union Medical College Hospital\, Chinese Academy of Medical Sciences\, Beijing\, China.,Department of Liver Surgery\, Peking Union Medical College Hospital\, Chinese Academy of Medical Sciences\, Beijing\, China.,Department of Medical Oncology\, Peking Union Medical College Hospital\, Chinese Academy of Medical Sciences\, Beijing\, China.",,,,,"bioinformatics analysis,cutaneous melanoma,functional enrichment analysis,gene expression profile,immune infiltration,prognosis,tumor mutation burden"
33073191,"Zhou Y,Mowlazadeh Haghighi S,Liu Z,Wang L,Hruby VJ,Cai M",Development of Ligand-Drug Conjugates Targeting Melanoma through the Overexpressed Melanocortin 1 Receptor.,"Melanoma is a lethal form of skin cancer. Despite recent breakthroughs of BRAF-V600E and PD-1 inhibitors showing remarkable clinical responses, melanoma can eventually survive these targeted therapies and become resistant. To solve the drug resistance issue, we designed and synthesized ligand-drug conjugates that couple cytotoxic drugs, which have a low cancer resistance issue, with the melanocortin 1 receptor (MC1R) agonist melanotan-II (MT-II), which provides specificity to MC1R-overexpressing melanoma. The drug-MT-II conjugates maintain strong binding interactions to MC1R and induce selective drug delivery to A375 melanoma cells through its MT-II moiety in vitro. Furthermore, using camptothecin as the cytotoxic drug, camptothecin-MT-II (compound 1) can effectively inhibit A375 melanoma cell growth with an IC50 of 16 nM. By providing selectivity to melanoma cells through its MT-II moiety, this approach of drug-MT-II conjugates enables us to have many more options for cytotoxic drug selection, which can be the key to solving the cancer resistant problem for melanoma.",ACS pharmacology & translational science,vol.3:5:921-930,2020,Journal Article,,,"Department of Chemistry and Biochemistry\, The University of Arizona\, Tucson\, Arizona 85721\, United States.,Department of Chemistry and Biochemistry\, The University of Arizona\, Tucson\, Arizona 85721\, United States.,Department of Chemistry and Biochemistry\, The University of Arizona\, Tucson\, Arizona 85721\, United States.,Department of Chemistry and Biochemistry\, The University of Arizona\, Tucson\, Arizona 85721\, United States.,Department of Chemistry and Biochemistry\, The University of Arizona\, Tucson\, Arizona 85721\, United States.,Department of Chemistry and Biochemistry\, The University of Arizona\, Tucson\, Arizona 85721\, United States.",,"NIDDK NIH HHS,NIGMS NIH HHS","United States,United States","R01 DK017420,R01 GM108040",
33176823,"Niu Z,Li Y,Chen W,Zhao J,Zheng H,Deng Q,Zha Z,Zhu H,Sun Q,Su L",Study on clinical and biological characteristics of ameloblastic carcinoma.,"Ameloblastic carcinoma (AC) is an odontogenic malignant tumor which is closely related to benign ameloblastoma. Because of its rarity\, diagnosis and treatment are difficult. In this study\, we summarized and analyzed the clinical and biological characteristics of AC.,Fifteen patients with AC and a median age of 53 years were identified. Among of them\, five patients who were tested carried a BRAF-V600E mutation. Two patients presented with cervical lymph nodes and lung metastases. Primary AC was more invasive\, and the bone destruction ability of the primary type was more radical than that of the secondary type.,This study revealed that the BRAF-V600E mutation was related to the aggressive behavior of AC\, and early radical resection is crucial. Moreover\, targeted therapy may be a new direction in the future.",Orphanet journal of rare diseases,vol.15:1:316,2020,"Research Support, Non-U.S. Gov't",,,"Department of Stomatology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, 450052\, Henan Province\, China.,Department of Pathology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, 450052\, Henan Province\, China.,Department of Oral and Maxillofacial-Head and Neck Oncology\, Ninth People's Hospital\, Shanghai Jiao Tong University School of Medicine\, 639 Zhizaoju Road\, Shanghai\, 200011\, China.,Department of Stomatology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, 450052\, Henan Province\, China.,Department of Stomatology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, 450052\, Henan Province\, China.,Department of Pathology\, The First Affiliated Hospital of Henan University of Science and Technology\, No. 24 Jinghua Road\, Jianxi District\, Luoyang City\, 471003\, Henan Province\, China.,Department of Stomatology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, 450052\, Henan Province\, China.,Academy of Medical Sciences\, Zhengzhou University\, No. 100 Science Avenue\, Zhengzhou\, 450000\, Henan Province\, China.,0000-0002-8624-2750Department of Stomatology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, 450052\, Henan Province\, China. laoniu6495@163.com.,Department of Radiology\, The First Affiliated Hospital of Zhengzhou University\, No. 1\, East Jian she Road\, Zhengzhou\, Henan Province\, China. 85244275@qq.com.",,,,,"Ameloblastic carcinoma,Ameloblastoma,BRAF gene,Targeted therapy"
33049752,"Vershinina T,Fomicheva Y,Muravyev A,Jorholt J,Kozyreva A,Kiselev A,Gordeev M,Vasichkina E,Segrushichev A,Pervunina T,Sjoberg G,Skyttner-Rahmani S,Sejersen T,Kostareva A",Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients.,"Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However\, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. Patient Group and Methods: Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic\, likely pathogenic\, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis.,The median age at presentation was 8.0 (0.1-17) years\, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%)\, often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants\, the positive genotyping rate was 45%\, and these variants were found mainly in non-contractile structural sarcomeric genes (ACTN2\, MYPN\, and TTN) or in metabolic and signal transduction genes (BRAF and TAZ). Likely pathogenic TAZ variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins\, but variants of unknown significance were detected in 3 out of 20 patients (MYH6\, MYH7\, and MYLK2). In 4 patients\, variants of unknown significance in ion-channel genes were detected.,We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years\, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.",Cardiology,vol.145:11:746-756,2020,"Research Support, Non-U.S. Gov't",,,"Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Department of Women's and Children's Health and Center for Molecular Medicine\, Karolinska Institute\, Stockholm\, Sweden.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,ITMO University\, Saint Petersburg\, Russian Federation.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation.,Department of Women's and Children's Health and Center for Molecular Medicine\, Karolinska Institute\, Stockholm\, Sweden.,Department of Women's and Children's Health and Center for Molecular Medicine\, Karolinska Institute\, Stockholm\, Sweden.,Department of Women's and Children's Health and Center for Molecular Medicine\, Karolinska Institute\, Stockholm\, Sweden.,Almazov National Medical Research Centre\, Saint Petersburg\, Russian Federation\, Anna.Kostareva@ki.se.",,,,,"Left ventricular non-compaction,Paediatric patients,Sarcomeric genes"
33050344,"Nestarenkaite A,Fadhil W,Rasmusson A,Susanti S,Hadjimichael E,Laurinaviciene A,Ilyas M,Laurinavicius A",Immuno-Interface Score to Predict Outcome in Colorectal Cancer Independent of Microsatellite Instability Status.,"Tumor-associated immune cells have been shown to predict patient outcome in colorectal (CRC) and other cancers. Spatial digital image analysis-based cell quantification increases the informative power delivered by tumor microenvironment features and leads to new prognostic scoring systems. In this study we evaluated the intratumoral density of immunohistochemically stained CD8, CD20 and CD68 cells in 87 cases of CRC (48 were microsatellite stable, MSS, and 39 had microsatellite instability, MSI) in both the intratumoral tumor tissue and within the tumor-stroma interface zone (IZ) which was extracted by a previously developed unbiased hexagonal grid analytics method. Indicators of immune-cell gradients across the extracted IZ were computed and explored along with absolute cell densities, clinicopathological and molecular data, including gene mutation (BRAF, KRAS, PIK3CA) and MSI status. Multiple regression modeling identified (p < 0.0001) three independent prognostic factors: CD8+ and CD20+ Immunogradient indicators, that reflect cell migration towards the tumor, were associated with improved patient survival, while the infiltrative tumor growth pattern was linked to worse patient outcome. These features were combined into CD8-CD20 Immunogradient and immuno-interface scores which outperformed both tumor-node-metastasis (TNM) staging and molecular characteristics, and importantly, revealed high prognostic value both in MSS and MSI CRCs.",Cancers,vol.12:10:,2020,Journal Article,,,"0000-0001-8285-5114National Center of Pathology\, Affiliate of Vilnius University Hospital Santaros Klinikos\, 08406 Vilnius\, Lithuania.,Molecular Pathology Group\, Unit of Academic Molecular Pathology\, Division of Cancer and Stem Cell\, School of Medicine\, Queen's Medical Centre\, University of Nottingham\, Nottingham NG7 2UH\, UK.,0000-0001-6705-6795National Center of Pathology\, Affiliate of Vilnius University Hospital Santaros Klinikos\, 08406 Vilnius\, Lithuania.,Molecular Pathology Group\, Unit of Academic Molecular Pathology\, Division of Cancer and Stem Cell\, School of Medicine\, Queen's Medical Centre\, University of Nottingham\, Nottingham NG7 2UH\, UK.,Molecular Pathology Group\, Unit of Academic Molecular Pathology\, Division of Cancer and Stem Cell\, School of Medicine\, Queen's Medical Centre\, University of Nottingham\, Nottingham NG7 2UH\, UK.,National Center of Pathology\, Affiliate of Vilnius University Hospital Santaros Klinikos\, 08406 Vilnius\, Lithuania.,Molecular Pathology Group\, Unit of Academic Molecular Pathology\, Division of Cancer and Stem Cell\, School of Medicine\, Queen's Medical Centre\, University of Nottingham\, Nottingham NG7 2UH\, UK.,National Center of Pathology\, Affiliate of Vilnius University Hospital Santaros Klinikos\, 08406 Vilnius\, Lithuania.",,,,,"CD20,CD8,Immunogradient,colorectal cancer,immuno-interface score,tumor growth pattern,tumor infiltrating lymphocytes,tumor microenvironment"
33052075,"Kim KO,Park WJ,Jung Y,Lee WS",Chemotherapeutic effects of MEK kinase inhibitor and BRAF kinase inhibitor on mutated human colon cancer cell lines with different microsatellite instability.,"We analyzed responsiveness of KRAS-mutated CRC cell lines with distinctive MSI status against mitogen-activated protein kinase (MEK) inhibitor (selumetinib; AZD) and/or B-raf proto-oncogene (BRAF) kinase inhibitor (vemurafenib; PLX). The viability of MSI-high (MSI-H) KRAS-mutated LS174T cells treated with AZD or PLX was 24.5 ± 0.9% or 71.4 ± 3.6%, respectively, and the viability of microsatellite stable (MSS) KRAS-mutated SW480 cells for AZD or PLX was 57.4 ± 3.1% or 43.1 ± 1.8%, respectively. These observations imply that the therapeutic efficacy of MEK kinase inhibitors or BRAF kinase inhibitors against KRAS-mutated colon cancer cells may differ between MSI-H and MSS. However, a combination of both inhibitors synergistically inhibits the proliferation of KRAS-mutated colon cancer cells regardless of MSI status. The underlying synergistic cytotoxic efficacy of AZD/PLX combination on KRAS-mutated colon cancer cells with different MSI status was further substantiated by markedly decreased phosphorylation of ERK in both LS74T and SW480 cell lines upon AZD and PLX treatment. Based on these collective data, we propose that MSI status should be considered when MEK kinase inhibitor or BRAF kinase inhibitor is treated for KRAS-mutated colon cancer, and that combination of both inhibitors synergistically inhibit proliferation of KRAS-mutated colon cancer cells independent of MSI status.","Journal of chemotherapy (Florence, Italy)",vol.32:8:437-444,2020,Journal Article,,,"Gachon Medical Research Institute\, Gil Medical Center\, Gachon University\, Incheon\, Korea.,Department of Biochemistry\, College of Medicine\, Gachon University\, Incheon\, Korea.,Gachon Advanced Institute for Health Science & Technology\, Gachon University\, Incheon\, Korea.,Department of Surgery and Peritoneal Surface Malignancy Clinic\, Gil Medical Center\, College of Medicine\, Gachon University\, Incheon\, Korea.",,,,," KRAS-mutation,BRAF kinase inhibitor,Colorectal cancer,MEK kinase inhibitor,chemotherapy,microsatellite instability"
33053439,"Lamberti G,Andrini E,Sisi M,Rizzo A,Parisi C,Di Federico A,Gelsomino F,Ardizzoni A","Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma.","Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs.",Critical reviews in oncology/hematology,vol.156::103119,2020,Review,"|Adenocarcinoma of Lung|drug therapy|genetics|,|Anaplastic Lymphoma Kinase|,|ErbB Receptors|genetics|,|Humans|,|Lung Neoplasms|drug therapy|genetics|,|Mutation|,|Protein-Tyrosine Kinases|,|Proto-Oncogene Proteins|genetics|,|Receptor Protein-Tyrosine Kinases|genetics|",,"Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy.,Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy.,Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy.,Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy.,Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy.,Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy.,Oncologia Medica\, Azienda Ospedaliero-Universitaria di Bologna\, Via Albertoni - 15\, Bologna\, Italy. Electronic address: francesco_gelsomino@aosp.bo.it.,Department of Specialized\, Experimental and Diagnostic Medicine\, S.Orsola-Malpighi Hospital\, University of Bologna\, Bologna\, Italy; Oncologia Medica\, Azienda Ospedaliero-Universitaria di Bologna\, Via Albertoni - 15\, Bologna\, Italy.","Proto-Oncogene Proteins,ALK protein\, human,Anaplastic Lymphoma Kinase,EGFR protein\, human,ErbB Receptors,Protein-Tyrosine Kinases,ROS1 protein\, human,Receptor Protein-Tyrosine Kinases",,,,"BRAF,HER2,KRAS,MET,NTRK,Next-generation sequencing,Non-small cell lung cancer,RET"
33054840,"Lee HK,Kwon MJ,Ra YJ,Lee HS,Kim HS,Nam ES,Cho SJ,Park HR,Min SK,Seo J,Choe JY,Min KW,Kang SY","Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma.","Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. Programmed death-ligand 1 (PD-L1)\, which is essential for immune evasion\, is involved in the pathogenesis of ESCC and thus is a potential therapeutic target. PIK3CA\, KRAS\, and BRAF mutations\, microsatellite instability (MSI) caused by deficient mismatch repair (dMMR)\, and human papillomavirus (HPV) can potentially upregulate PD-L1 expression\, which might contribute to the clinical outcome of patients with ESCC.,We investigated the significance of the present druggable markers [PD-L1\, PIK3CA\, KRAS\, and BRAF mutations\, MSI caused by deficient dMMR\, and HPV] in 64 curatively resected ESCCs\, using immunohistochemistry (PD-L1 and MMR protein expression)\, direct sequencing (KRAS\, BRAF\, and PIK3CA mutations)\, real-time PCR (HPV infection)\, and MSI using quasi-monomorphic markers.,PD-L1 expression\, PIK3CA mutation\, and MSI/dMMR were detected in 35.9\, 12.5\, and 17.2% of ESCCs\, respectively. HPV was rarely detected (1.6%) (high-risk HPV68)\, whereas KRAS and BRAF mutations were not detected in ESCCs. PD-L1-positive tumors were not correlated with PIK3CA mutation or MSI/dMMR (all P > 0.05). PD-L1\, PIK3CA mutation\, and MSI/dMMR characterized the patients associated with light smoking\, female and younger age\, and younger age and well-differentiated tumors\, respectively (all P < 0.05). In multivariate analysis\, only PD-L1-positivity was an independent favorable prognostic factor for overall survival (OS) and disease-free survival (DFS) (P = 0.023\, P = 0.014). In the PD-L1-negative ESCCs\, PIK3CA mutation had a poor prognostic impact on both OS and DFS (P = 0.006\, P = 0.002).,PIK3CA mutation may be an alternative prognostic biomarker in PD-L1-negative curatively resected ESCCs that can be optional to identify high-risk patients with worse clinical outcome who require more intensive therapy and follow-up.",Diagnostic pathology,vol.15:1:126,2020,Journal Article,,,"Department of Thoracic and Cardiovascular Surgery\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Anyang\, Republic of Korea.,http://orcid.org/0000-0002-2441-0448Department of Pathology\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Gwanpyeong-ro 170 beon-gil 22\, Dongan-gu\, Anyang-si\, Gyeonggi-do\, 14068\, Republic of Korea. mulank@hanmail.net.,Department of Thoracic and Cardiovascular Surgery\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Anyang\, Republic of Korea.,Department of Thoracic and Cardiovascular Surgery\, Hallym University Dongtan Sacred Heart Hospital\, Hallym University Medical Center\, Hwaseong-si\, Gyeonggi-do\, Republic of Korea.,Department of Thoracic and Cardiovascular Surgery\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Anyang\, Republic of Korea.,Department of Pathology\, Kangdong Sacred Heart Hospital\, Hallym University College of Medicine\, Chuncheon\, Republic of Korea.,Department of Pathology\, Kangdong Sacred Heart Hospital\, Hallym University College of Medicine\, Chuncheon\, Republic of Korea.,Department of Pathology\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Gwanpyeong-ro 170 beon-gil 22\, Dongan-gu\, Anyang-si\, Gyeonggi-do\, 14068\, Republic of Korea.,Department of Pathology\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Gwanpyeong-ro 170 beon-gil 22\, Dongan-gu\, Anyang-si\, Gyeonggi-do\, 14068\, Republic of Korea.,Department of Pathology\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Gwanpyeong-ro 170 beon-gil 22\, Dongan-gu\, Anyang-si\, Gyeonggi-do\, 14068\, Republic of Korea.,Department of Pathology\, Hallym University Sacred Heart Hospital\, Hallym University College of Medicine\, Gwanpyeong-ro 170 beon-gil 22\, Dongan-gu\, Anyang-si\, Gyeonggi-do\, 14068\, Republic of Korea.,Department of Pathology\, Hanyang University Guri Hospital\, Hanyang University College of Medicine\, Seoul\, Republic of Korea.,Department of Pathology\, Samsung Medical Center\, Sungkyunkwan University College of Medicine\, Seoul\, Republic of Korea.",,"Hallym University,Ministry of Education",",","HURF-2018-51,No. NRF-2019R1C1C100446312","Esophagus,Human papillomavirus,Microsatellite instability,PIK3CA,Programmed death-ligand 1,Squamous cell carcinoma"
33058026,"Oishi N,Vuong HG,Mochizuki K,Kondo T",Loss of 5-Hydroxymethylcytosine is an Epigenetic Hallmark of Thyroid Carcinomas with TERT Promoter Mutations.,"Epigenetic dysregulation is a hallmark of cancer, and aberrant methylation of cytosine residues plays a crucial role in abnormal gene expression in cancer cells. Recent studies demonstrate that 5-hydroxymethylcytosine (5-hmC) generated through 5-methylcytosine (5-mC) oxidation is significantly depleted in various cancers. However, whether 5-hmC levels change during the stepwise progression of thyroid carcinoma and the mechanisms underlying this effect remain unknown. The aims of this study were (i) to assess 5-hmC levels in normal and cancerous thyroid tissues, and (ii) identify clinicopathologic and genetic factors associated with the dysregulated hydroxymethylation of cytosine. Enzyme-linked immunosorbent assay (ELISA) showed that 5-hmC was significantly reduced in TERT promoter-mutated papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs), while there was no significant difference in 5-hmC levels between TERT promoter-wild-type PTCs and normal thyroid tissues. Results of semi-quantitative analysis of 5-hmC through immunohistochemistry correlated well with those of ELISA and confirmed the loss of 5-hmC in tumor cells. Immunohistochemistry confirmed lower 5-hmC positivity in TERT promoter-mutated PTCs (n = 10) and ATCs (n = 4) than in normal thyroid tissues (n = 8) and TERT promoter-wild-type PTCs (n = 63). Tumor size (> 1 cm) and advanced stage were associated with decreased global 5-hmC in PTCs, while age, gross extrathyroidal invasion, node metastasis, and BRAF mutation were not. Collectively, these findings demonstrated that loss of 5-hmC is an epigenetic hallmark of thyroid carcinomas with TERT promoter mutation, indicating that TERT promoter-mutated thyroid carcinoma has a distinct molecular profile.",Endocrine pathology,vol.31:4:359-366,2020,Journal Article,,,"Faculty of Medicine\, Department of Pathology\, University of Yamanashi\, 1110 Shimokato\, 409-3898\, Chuo\, Yamanashi\, Japan. nohishi@yamanashi.ac.jp.,Faculty of Medicine\, Department of Pathology\, University of Yamanashi\, 1110 Shimokato\, 409-3898\, Chuo\, Yamanashi\, Japan.,Faculty of Medicine\, Department of Pathology\, University of Yamanashi\, 1110 Shimokato\, 409-3898\, Chuo\, Yamanashi\, Japan.,Faculty of Medicine\, Department of Pathology\, University of Yamanashi\, 1110 Shimokato\, 409-3898\, Chuo\, Yamanashi\, Japan.",,Japan Society for the Promotion of Science (JP),,19K07412,"5-Hydroxymethylcytosine,BRAF V600E,Epigenetics,Immunohistochemistry,TERT promoter mutation,Thyroid cancer"
33061436,"Wei W,Li X,Song M,Wang C",Molecular Analysis of Oncogenic Mutations in Resected Margins by Next-Generation Sequencing Predicts Relapse in Non-Small Cell Lung Cancer Patients.,"To investigate the genetic mutations in both tumor and marginal tissues in patients with non-small cell lung cancer (NSCLC)\, and to evaluate the potential prognostic value in patients with margins gene positive.,Next-generation sequencing (NGS) technique was used to detect genetic mutation in tumor and marginal tissues of the bronchus in 88 patients with NSCLC. Correlation of genetic mutations with pathology\, lymph node metastasis\, disease-free survival and overall survival was analyzed.,Of the 88 patients\, 83 cases (94.3%) had gene mutations in the tumor samples and 12 cases (13.6%) had genetic alterations in their margins. Most of the gene mutations detected were cancer drivers. Six common driver genes between tumor and marginal tissues were identified\, including EGFR\, TP53\, CDKN2A\, CTNNB1\, BRAF\, and NF1. Kaplan-Meier analysis revealed that the median disease-free survival (DFS) was significantly shorter in patients with detectable gene mutations in marginal tissues compared with patients without mutations in margins (30.7 versus 24.4 months\, log-rank χ 2 = 4.78\, P =0.029). Consistently\, a shorter median OS was observed in patients harboring gene mutations in margins compared with patients with no mutations in margins (49.1 versus 32.2 months\, log-rank χ 2 = 3.669\, P =0.055).,These findings identify the presence of oncogenic alterations in microscopically negative margins in NSCLC patients associated with elevated risk of relapse and shorter survival time. Thus\, examination of microscopically negative margins by NGS represents a valuable approach to predict the clinical outcome of NSCLC patients.",OncoTargets and therapy,vol.13::9525-9531,2020,Journal Article,,,"Institute of Cancer and Basic Medicine (ICBM)\, Chinese Academy of Sciences\, Hangzhou 310022\, People's Republic of China.,Department of Thoracic Disease Diagnosis and Treatment Center\, Zhejiang Rongjun Hospital\, Jiaxing\, Zhejiang 314000\, People's Republic of China.,Geneplus-Beijing Institute\, Beijing 102206\, People's Republic of China.,Institute of Cancer and Basic Medicine (ICBM)\, Chinese Academy of Sciences\, Hangzhou 310022\, People's Republic of China.",,,,,"gene mutation,lung cancer,next-generation sequencing,surgical margin"
33067182,,Intermittent Inhibition of BRAF plus MEK Is Not Beneficial in Melanoma.,"Compared with standard continuous dosing, intermittent dosing did not improve patient outcomes.",Cancer discovery,vol.10:12:OF7,2020,Journal Article,,,,,,,,
33067454,"Newell F,Wilmott JS,Johansson PA,Nones K,Addala V,Mukhopadhyay P,Broit N,Amato CM,Van Gulick R,Kazakoff SH,Patch AM,Koufariotis LT,Lakis V,Leonard C,Wood S,Holmes O,Xu Q,Lewis K,Medina T,Gonzalez R,Saw RPM,Spillane AJ,Stretch JR,Rawson RV,Ferguson PM,Dodds TJ,Thompson JF,Long GV,Levesque MP,Robinson WA,Pearson JV,Mann GJ,Scolyer RA,Waddell N,Hayward NK",Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.,"To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.",Nature communications,vol.11:1:5259,2020,"Research Support, Non-U.S. Gov't","|Female|,|GTP Phosphohydrolases|genetics|metabolism|,|Gene Amplification|,|Gene Dosage|,|Genomics|,|Humans|,|Male|,|Melanoma|genetics|metabolism|,|Membrane Glycoproteins|genetics|metabolism|,|Membrane Proteins|genetics|metabolism|,|Mutation|,|Oxidoreductases|genetics|metabolism|,|Proto-Oncogene Proteins B-raf|genetics|metabolism|,|Receptor\, Notch2|genetics|metabolism|,|Skin Neoplasms|genetics|metabolism|,|Whole Genome Sequencing|",,"0000-0003-0469-2705QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia. felicity.newell@qimrberghofer.edu.au.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0002-3569-2065QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0001-8490-5437QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0002-4945-8819Center for Rare Melanomas\, University of Colorado Cancer Center\, Aurora\, Colorado\, USA.,Center for Rare Melanomas\, University of Colorado Cancer Center\, Aurora\, Colorado\, USA.,0000-0001-6562-1383QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0001-6121-4019QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0002-4131-2065QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0003-4543-8850QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,Center for Rare Melanomas\, University of Colorado Cancer Center\, Aurora\, Colorado\, USA.,Center for Rare Melanomas\, University of Colorado Cancer Center\, Aurora\, Colorado\, USA.,Center for Rare Melanomas\, University of Colorado Cancer Center\, Aurora\, Colorado\, USA.,0000-0002-3354-806XMelanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,0000-0002-8354-434XMelanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,0000-0002-2816-2496Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,0000-0001-8894-3545Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Dermatology Clinic\, University Hospital Zürich\, University of Zurich\, Zurich\, Switzerland.,Center for Rare Melanomas\, University of Colorado Cancer Center\, Aurora\, Colorado\, USA.,QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,0000-0002-8991-0013Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,0000-0002-3950-2476QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.,0000-0003-4760-1033QIMR Berghofer Medical Research Institute\, Brisbane\, QLD\, Australia.","Membrane Glycoproteins,Membrane Proteins,NOTCH2 protein\, human,Receptor\, Notch2,Oxidoreductases,TYRP1 protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human",,,,
33178273,"Diniz PHC,Silva SDC,Vidigal PVT,Xavier MAP,Lima CX,Faria LC,Ferrari TCA",Expression of MAPK and PI3K/AKT/mTOR Proteins according to the Chronic Liver Disease Etiology in Hepatocellular Carcinoma.,"Chronic liver disease (CLD) of different etiologies leads to hepatocellular carcinoma (HCC) by multiple mechanisms that may be translated into clinicopathological differences. We evaluated the tissue expression of the MAPK and PI3K/Akt/mTOR pathway proteins and their association with long-term outcome and other parameters\, according to the etiology of the CLD\, in HCC patients.,Clinicopathological data from 80 patients who underwent orthotopic liver transplantation for HCC treatment in a Brazilian referral center were compared according to CLD etiology. Event (tumor recurrence or death from any cause) occurrence and event-free survival (EFS) were analyzed. Pathway protein expression was assessed by immunohistochemistry (IHQ) in both tumor and underlying cirrhosis and by RT-PCR in tumor tissue.,Strong expression (SE) of KRAS was more frequent in tumors arising from viral (26.8%) than the nonviral group of liver disease (7.7%\, p=0.024) and also than cirrhotic parenchyma (0%\, p=0.004). SE of PI3K was more frequent in tumor than in cirrhosis (p=0.048\, p < 0.01)\, without differences in its tumor expression among etiologic groups (p=0.111). mRNA of ERK\, PI3K\, and BRAF was expressed in the tumor\, without differences between CLD etiologies\, and there was no association with IHQ findings. Older age and microvascular invasion (MIV) were the only parameters independently associated with the event. MIV was also associated with shorter EFS.,Hepatitis B and C virus can lead to HCC by different mechanisms compared with nonviral hepatopathy. KRAS and PI3K may have a role in carcinogenesis. The prognostic and therapeutic implications need to be investigated.",Journal of oncology,vol.2020::4609360,2020,Journal Article,,,"https://orcid.org/0000-0003-2016-5593Departamento de Clínica Médica\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.,https://orcid.org/0000-0002-6705-0323Departamento de Clínica Médica\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.,https://orcid.org/0000-0002-7003-5159Departamento de Anatomia Patológica e Medicina Legal\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.,https://orcid.org/0000-0002-9081-1493Departamento de Anatomia Patológica e Medicina Legal\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.,https://orcid.org/0000-0001-7724-890XDepartamento de Cirurgia\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.,https://orcid.org/0000-0002-0226-3491Departamento de Clínica Médica\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.,https://orcid.org/0000-0001-9459-2294Departamento de Clínica Médica\, Faculdade de Medicina\, Universidade Federal de Minas Gerais\, Belo Horizonte\, MG\, Brazil.",,,,,
33178341,"Huang K,Gao N,Bian D,Zhai Q,Yang P,Zhang Y","Associations of BRAF V600E, clinical pathology and imaging factors with the recurrence rate of papillary thyroid microcarcinoma.","In the present study, the recurrence rate of papillary thyroid microcarcinoma (PTMC) was assessed by analyzing postoperative follow-up data of affected patients and its associations with BRAF V600E, clinical pathology and imaging factors were explored. A total of 506 patients with PTMC were selected who underwent surgery from January 2014 to March 2016. The maximal diameter of thyroid nodules was ≤1 cm and all patients who underwent BRAF V600E testing and evaluation for lymph node metastasis. Postoperatively, each patient was regularly followed up to detect recurrence. Categorical variables were comparatively analyzed using univariate Cox linear regression analysis to screen for protective and adverse factors influencing recurrence of PTMC. A stepwise Cox proportional hazards regression model analysis was performed to explore risk factors affecting recurrence. Among the 506 patients, 477 were followed up, 29 were lost to follow-up and 26 patients experienced recurrence. The 5-year recurrent rate of PTMC was 5.45%. The univariate Cox regression analysis indicated that PTMC recurrence was influenced by BRAF V600E, sex, multifocality, capsular invasion and lateral cervical lymph node metastasis (P<0.05), but not by age, tumor location on the thyroid, size, single central lymph node metastasis, distant metastasis and operative approach (P>0.05). The significant factors associated with recurrent PTMC were subjected to stepwise multivariate Cox proportional hazards regression model analysis and the results indicated that BRAF V600E, sex, multifocality and lateral cervical lymph node metastasis were independent factors influencing recurrence in patients with PTMC, with a statistically significant difference (P<0.05). In conclusion, BRAF V600E, sex, multifocality and lateral cervical lymph node metastasis are independent risk factors for recurrent PTMC.",Experimental and therapeutic medicine,vol.20:6:243,2020,Journal Article,,,"Department of Ultrasonic Diagnosis\, The First Affiliated Hospital of China Medical University\, Shenyang\, Liaoning 110001\, P.R. China.,Department of Ultrasonic Diagnosis\, Liaoning Province Cancer Hospital and Institute\, Shenyang\, Liaoning 110042\, P.R. China.,Department of Ultrasonic Diagnosis\, The First Affiliated Hospital of China Medical University\, Shenyang\, Liaoning 110001\, P.R. China.,Department of Ultrasonic Diagnosis\, The First Affiliated Hospital of China Medical University\, Shenyang\, Liaoning 110001\, P.R. China.,Department of Ultrasonic Diagnosis\, The First Affiliated Hospital of China Medical University\, Shenyang\, Liaoning 110001\, P.R. China.,Department of Ultrasonic Diagnosis\, The First Affiliated Hospital of China Medical University\, Shenyang\, Liaoning 110001\, P.R. China.",,,,,"BRAF V600E,color Doppler ultrasonography,papillary thyroid microcarcinoma,recurrence rate"
33178599,"Huang YF,Xie WJ,Fan HY,Du J",Comparative Risks of High-Grade Adverse Events Among FDA-Approved Systemic Therapies in Advanced Melanoma: Systematic Review and Network Meta-Analysis.,"Background: Head-to-head evidence is lacking in comparative risks of high-grade adverse events (AEs) among different systemic treatment options for advanced melanoma. Methods: An up-to-date systematic review and network meta-analysis (NMA) was performed. Randomized controlled trials (RCTs) of patients with advanced melanoma were eligible if at least one intervention was the Food and Drug Administration-approved targeted or immune checkpoint inhibitors. Risks of high-grade AEs were estimated by random-effects Bayesian NMAs, based on relative risks. Surface under the cumulative ranking probabilities was used to assess relative ranking of treatments. The summary incidences were calculated. Results: Twenty-five RCTs (12,925 patients) comparing 10 different systemic treatment options were included. BRAF/MEK had the highest risk of overall high-grade AEs (pooled incidence: 32.11%). BRAF had the highest risk of high-grade arthralgia (0.39%), whereas MEK had the highest risk of high-grade hypertension (2.28%) and nausea (0.37%). Cytotoxic T-lymphocyte antigen 4 (CTLA-4)/chemo had the highest risk of high-grade diarrhea (1.31%), alanine aminotransferase (0.60%), and aspartate aminotransferase elevation (0.59%). Programmed cell death 1 (PD-1)/CTLA-4 had the highest risks of high-grade pyrexia (1.14%) and rash (0.94%). Using PD-1 inhibitor alone had the lowest risks of overall high-grade AEs. Conclusions: Different systemic treatment options have varying high-grade AEs in advanced melanoma treatment. Current evidences highlight the important risks of BRAF/MEK, CTLA-4/chemo, and PD-1/CTLA-4.",Frontiers in oncology,vol.10::571135,2020,Systematic Review,,,"School of General Practice and Continuing Education\, Capital Medical University\, Beijing\, China.,Department Clinical Research\, University of Bern\, Bern\, Switzerland.,Center of Stroke\, Beijing Institute for Brain Disorders\, Capital Medical University\, Beijing\, China.,School of General Practice and Continuing Education\, Capital Medical University\, Beijing\, China.",,,,,"advanced melanoma,high-grade adverse event,immune checkpoint inhibitor (ICI),network meta-analysis,targeted inhibitor"
33178750,"Alos L,Fuster C,Castillo P,Jares P,Garcia-Herrera A,Marginet M,Agreda F,Arance A,Gonzalvo E,Garcia M,Puig S,Teixido C"," mutation and tumoral PD-L1 expression are associated with depth of invasion in desmoplastic melanomas.","Desmoplastic melanoma (DM) is a rare subtype of spindle cell malignant melanoma characterized by frequent local recurrences and hematogenous spread\, but without molecular classification. The aim of the study was to investigate in a DM series the incidence of relevant gene alterations in cancer\, the programmed death-ligand 1 (PD-L1) expression status and the association with clinicopathological features and melanoma progression.,A total of 38 patients were included. Clinical follow-up and the histopathological features of all cases were retrospectively collected. PD-L1 expression by immunohistochemistry (IHC) and BRAF genomic alterations by real-time PCR were determined in 34 samples. Additionally\, a molecular analysis by next-generation sequencing was performed in 25 DMs.,Tumors occurred predominantly in men (76%) and in the head and neck region (50%). Most tumors were pure DMs (66%)\, containing less than 10% of conventional melanoma. Overall\, 48% of our cohort harbored TP53 mutations\, most of them showing a molecular signature associated with ultraviolet (UV)-oncogenesis\, and 29%\, BRAF mutations. A positive correlation between TP53 with depth of invasion (P=0.005) and presence of elastosis (P=0.002) was found. High-expression of PD-L1 in tumor cells was observed in 38% of cases and correlated with depth of tumoral infiltration (P=0.003)\, TP53 (P=0.016)\, PD-1 (P<0.001) and tumor-infiltrating lymphocytes (TILS) (P<0.001). PD-L1 expression in immune cells correlated with PD-1 (P=0.006)\, tumoral PD-L1 expression (P=0.029) and TP53 mutation (P=0.002). Survival correlated with depth of invasion (P=0.003)\, stage of tumors (P=0.015)\, positive sentinel lymph node (P=0.004)\, lymph node metastasis (P=0.024) and distant metastasis (P<0.001).,Our results suggest that progressed DMs with deep tumoral infiltration frequently harbor TP53 mutations\, PD-L1 expression and present a high inflammatory response\, probably related to adaptive immune resistance in this tumor-type.",Annals of translational medicine,vol.8:19:1218,2020,Journal Article,,,"Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Urological Surgery\, Hospital Trias I Pujol\, Carretera de Canyet\, Badalona\, Spain.,Department of Medical Oncology\, Hospital Clínic of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS)\, Barcelona\, Spain.,Department of Pathology\, Hospital Clínic of Barcelona\, University of Barcelona\, Barcelona\, Spain.",,,,,"Desmoplastic melanoma (DM),Oncomine,TP53,next-generation sequencing (NGS),programmed death-ligand 1 (PD-L1)"
33178757,"Cao S,Yu S,Yin Y,Su L,Hong S,Gong Y,Lv W,Li Y,Xiao H",Genetic alterations in cfDNA of benign and malignant thyroid nodules based on amplicon-based next-generation sequencing.,"Circulating cell-free DNA (cfDNA) serves as a biomarker in multiple malignant diseases. However\, controversy still surrounds the role of cfDNA detection in the diagnosis and monitoring of papillary thyroid carcinoma (PTC). This study set out to identify the role of cfDNA detection in distinguishing between benign and malignant thyroid nodules.,Tissue\, blood cell\, and plasma samples were collected from 10 patients with benign nodules and 10 patients with malignant nodules. The DNA isolated from these samples was subject to PCR-based amplification using primers designed for 50 proto-oncogenes and tumor suppressor genes. PCR products were sequenced using Illumina technology\, and the mutations were detected with varScan among sequencing data for each sample and comparative analysis was carried out.,Through amplicon sequencing\, we found one non-synonymous somatic mutation in the benign nodules and three in the malignant nodules. Among these four mutations\, BRAFV600E mutation was detected in the tissue samples of 8 out of the 10 PTC patients\, but it was not detected in the benign nodules. However\, no BRAFV600E mutation was detected in cfDNA. Further differential analysis of cfDNA indicated that some genes had more mutations in benign patients than in malignant patients\, such as MET and IDH\, and some genes had more mutations in malignant patients\, such as PIK3CA and EZH2.,We found that BRAFV600E mutation was a credible disease-related mutation in PTC; however\, it could not be detected in cfDNA. Moreover\, there was a large difference in mutation gene distribution between benign and malignant thyroid nodules.",Annals of translational medicine,vol.8:19:1225,2020,Journal Article,,,"Department of Endocrinology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Endocrinology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Endocrinology\, Peking University Shenzhen Hospital\, Shenzhen\, China.,Department of Gerontology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Endocrinology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Gerontology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Breast and Thyroid Surgery\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Endocrinology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.,Department of Endocrinology\, The First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, China.",,,,,"BRAF,Cell-free DNA (cfDNA),papillary thyroid carcinoma,thyroid nodule"
33178761,"Xu M,Zhou J,Zhang Q,Le K,Xi Z,Yi P,Zhao X,Tan J,Huang T",MiR-3121-3p promotes tumor invasion and metastasis by suppressing Rap1GAP in papillary thyroid cancer .,"Rap1GAP is a tumor suppressor and is downregulated in human malignancies including papillary thyroid cancer (PTC). The mechanism of its suppression in PTC remains unclear.,Bioinformatic analyses were carried out to evaluate clinical significance and to predict upstream miRNA bindings of Rap1GAP. Three PTC cell lines\, TPC-1\, B-CPAP\, and K1\, were employed for functional verification and further experiments. We used dual-luciferase reporter gene assay to confirm the miRNA binding prediction\, Western blotting and quantitative polymerase chain reaction (qPCR) to explore miRNA and Rap1GAP regulation\, Transwell and wound healing assays to compare cell migration and invasion after protein knockout or overexpression\, and Cell Counting Kit-8 (CCK-8) assay to evaluate cell proliferation.,Rap1GAP expression was suppressed in thyroid cancer compared to adjacent normal tissues and was a potential diagnostic marker of PTC. Rap1GAP suppression was correlated to younger age\, advanced T stage\, N stage\, extrathyroidal extension\, BRAF-like tumors\, and higher risk of recurrence. Combined analysis of bioinformatic prediction and dual-luciferase assay revealed binding between miR-3121-3p with 3'UTR of Rap1GAP promoter. MiR-3121-3p promoted cell migration\, invasion\, and proliferation via inhibiting Rap1GAP and thus upregulating MAPK pathway. Overexpression and knockdown of Rap1GAP could counteract the influence on cell migration and invasion carried out by miR-3121-3p mimic and inhibitor\, respectively. Rap1GAP partially impaired the effect of miR-3121-3p in cell growth in the CCK-8 assay.,Rap1GAP expression is suppressed in PTC and is a potential diagnostic marker. Its upstream regulator\, miR-3121-3p\, affects tumor metastasis and proliferation via regulating Rap1GAP expression. MAPK signaling pathway may be involved in this effect.",Annals of translational medicine,vol.8:19:1229,2020,Journal Article,,,"Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,Department of Breast and Thyroid Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.",,,,,"Papillary thyroid cancer (PTC),Rap1GAP,miR-3121-3p,tumor metastasis,tumor proliferation"
33182067,"Chen D,Wang H",The clinical and immune features of CD14 in colorectal cancer identified via large-scale analysis.,"Cancer immunotherapies have achieved great progress in colorectal cancer (CRC). However\, only a small subset of CRC patients with microsatellite instability (MSI) can obtain benefits from immune checkpoint inhibitors (ICIs). Nearly 85% of all CRC patients have microsatellite-stable (MSS) disease\, which does not respond to ICIs. Increasing evidence has revealed that CD14 promotes tumor growth and induces an immunosuppressive environment through CD14+ immunosuppressive cells. However\, a systematic exploration of CD14 in CRC is lacking.,A total of 644 samples with transcriptome data and 566 samples with microarray data were investigated in this study\, including TCGA RNA-Seq and GSE39582 microarray. R software was the main tool for graphical work and statistical analysis.,CD14 was upregulated in the MSI-H\, BRAF-mutant\, right-sided disease\, and hypermethylation groups. Cases with high CD14 expression were related to the CMS4 subtype and had frequent mutation of driver oncogenes. CD14 expression was associated with the regulation of immune system processes in gene ontology analysis. The cytokine-cytokine receptor interaction was associated with CD14 expression. Moreover\, CD14 was associated with high immune and stromal infiltration\, and CD14 synergized with immune checkpoints. Additionally\, CD14 was involved in immune and inflammatory responses. Finally\, high CD14 expression predicted worse outcomes and was an independent negative indicator of prognosis in CRC\, which was further confirmed in tissue microarray.,Our findings indicated that CD14 expression was associated with specific clinical characteristics. High CD14 expression might represent pre-existing immunity and have a high correlation with immune checkpoints. Moreover\, CD14 correlated with poor clinical outcomes in CRC. Therefore\, the CD14 molecule promises to be a potential target to enhance the immunotherapy of colorectal cancers.",International immunopharmacology,vol.88::106966,2020,Journal Article,,,"Department of Oncology\, Haimen People's Hospital Affiliated to Nantong University\, Haimen\, China.,Department of Oncology\, Wuxi People's Hospital Affiliated to Nanjing Medical University\, Wuxi\, China. Electronic address: wanghuiyu2011@126.com.",,,,,"CD14,Colorectal cancer,Immune checkpoints,Immune response,Prognosis"
33182254,"Mustachio LM,Roszik J",Current Targeted Therapies for the Fight against Non-Small Cell Lung Cancer.,"Lung cancers contribute to the greatest number of cancer-related deaths worldwide and still pose challenges in response to current treatment strategies. Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers diagnosed in the United States and novel therapeutics are needed for the treatment of this disease. First and second generation targeted therapies against specific mutated or rearranged oncogenes in NSCLCs show anti-tumor activity and also increase survival. However, many NSCLC patients eventually develop resistance to these therapies or do not properly respond if they have central nervous system metastases. Thus, this review summarizes recent developments and findings related to the generation of novel targeted therapies recently or currently being developed to tackle hurdles that prior therapies were not able to overcome.","Pharmaceuticals (Basel, Switzerland)",vol.13:11:,2020,Review,,,"Department of Epigenetics and Molecular Carcinogenesis\, The University of Texas MD Anderson Cancer Center\, Houston\, TX 77030\, USA.,0000-0002-4561-6170Department of Genomic Medicine\, Division of Cancer Medicine\, The University of Texas MD Anderson Cancer Center\, Houston\, TX 77030\, USA.",,,,,"ALK,BRAF,EGFR,NSCLC,ROS1,clinical trials,targeted therapy"
33183728,Treece AL,Pediatric Renal Tumors: Updates in the Molecular Era.,"Molecular characterization has led to advances in the understanding of pediatric renal tumors, including the association of pediatric cystic nephromas with DICER1 tumor syndrome, the metanephric family of tumors with somatic BRAF mutations, the characterization of ETV6-NTRK3-negative congenital mesoblastic nephromas, the expanded spectrum of gene fusions in translocation renal cell carcinoma, the relationship of clear cell sarcoma of the kidney with other BCOR-altered tumors, and the pathways affected by SMARCB1 alterations in rhabdoid tumors of the kidney. These advances have implications for diagnosis, classification, and treatment of pediatric renal tumors.",Surgical pathology clinics,vol.13:4:695-718,2020,Review,,,"Department of Pathology, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 1 Avenue, Box 120, Aurora, CO 80045, USA. Electronic address: Amy.treece@childrenscolorado.org.",,,,,"Clear cell sarcoma of kidney,Cystic nephroma,Mesoblastic nephroma,Metanephric,Renal cell carcinoma,Rhabdoid tumor"
32883694,"Peng C,Jie-Xin L",The incidence and risk of cutaneous toxicities associated with dabrafenib in melanoma patients: a systematic review and meta-analysis.,"Dabrafenib\, an inhibitor of mutated BRAF\, has significant clinical activity in melanoma patients but is linked to a spectrum of cutaneous toxicities. Thus\, our meta-analysis was conducted to evaluate the type\, incidence and risks of dermatological toxicities from dabrafenib.,Systematic searches were performed using electronic databases such as Embase and PubMed and conference abstracts published by the American Society of Clinical Oncology. Eligible studies were limited to prospective phase I\, II and III clinical trials and expanded-access (ie\, outside clinical trials) programmes of melanoma patients receiving dabrafenib monotherapy (150 mg\, twice daily) or combination therapy of dabrafenib (150 mg\, twice daily) plus trametinib (2 mg\, once daily). The outcomes were mainly the incidence rate and risk of all-grade cutaneous toxicities associated with dabrafenib in melanoma patients.,Twenty trials comprising a total of 3359 patients were included in the meta-analysis. The meta-analysis showed that the overall incidence of all-grade rash for melanoma patients assigned dabrafenib was 30.00% (95% CI 0.07 to 0.71)\, cutaneous squamous-cell carcinoma (cSCC) 16.00% (95% CI 0.11 to 0.24)\, alopecia 21% (95% CI 0.11 to 0.37)\, keratoacanthoma (KA) 20.00% (95% CI 0.12 to 0.31)\, hyperkeratosis (HK) 14.00% (95% CI 0.09 to 0.22) and pruritus 8.00% (95% CI 0.05 to 0.12). All-grade rash occurred in 19.00% (95% CI 0.15 to 0.25)\, cSCC in 10.00% (95% CI 0.04 to 0.22)\, alopecia in 6.00% (95% CI 0.03 to 0.12)\, KA in 6.00% (95% CI 0.04 to 0.09) and pruritus in 2/1265 patients assigned dabrafenib plus trametinib. The summary risk ratio (RR) showed that the combination of dabrafenib with trametinib versus dabrafenib was associated with a significantly increased risk of all-grade rash (RR 1.35\, 95% CI 1.01 to 1.80) and a decreased risk of cSCC (RR 0.40\, 95% CI 0.18 to 0.89)\, alopecia (RR 0.19\, 95% CI 0.12 to 0.30) and HK (RR 0.25\, 95% CI 0.10 to 0.62).,In summary\, the most frequent cutaneous adverse reactions from dabrafenib were rash\, cSCC\, alopecia\, KA\, HK and pruritus. There was a significantly decreased risk of cSCC\, alopecia and HK with the combination of dabrafenib with trametinib versus dabrafenib alone. Clinicians should be aware of these risks and perform regular clinical monitoring.",European journal of hospital pharmacy : science and practice,vol.::,2020,Review,,,"http://orcid.org/0000-0003-4936-2064Department of Pharmacy\, Renmin Hospital of Wuhan University\, Wuhan University\, Wuhan\, China 2282968908@qq.com.,wuhan\, China.",,,,,"adverse effects,cancer pain,drug administration (others),risk management,side effects of drugs"
32888274,"Bukhari SNA,Alotaibi NH,Ahmad W,Alharbi KS,Abdelgawad MA,Al-Sanea MM,Ahmad MM,Amjad MW,Raja MAG,Hussain MA",Evaluation of ligustrazine based synthetic compounds for mechanism based antiproliferative effects.,"Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects.,Based on the multitargeted biological activities approach of ligustrazine based chalcones\, in current study 18 synthetic ligustrazine-containing α\, β-unsaturated carbonyl-based 1\, 3-Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on growth of five different types of cancer cells.,All compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies.,Majority of compounds exhibited strong inhibition of cancer cells especially synthetic compounds 4a and 4b bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in main structural backbone were found most powerful inhibitors of cancer cell growth. Most active 9 compounds among whole series were selected for further studies related to different cancer targets including EGFR TK kinases\, tubulin polymerization\, KAF and BRAFV600E.,Synthetic derivatives including 4a-b and 5a-b showed multitarget approach and showed strong inhibitory effects on EGFR\, FAK and BRAF while three compounds including 3e bearing methoxy substitution\, 4a and 4b with 1- pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.",Medicinal chemistry (Shariqah (United Arab Emirates)),vol.::,2020,Journal Article,,,"Department of Pharmaceutical Chemistry\, College of Pharmacy\, Jouf University\, Aljouf\, Sakaka\, 2014. Saudi Arabia.,Department of Clinical Pharmacy\, College of Pharmacy\, Jouf University\, Aljouf\, Sakaka\, 2014. Saudi Arabia.,School of Pharmaceutical Sciences\, Universiti Sains Malaysia\, 11800\, Minden\, Penang. Malaysia.,Department of Pharmacology\, College of Pharmacy\, Jouf University\, Aljouf\, Sakaka\, 2014. Saudi Arabia.,Department of Pharmaceutical Chemistry\, College of Pharmacy\, Jouf University\, Aljouf\, Sakaka\, 2014. Saudi Arabia.,Department of Pharmaceutical Chemistry\, College of Pharmacy\, Jouf University\, Aljouf\, Sakaka\, 2014. Saudi Arabia.,Department of Pharmaceutical Chemistry\, College of Pharmacy\, Jouf University\, Aljouf\, Sakaka\, 2014. Saudi Arabia.,College of Pharmacy\, Northern Border University\, Rafha. 0.,College of Pharmacy\, Northern Border University\, Rafha. 0.,Department of Chemistry\, University of Sargodha\, Sargodha 40100. Pakistan.",,,,,"Antiproliferative. ,Cell lines,Chalcones,Claisen-Schmidt condensation,Organic synthesis"
32892555,"Dong RF,Gong LH,Zhang W,Li L,Sun XQ,Zhang M,Ding Y",[Primary intraosseous Rosai-Dorfman disease: a clinicopathological analysis of fourteen cases].,"Objective: To investigate the clinicopathological characteristics, histogenesis, immunophenotypes and molecular genetic features of primary intraosseous Rosai-Dorfman disease (RDD) for improving diagnostic accuracy and differential diagnosis. Methods: This retrospective study included 14 RDD cases diagnosed from January 2009 to January 2019 at Beijing Jishuitan Hospital, China. The immunohistochemical staining for S-100, cyclin D1, CD1a and CD207 expression was analyzed. The BRAF V600E and KRAS mutation analyses were performed using the Scorpions amplification refractory mutation system (ARMS) fluorescence quantitative PCR. Results: There were 6 female and 8 male patients, aged from 2 to 64 years (mean 31.4 years). All of the 14 cases occurred in the bone without lymph node disease, while one patient developed additional lesions within vertebra and nasal cavity. Radiographically, the lesions were lytic with sclerotic margins. Histologically, the lesions percolated through the medullary cavity in an infiltrative fashion and alternating hyper- and hypo-cellular regions of histiocytic clusters (seen as alternating dark and light zones at low magnification). Large histiocytes also showed emperipolesis. Some cases had areas of fibrosis and dense lymphoplasmacytic infiltrates. There were vasculitis and an increased number of plasma cells in the cases involving multiple sites. One case showed concurrence of RDD and Langerhans cell histiocytosis(LCH) with inconspicuous increase of Langerhans histiocytes. Immunohistochemical staining showed that the large histiocytes were positive for S-100, CD68 and CD163 in all cases. The nuclear immunoreactivity for cyclin D1 was observed in 13 of the 14 cases. S-100, CD1a and CD207 were positive in the case with concurrence of RDD and LCH. ARMS-PCR results showed that BRAF V600E mutation was observed in the cases with concurrence of RDD and LCH, while there were no KRAS mutations (7/7). Follow-up information was available for 12 patients and ranged from 9 to 49 months. Three of the 12 patients experienced recurrences after the first surgery. Conclusions: Primary intraosseous RDD is rare, and its concurrence with LCH is a very rare phenomenon. Its clinical symptoms, imaging, and pathological manifestations need to be distinguished from other bone lesions. The molecular detection of BRAF V600E and the nuclear expression of cyclin D1 mutations can be used for the diagnosis and differential diagnosis of RDD.",Zhonghua bing li xue za zhi = Chinese journal of pathology,vol.49:9:904-909,2020,Journal Article,"|Adolescent|,|Adult|,|Child|,|Child\, Preschool|,|China|,|Female|,|Histiocytes|,|Histiocytosis\, Sinus|,|Humans|,|Male|,|Middle Aged|,|Retrospective Studies|,|S100 Proteins|,|Young Adult|",,"Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.,Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.,Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.,Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.,Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.,Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.,Department of Pathology\, Beijing Jishuitan Hospital\, Beijing 100035\, China.",S100 Proteins,,,,"Cyclin D1,Histiocytosis\, Langerhans-cell,Histiocytosis\, sinus,Proto-oncogene proteins B-raf"
32892557,"Huang HJ,Zhong DR,Lu T",[Clinicopathological characteristics of indeterminate dendritic cell tumor of four cases].,"Objective: To investigate the clinicopathologic features, diagnosis, differential diagnosis and molecular pathological characteristics of indeterminate dendritic cell tumor (IDCT). Methods: Four cases of IDCT were collected at Peking Union Medical College Hospital (3 cases) and Fujian Provincial Hospital (1 case). The 4 cases were analyzed, with focus on morphology, immunohistochemistry and BRAF V600E detection. Related literature was reviewed to reveal the characteristics of this tumor. Results: There were 2 males and 2 females aged 30-52 years (mean=40 years). Histopathological characteristics of the tumor cells were round, polygonal. The nuclei were round, with rich eosinophils cytoplasm. The tumor cells arranged in diffuse, sheet, whorl, and fascicle patterns. Mitosis was variable [generally(1-3)/10 HPF] and nucleoli were obvious. Lymphocytes, plasma cells and other infiltrates could be seen in the stroma. Immunohistochemically, tumor cells were positive for S-100 (4/4), CD1a (4/4), CD68 (4/4) and cyclin D1 (3/3), while CD207/Langerin, CKpan, CD21, HMB45, ALK and actin were negative. Ki-67 index was 5%-30%. Gene detection showed BRAF V600E mutations were not present in any of the four cases. Conclusions: IDCT is a rare type of dendritic cell tumor. There are no specific morphology characteristics. The diagnosis depends on clinical, histopathological and immunophenotype. Thus, electron microscopy and molecular testing are helpful if necessary.",Zhonghua bing li xue za zhi = Chinese journal of pathology,vol.49:9:916-921,2020,Journal Article,"|Adult|,|Dendritic Cells|,|Diagnosis\, Differential|,|Female|,|Humans|,|Immunohistochemistry|,|Immunophenotyping|,|Lymphoma\, Non-Hodgkin|,|Male|,|Middle Aged|",,"Department of Pathology\, Peking Union Medical College Hospital\, Peking Union Medical College and Chinese Academy of Medical Science\, Beijing 100730\, China(Huang Haijian is working on the Department of Pathology\, Fujian Provincial Hospital\, Provincial Clinical Medical College of Fujian Medical University\, Fuzhou 350001\, China).,Department of Pathology\, Peking Union Medical College Hospital\, Peking Union Medical College and Chinese Academy of Medical Science\, Beijing 100730\, China(Zhong Dingrong is working on the Department of Pathology\, China-Japan Friendship Hospital\, Beijing 100029\, China).,Department of Pathology\, Peking Union Medical College Hospital\, Peking Union Medical College and Chinese Academy of Medical Science\, Beijing 100730\, China.",,,,,"Diagnosis\, differential,Immunohistochemistry,Soft tissue neoplasms"
32872561,"Roberto M,Arrivi G,Lo Bianco F,Cascinu S,Gelsomino F,Caputo F,Cerma K,Ghidini M,Ratti M,Pizzo C,Ficorella C,Parisi A,Cortellini A,Urbano F,Calandrella ML,Dell'Aquila E,Minelli A,Fulgenzi CAM,Gariazzo L,Montori A,Pilozzi E,Di Girolamo M,Marchetti P,Mazzuca F",Evaluation of Prognostic Factors for Survival in Transverse Colon Cancer.,"Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I-IV TCC were included in this multicenter study; clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with ≤70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index ≥5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27-25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01-7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97-9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98-14.01) and BRAF mutation status (3.71, 95% CI 1.07-12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome.",Cancers,vol.12:9:,2020,Journal Article,,,"0000-0001-5339-8348Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,Division of Oncology\, Department of Oncology and Hematology\, University Hospital of Modena\, 41125 Modena\, Italy.,Division of Oncology\, Department of Oncology and Hematology\, University Hospital of Modena\, 41125 Modena\, Italy.,Division of Oncology\, Department of Oncology and Hematology\, University Hospital of Modena\, 41125 Modena\, Italy.,Division of Oncology\, Department of Oncology and Hematology\, University Hospital of Modena\, 41125 Modena\, Italy.,0000-0001-5435-1218Oncology Unit\, Oncology Department\, ASST of Cremona\, 26100 Cremona\, Italy.,Oncology Unit\, Oncology Department\, ASST of Cremona\, 26100 Cremona\, Italy.,Oncology Unit\, Oncology Department\, ASST of Cremona\, 26100 Cremona\, Italy.,Medical Oncology\, St. Salvatore Hospital\, University of L'Aquila\, Department of Biotechnological and Applied Clinical Sciences\, University of L'Aquila\, 67100 L'Aquila\, Italy.,0000-0003-4629-7762Medical Oncology\, St. Salvatore Hospital\, University of L'Aquila\, Department of Biotechnological and Applied Clinical Sciences\, University of L'Aquila\, 67100 L'Aquila\, Italy.,0000-0002-1209-5735Medical Oncology\, St. Salvatore Hospital\, University of L'Aquila\, Department of Biotechnological and Applied Clinical Sciences\, University of L'Aquila\, 67100 L'Aquila\, Italy.,Department of Radiology\, Oncology and Pathology\, Policlinico Umberto I\, Sapienza University of Rome\, 00185 Rome\, Italy.,Department of Radiology\, Oncology and Pathology\, Policlinico Umberto I\, Sapienza University of Rome\, 00185 Rome\, Italy.,Medical Oncology Department\, Campus Bio-Medico University of Rome\, 00128 Rome\, Italy.,Medical Oncology Department\, Campus Bio-Medico University of Rome\, 00128 Rome\, Italy.,0000-0002-5654-9225Medical Oncology Department\, Campus Bio-Medico University of Rome\, 00128 Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,0000-0003-1013-8460Department of Clinical and Molecular Medicine\, UOC Anatomia Patologica\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,Department of Clinical and Molecular Medicine\, UOC Anatomia Patologica\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,Department of Radiology\, Sant'Andrea University Hospital\, 00187 Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, Sapienza University of Rome\, 00187 Rome\, Italy.",,,,,"BRAF,TCC,prognostic factors,sidedness,tumor grade"
32873703,"Jouenne F,Sadoux A,Lorillon G,Louveau B,Bugnet E,Meignin V,Mourah S,Tazi A",Custom pyrosequencing assay to detect short deletions in Langerhans cell histiocytic lesions.,"Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplastic disease driven by activating mutations in the mitogen-activating protein kinase signalling pathway, including the BRAF V600E mutation and BRAF deletions (BRAFdel). Next-generation sequencing and whole exome sequencing (WES) are valuable and powerful approaches for BRAFdel identification, but these techniques are costly and time consuming. Pyrosequencing is an alternative method that has the potential to rapidly and reliably identify gene deletions. We developed a custom pyrosequencing assay to detect the exon-12 BRAFdel in 18 biopsies from adult patients with LCH, which were all genotyped in parallel using Sanger sequencing and WES. A BRAFdel was detected in 7/18 (39%), 6/18 (33%) and 3/18 (17%) LCH lesions using WES, pyrosequencing and Sanger, respectively, with good concordance between the WES and pyrosequencing results (Kappa-coefficient=0.88). Therefore, our pyrosequencing assay is reliable and useful for detecting BRAFdel, particularly in BRAF V600E-negative LCH lesions, for which targeted treatment is indicated.",Journal of clinical pathology,vol.::,2020,Journal Article,,,"http://orcid.org/0000-0002-6706-7424Pharmacogenomics Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,Pharmacogenomics Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,National Reference Centre for Histiocytoses\, Pulmonology Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,Pharmacogenomics Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,National Reference Centre for Histiocytoses\, Pulmonology Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,Pathology Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,Pharmacogenomics Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris\, Paris\, Île-de-France\, France.,http://orcid.org/0000-0003-0788-7444INSERM U976\, Université de Paris\, Paris\, Île-de-France\, France abdellatif.tazi@aphp.fr.",,,,,"genetics,molecular biology,neoplasms"
32873927,"Soffietti R,Ahluwalia M,Lin N,Rudà R",Management of brain metastases according to molecular subtypes.,"The incidence of brain metastases has markedly increased in the past 20 years owing to progress in the treatment of malignant solid tumours, earlier diagnosis by MRI and an ageing population. Although local therapies remain the mainstay of treatment for many patients with brain metastases, a growing number of systemic options are now available and/or are under active investigation. HER2-targeted therapies (lapatinib, neratinib, tucatinib and trastuzumab emtansine), alone or in combination, yield a number of intracranial responses in patients with HER2-positive breast cancer brain metastases. New inhibitors are being investigated in brain metastases from ER-positive or triple-negative breast cancer. Several generations of EGFR and ALK inhibitors have shown activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer. Immune-checkpoint inhibitors (ICIs) hold promise in patients with non-small-cell lung cancer without druggable mutations and in patients with triple-negative breast cancer. The survival of patients with brain metastases from melanoma has substantially improved after the advent of BRAF inhibitors and ICIs (ipilimumab, nivolumab and pembrolizumab). The combination of targeted agents or ICIs with stereotactic radiosurgery could further improve the response rates and survival but the risk of radiation necrosis should be monitored. Advanced neuroimaging and liquid biopsy will hopefully improve response evaluation.",Nature reviews. Neurology,vol.16:10:557-574,2020,Review,,,"http://orcid.org/0000-0002-9204-7038Department of Neuro-Oncology\, University and City of Health and Science Hospital\, Turin\, Italy. riccardo.soffietti@unito.it.,Burkhardt Brain Tumor and Neuro-Oncology Center\, Taussig Center Institute\, Cleveland Clinic\, Cleveland\, Ohio\, USA.,Department of Medical Oncology\, Dana-Farber Cancer Institute\, Boston\, Massachusetts\, USA.,Department of Neuro-Oncology\, University and City of Health and Science Hospital\, Turin\, Italy.",,,,,
32875153,"van Landingham SW,Puccetti D,Potter H,Gamm D,Diamond EL,Lucarelli MJ",Necrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment.,"to describe an unusual case of necrotizing myositis in a rectus muscle\, possibly related to BRAF inhibitor therapy.,An 18-year old man with neurodegenerative Langerhans cell histiocytosis (LCH)\, recently started on the BRAF inhibitor dabrafenib\, presented with right eye pain. Magnetic resonance imaging (MRI) orbits revealed a rectus muscle mass concerning for LCH recurrence or malignancy. Dabrafenib was stopped\, and incisional biopsy of the mass was performed. The mass was absent on post-operative MRI\, so no further treatment was pursued. Histopathologic evaluation was initially concerning for sarcoma\, but on further analysis\, appeared more consistent with necrotizing myositis. The mass did not recur\, nor did the patient develop other signs or symptoms concerning for myositis or malignancy over a 24-month follow-up period.,Necrotizing myositis has not been previously described in a rectus muscle or with BRAF inhibitor use\, though myalgias and malignancies are established side effects. Necrotizing myositis may masquerade as sarcoma and should be on the differential diagnosis for a new mass in the setting of dabrafenib therapy.",American journal of ophthalmology case reports,vol.20::100868,2020,Case Reports,,,"Department of Ophthalmology and Visual Sciences\, University of Wisconsin-Madison\, 2828 University Avenue\, Madison\, WI\, 53705\, USA.,Department of Pediatrics\, American Family Children's Hospital University of Wisconsin-Madison\, 1675 Highland Avenue\, Madison\, WI\, 53792\, USA.,Department of Ophthalmology and Visual Sciences\, University of Wisconsin-Madison\, 2828 University Avenue\, Madison\, WI\, 53705\, USA.,Department of Ophthalmology and Visual Sciences\, University of Wisconsin-Madison\, 2828 University Avenue\, Madison\, WI\, 53705\, USA.,Department of Neurology\, Memorial Sloan Kettering Cancer Center\, 1275 York Avenue\, New York\, NY\, 10065\, USA.,Department of Ophthalmology and Visual Sciences\, University of Wisconsin-Madison\, 2828 University Avenue\, Madison\, WI\, 53705\, USA.",,,,,"B-raf inhibitor,Dabrafenib,Langerhans cell histiocytosis,Mass,Necrotizing myopathy,Necrotizing myositis,Orbital myositis,Rectus muscle,Sarcoma,braf inhibitor"
32877390,"Manubens-Vargas V,Rodríguez-Ortubia M,Salas-Gianini A,Valenzuela F,Carreño-Toro L","[Panniculitis in association with target therapy in melanoma patient, what the dermatologist should know: A case report].","Target therapies are currently a therapeutic option increasingly used for the management of patients with metastatic melanoma. However, there are multiple adverse pharmacological effects associated with their use that have been described. Cutaneous adverse reactions are the most frequent. We report the case of a 55-year-old man with a diagnosis of stage IV BRAFV600E-mutated metastatic cutaneous melanoma undergoing treatment with dabrafenib/trametinib, who consulted due to the development of erythematous nodular lesions in the upper and lower limbs associated with febrile sensation during the course of treatment. Infection was ruled out and a biopsy of the skin lesions was done, which provided the histopathological confirmation of a predominantly septal, granulomatous with leukocytoclastic vasculitis, mixed panniculitis. Panniculitis associated with this therapy has been described in the literature and has been considered an immune-mediated pharmacological adverse effect. It is considered to be related to a better prognosis in the treatment of metastatic melanoma. Consequently, as shown in this case report, target therapy should not be discontinued and symptomatic medication should be given to alleviate patient discomfort. The dermatologist should know and properly interpret this adverse effect and prescribe the most appropriate management for the patient.",Medwave,vol.20:7:e8010,2020,Journal Article,,,"Departamento de Dermatología\, Facultad de Medicina\, Universidad de Chile\, Santiago\, Chile. Adress: Santos Dumont 999\, Independencia\, Santiago\, Chile. Email: victor.manubens.v@gmail.com. ORCID: 0000-0002-6242-6408.,Departamento de Dermatología\, Facultad de Medicina\, Universidad de Chile\, Santiago\, Chile. ORCID: 0000-0002-5385-6916.,Departamento de Dermatología\, Facultad de Medicina\, Universidad de Chile\, Santiago\, Chile. ORCID: 0000-0001-8793-8234.,Departamento de Dermatología\, Facultad de Medicina\, Universidad de Chile\, Santiago\, Chile. ORCID: 0000-0003-1032-9347.,Servicio de Anatomía Patológica\, Hospital Clínico Universidad de Chile\, Santiago\, Chile. ORCID: 0000-0002-1600-1791.",,,,," BRAF kinases, adverse drug reaction, panniculitis,melanoma"
32877599,"Dummer R,Hauschild A,Santinami M,Atkinson V,Mandalà M,Kirkwood JM,Chiarion Sileni V,Larkin J,Nyakas M,Dutriaux C,Haydon A,Robert C,Mortier L,Schachter J,Lesimple T,Plummer R,Dasgupta K,Gasal E,Tan M,Long GV,Schadendorf D",Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.,"In the previously reported primary analysis of this phase 3 trial\, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit\, longer-term data were needed.,We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here\, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed\, since the required number of events to trigger the final overall survival analysis had not been reached.,The minimum duration of follow-up was 59 months (median patient follow-up\, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years\, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI]\, 48 to 58) with dabrafenib plus trametinib and 36% (95% CI\, 32 to 41) with placebo (hazard ratio for relapse or death\, 0.51; 95% CI\, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI\, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI\, 49 to 60) with placebo (hazard ratio for distant metastasis or death\, 0.55; 95% CI\, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.,In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations\, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number\, NCT01682083; EudraCT number\, 2012-001266-15.).",The New England journal of medicine,vol.383:12:1139-1148,2020,"Research Support, Non-U.S. Gov't","|Adjuvants\, Immunologic|therapeutic use|,|Administration\, Oral|,|Adult|,|Aged|,|Antineoplastic Combined Chemotherapy Protocols|therapeutic use|,|Disease-Free Survival|,|Double-Blind Method|,|Female|,|Follow-Up Studies|,|Humans|,|Imidazoles|therapeutic use|,|Male|,|Melanoma|drug therapy|genetics|,|Middle Aged|,|Mutation|,|Neoplasm Metastasis|,|Neoplasm Staging|,|Oximes|therapeutic use|,|Protein Kinase Inhibitors|therapeutic use|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|,|Pyridones|therapeutic use|,|Pyrimidinones|therapeutic use|,|Skin Neoplasms|drug therapy|genetics|,|Survival Analysis|",,"From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).,0000-0003-3524-7858From University Hospital Zurich Skin Cancer Center\, Zurich\, Switzerland (R.D.); University Hospital Schleswig-Holstein\, Kiel (A. Hauschild)\, University Hospital Essen\, Essen (D.S.)\, and German Cancer Consortium\, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan (M.S.)\, Papa Giovanni XXIII Cancer Center Hospital\, Bergamo (M.M.)\, and the Melanoma Oncology Unit\, Veneto Oncology Institute-IRCCS\, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane (V.A.)\, Alfred Hospital\, Melbourne\, VIC (A. Haydon)\, and Melanoma Institute Australia\, University of Sydney\, and Royal North Shore and Mater Hospitals\, Sydney (G.V.L.) - all in Australia; the Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust\, London (J.L.)\, and the Northern Centre for Cancer Care\, Freeman Hospital and Newcastle University\, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital\, the Norwegian Radium Hospital\, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux\, Hôpital Saint-André\, Bordeaux (C.D.)\, Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif (C.R.)\, Université de Lille\, INSERM Unité 1189\, Lille (L.M.)\, and the Medical Oncology Department\, Centre Eugène Marquis\, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma\, Sheba Medical Center\, Tel Hashomer\, and Sackler School of Medicine\, Tel-Aviv University\, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare\, Hyderabad\, India (K.D.); and Novartis Pharmaceuticals\, East Hanover\, NJ (E.G.\, M.T.).","Adjuvants\, Immunologic,Imidazoles,Oximes,Protein Kinase Inhibitors,Pyridones,Pyrimidinones,trametinib,BRAF protein\, human,Proto-Oncogene Proteins B-raf,dabrafenib",,,,
32878000,"Vidal A,Redmer T",Decoding the Role of CD271 in Melanoma.,"The evolution of melanoma, the most aggressive type of skin cancer, is triggered by driver mutations that are acquired in the coding regions of particularly BRAF (rat fibrosarcoma serine/threonine kinase, isoform B) or NRAS (neuroblastoma-type ras sarcoma virus) in melanocytes. Although driver mutations strongly determine tumor progression, additional factors are likely required and prerequisite for melanoma formation. Melanocytes are formed during vertebrate development in a well-controlled differentiation process of multipotent neural crest stem cells (NCSCs). However, mechanisms determining the properties of melanocytes and melanoma cells are still not well understood. The nerve growth factor receptor CD271 is likewise expressed in melanocytes, melanoma cells and NCSCs and programs the maintenance of a stem-like and migratory phenotype via a comprehensive network of associated genes. Moreover, CD271 regulates phenotype switching, a process that enables the rapid and reversible conversion of proliferative into invasive or non-stem-like states into stem-like states by yet largely unknown mechanisms. Here, we summarize current findings about CD271-associated mechanisms in melanoma cells and illustrate the role of CD271 for melanoma cell migration and metastasis, phenotype-switching, resistance to therapeutic interventions, and the maintenance of an NCSC-like state.",Cancers,vol.12:9:,2020,Review,,,"0000-0001-6172-0130Department of Biomedical Sciences\, University of Veterinary Medicine\, Institute of Medical Biochemistry (HA/I)\, Veterinärplatz 1\, 1210 Vienna\, Austria.,Department of Biomedical Sciences\, University of Veterinary Medicine\, Institute of Medical Biochemistry (HA/I)\, Veterinärplatz 1\, 1210 Vienna\, Austria.",,Deutsche Forschungsgemeinschaft,,392534127,"CD271,melanoma,metastasis,migration,neural crest stem cells"
32878554,"Darrigade Fleury M,Masson Regnault M,Cales S,Frouin E,Wierbiecka-Hainaut E",Alternative use of BRAF inhibitors in patients with metastatic melanoma unable to swallow pills.,"BRAF and MEK inhibitors have been approved for use in metastatic melanoma therapies. All of them are administered as oral capsules or pills. We report two cases treated applying an alternative method of vemurafenib or debrafenib-trametinib administration in patients unable to swallow.,The first case involved a 38-year-old man who was referred to a dermatologist for dysphagia and anorexia. After a computerized tomography (CT) scan it was concluded that the dysphagia was due to compression by mediastinal metastasis in a context of metastatic BRAF mutant melanoma. The second case involved a 35-year-old man who was diagnosed in March 2017 with melanoma of the back of the hand. Several months later a positron emission tomography (PET)/CT scan was performed. It revealed multiple disseminated metastasis.Management & Outcome: The first patient presented total dysphagia and was unable to swallow pills. It was decided to dissolve vemurafenib in order to facilitate administration. Dysphagia was improved 48 hours later\, and oral feeding was reintroduced. Due to severe tablet phobia\, the second patient was unable to swallow pills. Dabrafenib capsules were emptied and trametinib pills were grinded. One month later\, we noted improved health associated with reduction of the metastases.,Our study highlights the possibility of crushing or dissolving BRAF and MEK inhibitors in metastatic melanoma patients for whom it is impossible to swallow pills\, eliciting a response and achieving significant if temporary clinical benefit.",Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners,vol.::1078155220953877,2020,Journal Article,,,"https://orcid.org/0000-0002-8767-8054Department of Dermatology\, CHU de Poitiers\, Poitiers\, France.,Department of Dermatology\, CHU de Poitiers\, Poitiers\, France.,Department of Dermatology\, CHU de Poitiers\, Poitiers\, France.,Department of Pathology\, CHU de Poitiers\, Poitiers\, France.,Department of Dermatology\, CHU de Poitiers\, Poitiers\, France.",,,,,"Melanoma,anti-BRAF therapy,anti-MEK therapy,benefit"
32879641,"Durślewicz J,Klimaszewska-Wiśniewska A,Antosik P,Kasperska A,Grzanka D,Szylberg T,Szylberg Ł",Detection of BRAF V600E Mutation in Ganglioglioma and Pilocytic Astrocytoma by Immunohistochemistry and Real-Time PCR-Based Idylla Test.,"The BRAF V600E mutation is an important oncological target in certain central nervous system (CNS) tumors, for which a possible application of BRAF-targeted therapy grows continuously. In the present study, we aim to determine the prevalence of BRAF V600E mutations in a series of ganglioglioma (GG) and pilocytic astrocytoma (PA) cases. Simultaneously, we decided to verify whether the combination of fully automated tests-BRAF-VE1 immunohistochemistry (IHC) and Idylla BRAF mutation assay-may be useful to accurately predict it in the case of specified CNS tumors. The study included 49 formalin-fixed, paraffin-embedded tissues, of which 15 were GG and 34 PA. Immunohistochemistry with anti-BRAF V600E (VE1) antibody was performed on tissue sections using the VentanaBenchMark ULTRA platform. All positive or equivocal cases on IHC and selected negative ones were further assessed using the Idylla BRAF mutation assay coupled with the Idylla platform. The BRAF-VE1 IHC was positive in 6 (6/49; 12.3%) and negative in 39 samples (39/49; 79.6%). The interpretation of immunostaining results was complicated in 4 cases, of which 1 tested positive for the Idylla BRAF mutation assay. Therefore, the overall positivity rate was 14.3%. This included 2 cases of GG and 5 cases of PA. Our study found that BRAF V600E mutations are moderately frequent in PA and GG and that for these tumor entities, IHC VE1 is suitable for screening purposes, but all negative, equivocal, and weak positive cases should be further tested with molecular biology techniques, of which the Idylla system seems to be a promising tool.",Disease markers,vol.2020::8880548,2020,Journal Article,,,"Department of Clinical Pathomorphology\, Nicolaus Copernicus University in Toruń\, Faculty of Medicine\, Collegium Medicum in Bydgoszcz\, 85-092 Bydgoszcz\, Poland.,https://orcid.org/0000-0002-8493-3806Department of Clinical Pathomorphology\, Nicolaus Copernicus University in Toruń\, Faculty of Medicine\, Collegium Medicum in Bydgoszcz\, 85-092 Bydgoszcz\, Poland.,Department of Clinical Pathomorphology\, Nicolaus Copernicus University in Toruń\, Faculty of Medicine\, Collegium Medicum in Bydgoszcz\, 85-092 Bydgoszcz\, Poland.,Department of Clinical Pathomorphology\, Nicolaus Copernicus University in Toruń\, Faculty of Medicine\, Collegium Medicum in Bydgoszcz\, 85-092 Bydgoszcz\, Poland.,Department of Clinical Pathomorphology\, Nicolaus Copernicus University in Toruń\, Faculty of Medicine\, Collegium Medicum in Bydgoszcz\, 85-092 Bydgoszcz\, Poland.,1 Military Research Hospital and Polyclinic\, 85-681 Bydgoszcz\, Poland.,Department of Clinical Pathomorphology\, Nicolaus Copernicus University in Toruń\, Faculty of Medicine\, Collegium Medicum in Bydgoszcz\, 85-092 Bydgoszcz\, Poland.",,,,,
33193858,"Liu J,Zhong F,Cao L,Zhu R,Qu J,Yang L,Chen T,Hu Y,Wang Y,Yao M,Xiao W,Li C,Li B,Yuan Y",7-dehydrocholesterol suppresses melanoma cell proliferation and invasion via Akt1/NF-κB signaling.,"Melanoma is the most lethal cutaneous cancer with a high metastatic rate worldwide, causing ~55,500 deaths annually. Although the selective B-Raf oncogene serine/threonine-kinase (BRAF) inhibitors, dabrafenib and vemurafenib, have been approved for the treatment of BRAF-mutant metastatic melanoma, the 5-year survival rate remains unfavorable due to acquired therapy resistance. Therefore, it is of great importance to develop alternative therapeutic drugs and uncover their mechanisms for the treatment of melanoma. 7-dehydrocholesterol (7-DHC) has been demonstrated to inhibit melanoma, but the mechanism is unclear. Therefore, the present study aimed to elucidate the mechanisms of the inhibitory effect of 7-DHC in melanoma cells via analyzing the proliferation, migration, apoptosis, cell cycle and transcriptional sequencing of melanoma cells treated with 7-DHC, as well as constructing a gene signature according to public data of patients with melanoma. In the present study, 7-DHC, the precursor of vitamin D3, was able to induce apoptosis and inhibit cell proliferation and invasion of melanoma cells in a dose-dependent manner. RNA sequencing of melanoma cells treated with different concentrations of 7-DHC revealed that, compared with untreated melanoma cells, 65 genes were downregulated, and genes involved in the regulation of NF-ĸB import into the nucleus and NF-ĸB signaling were significantly repressed. Consistently, the Akt kinase family was one of most common somatic mutation hotspots in patients with melanoma according to The Cancer Genome Atlas enrichment analysis. Furthermore, 7-DHC decreased the phosphorylation of Akt1-Ser473 rather than that of MEK1, and the decreased phosphorylation of Akt1 subsequently inhibited the translocation of free RELA proto-oncogene NF-κB subunit to the nucleus. Finally, by intersecting downregulated genes by 7-DHC treatment and upregulated genes in patients with melanoma, a 7-DHC gene signature was identified, which was negatively associated with the prognosis. Overall, the present results demonstrated that 7-DHC suppressed melanoma cell proliferation and invasion via the Akt1/NF-ĸB signaling pathway, and 7-DHC key target genes were negatively associated with the prognosis. These findings highlight the potential application of 7-DHC for the treatment of melanoma in the future.",Oncology letters,vol.20:6:398,2020,Journal Article,,,"Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Centre for Reproductive Medicine\, Tianjin Medical University General Hospital\, Tianjin 300041\, P.R. China.,Department of Physiology\, School of Basic Medical Sciences\, Health Sciences Center\, Shenzhen University\, Shenzhen\, Guangdong 518060\, P.R. China.,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases\, Department of Pathogen Biology\, Health Sciences Center\, Shenzhen University\, Shenzhen\, Guangdong 518055\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.,Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education)\, Tianjin University\, Tianjin 300072\, P.R. China.",,,,,"7-dehydrocholesterol,Akt1/NF-ĸB,RNA sequencing,melanoma,prognosis"
33194656,"Xu T,Zhang Y,Zhang J,Qi C,Liu D,Wang Z,Li Y,Ji C,Li J,Lin X,Hou T,Liu H,Zhang L,Han-Zhang H,Shen L,Wang X",Germline Profiling and Molecular Characterization of Early Onset Metastatic Colorectal Cancer.,"Early onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC.,330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed.,Of the 330 EO mCRC patients\, 31 carried pathogenic or likely pathogenic germline mutations\, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes\, including four in MUTHY\, three in RAD50\, one in TP53\, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC\, including TP53\, APC\, KRAS\, SMAD4\, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43\, RBM10\, TSC\, and BRAF V600E mutations were more commonly observed in EO mCRC\, while APC\, ASXL1\, DNMT3B\, and MET genes were more commonly altered in AO patients. At the pathway level\, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGF-β pathway (p = 0.023) were associated with unfavorable OS in EO mCRC.,Approximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.",Frontiers in oncology,vol.10::568911,2020,Journal Article,,,"Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Sichuan Cancer Center\, School of Medicine\, Sichuan Cancer Hospital and Institute\, University of Electronic Science and Technology of China\, Chengdu\, China.,Department of Radiation Oncology\, Beijing Tiantan Hospital\, Capital Medical University\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Burning Rock Biotech\, Guangzhou\, China.,Burning Rock Biotech\, Guangzhou\, China.,Burning Rock Biotech\, Guangzhou\, China.,Burning Rock Biotech\, Guangzhou\, China.,Burning Rock Biotech\, Guangzhou\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.,Department of Gastrointestinal Oncology\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing\, China.",,,,,"early onset colorectal cancer,genomic alternation,next generation sequencing,prognosis,susceptibility gene"
33195668,"Wang BB,Ye JR,Li YL,Jin Y,Chen ZW,Li JM,Li YP",Multisystem involvement Langerhans cell histiocytosis in an adult: A case report.,"Langerhans cell histiocytosis (LCH) is a rare condition wherein Langerhans cells proliferate abnormally\, adversely impacting organs including lymph nodes\, bones\, skin\, lungs\, and pituitary gland. The LCH disease course varies widely among patients from a self-limiting condition to one that progresses rapidly and culminates in death. It is uncommon for multisystem LCH to be observed in adults. Herein we describe a woman suffering from multi-system LCH involvement.,A 37-year old Chinese woman was admitted to the hospital in June 2019 suffering from dyspnea that had progressed over the course of 5 years. Her medical history included: central diabetes insipidus (DI) that had been treated via radiotherapy\, desmopressin acetate\, and bromocriptine; bilateral pneumothorax with two surgeries having been performed to remove bullae; and autoimmune hepatitis that had been unsuccessfully treated using a combination of methylprednisolone and mycophenolate mofetil. A chest computed tomography (CT) scan revealed the presence of multiple pulmonary cysts of varying sizes. We re-analyzed right pulmonary bullae samples that had been removed in 2014\, performed a systematic 18F-FDG PET/CT analysis\, and convened a multidisciplinary medical team to diagnose and treat this patient. As a result\, we were able to eventually diagnose this patient with LCH that was not associated with BRAF-V600E mutations.,We hope to emphasize the importance of systemic evaluation and of cooperation between multidisciplinary physicians with the goal of improving awareness and detection of this orphan disease.",World journal of clinical cases,vol.8:20:4966-4974,2020,Case Reports,,,"Department of Pulmonary and Critical Care Medicine\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China.,Department of Pulmonary and Critical Care Medicine\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China.,Department of Pulmonary and Critical Care Medicine\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China.,Pathology Department\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China.,Radiology Department\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China.,Pathology Department\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China.,Department of Pulmonary and Critical Care Medicine\, The First Affiliated Hospital of Wenzhou Medical University\, Wenzhou 325000\, Zhejiang Province\, China. wzliyp@163.com.",,,,,"Case report,Langerhans cell histiocytosis,Liver,Lung,Pituitary gland"
32712102,"Shi HA,Ng CWB,Kwa CT,Sim QXC","Ameloblastoma: A succinct review of the classification, genetic understanding and novel molecular targeted therapies.","Ameloblastomas are benign but locally invasive neoplasms which may grow to massive proportions and cause significant morbidity. Although some types of ameloblastoma can be treated predictably with aggressive surgical treatment, recurrent ameloblastoma and metastasising ameloblastoma are still difficult to treat. Recent studies have identified recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) signalling pathways in ameloblastoma. This development provided a possibility that molecular targeted therapies can be used as neoadjuvant treatment. In this review, we provide a summary of the latest WHO classification of ameloblastoma, the current understanding of genetic mutations and novel molecular targeted therapies arising from the recent developments.",The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland,vol.::,2020,Review,,,"Department of Oral & Maxillofacial Surgery\, National Dental Centre Singapore\, Singapore. Electronic address: adrian.shi.h.y@ndcs.com.sg.,Department of Oral & Maxillofacial Surgery\, National Dental Centre Singapore\, Singapore.,Department of Oral & Maxillofacial Surgery\, National Dental Centre Singapore\, Singapore.,Department of Oral & Maxillofacial Surgery\, National Dental Centre Singapore\, Singapore.",,,,,"Ameloblastoma,BRAF,Immunohistochemistry,Molecular targeted therapy,Odontogenic tumours"
32714544,"Dang Y,Gao H,Huang S,Qi T",Clinical complete regression after local radiotherapy combined with chemotherapy for stage IV rectal cancer: A case report.,"Colorectal cancer is the fourth most common type of cancer worldwide with about 0.8 million new cases annually. Improving patient survival remains a challenge for clinicians. Observation waiting method provides improved quality of life compared with direct surgery. This case report suggested that colorectal cancer patients could choose active observation waiting method for treatment. A 59-year-old male patient, with rectal bleeding and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, was admitted to the hospital due to increased fecal blood volume. The electronic colonoscopy revealed multiple polyps in colon and rectum, whereas the pathological biopsy indicated poorly differentiated rectal adenocarcinoma. The clinical stage was defined as T3N2M1a according to the TNM classification of the American Joint Committee on Cancer (AJCC) staging manual (version 8). In addition, positron emission tomography/computed tomography (PET/CT) examination showed non-regional lymph node metastasis (subclavian). Subsequently, the expression of PD-L1 (-), NRAS (-), KRAS (-), HRAS (-), BRAF (-) (-, negative) and the microsatellite stability (MSS) were detected in the rectal cancer lesion using molecular pathological examination. Patients with primary rectal cancer and pelvic lymph node metastasis were treated with three-dimensional conformal radiotherapy (3D-CRT; dose, 60 Gy/30 Fr) and XELOX chemotherapy (200 mg oxaliplatin at day 1 plus 1.5 g capecitabine twice a day from day 1-14 for a total of 5 cycles). PET/CT scan revealed that the metabolism levels of the lesion returned to normal. In addition, the routine re-examination showed progressive improvement of tumor lesions. Until recently, the carcinoembryonic antigen (CEA) level of the male patient has been within normal range. The observation waiting method rather than the direct sequential surgical resection of the primary lesion in patients with advanced rectal cancer who achieved complete clinical remission (CCR) may provide a novel treatment method for rectal cancer. Thus, overall survival (OS) and quality of survival (QoS) differences between the two strategies need to be further verified by multicenter clinical trials.",Molecular and clinical oncology,vol.13:2:186-190,2020,Journal Article,,,"Department of Radiation Oncology\, 986 Hospital of People's Liberation Army Air Force\, Xi'an\, Shaanxi 710054\, P.R. China.,Department of Oncology\, Chang An Hospital\, Xi'an\, Shaanxi 710018\, P.R. China.,Cancer Center\, Faculty of Health Sciences\, University of Macau\, Taipa\, Macao SAR 999078\, P.R. China.,Department of Radiation Oncology\, 986 Hospital of People's Liberation Army Air Force\, Xi'an\, Shaanxi 710054\, P.R. China.",,,,,"clinical complete response,observation waiting,radiotherapy,rectal cancer"
32714871,"Freitas HC,Torrezan GT,da Cunha IW,Macedo MP,Karen de Sá V,Corassa M,Ferreira ENE,Saito AO,Dal Molin GZ,Cordeiro de Lima VC,Carraro DM","Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic.","Objectives: Approximately 60% of lung adenocarcinomas (LAs) carry mutations that can guide treatment with tyrosine-kinase inhibitors (TKI) and other targeted therapies. Data on activating mutations in EGFR and other tyrosine-kinase receptor (TKR) genes in highly admixed populations, such as that of Brazil, are scarce. In this study, we comprehensively analyzed the actionable alteration profile of LA in Brazilian patients. Materials and Methods: EGFR driver mutation data were collected from a large Brazilian LA cohort covering an 8-year period of molecular testing in a single institution. Tests were performed using three distinct methods, and demographic and histopathological data were analyzed. For a subset of patients, driver mutations in KRAS, NRAS, and BRAF and gene fusions involving TKR genes (before TKI treatment) and EGFR T790M (after TKI treatment) were assessed. Results: EGFR mutations were detected in 25% of 1,316 LAs evaluated, with exon 19 deletions and exon 21 L858R TKI sensitizing mutations representing 72.5% of all mutations. Mutation rates were higher in women and non-smokers (p < 0.001). Next-generation sequencing was very sensitive, with a lower rate of inconclusive results compared with Sanger sequencing and pyrosequencing. EGFR/RAS/BRAF hotspot gene panels were applied in 495 LA cases and detected oncogenic mutations in 51.3% of samples, most frequently in EGFR (22.4%) and KRAS (26.9%). In subgroups of 36 and 35 patients, gene fusions were detected in 11.1% of tumors and EGFR T790M resistance mutations were detected in 59% of plasma samples from patients previously treated with TKI, respectively. Conclusion: This report provides the first comprehensive actionable alteration portrait of LA in Brazil. The high rate of actionable alterations in EGFR and other driver genes in LA reinforces the need to incorporate TKI guided by molecular diagnostics into clinical routines for patients in both public and private healthcare systems.",Frontiers in oncology,vol.10::1068,2020,Journal Article,,,"Medical Oncology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Genomics and Molecular Biology Group\, International Research Center\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Anatomic Pathology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Anatomic Pathology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Medical Oncology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Medical Oncology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Genomics and Molecular Biology Group\, International Research Center\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Medical Oncology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Medical Oncology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Medical Oncology Department\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.,Genomics and Molecular Biology Group\, International Research Center\, A.C. Camargo Cancer Center\, São Paulo\, Brazil.",,,,,"EGFR,driver mutations,lung adenocarcinoma,molecular testing,targeted therapies"
32718285,"Sur D,Havasi A,Gorzo A,Burz C",A Critical Review of Second-generation anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer.,"Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems\, including resistance and non-durable response\, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment\, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon.,In this review\, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies.,Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer\, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.",Current drug targets,vol.::,2020,Journal Article,,,"Department of Medical Oncology\, Faculty of Medicine\, ""Iuliu Hatieganu"" University of Medicine and Pharmacy\, ClujNapoca. Romania.,Department of Medical Oncology\, ""Ion Chiricuta"" Oncology Institute\, Cluj-Napoca. Romania.,Department of Medical Oncology\, ""Ion Chiricuta"" Oncology Institute\, Cluj-Napoca. Romania.,Department of Immunology and Allergology\, Faculty of Medicine\, ""Iuliu Hatieganu"" University of Medicine and Pharmacy\, Cluj-Napoca. Romania.",,,,,"Colorectal cancer,anti-EGFR,drug targets,metastatic,monoclonal antibodies,second-generation,therapy,trials"
31578731,"Verrienti A,Sponziello M,Durante C,Filetti S,Grani G",Comment on: BRAF mutation analysis by ARMS-PCR refines thyroid nodule management.,,Clinical endocrinology,vol.92:5:482-483,2020,Comment,"|Humans|,|Mutation|,|Polymerase Chain Reaction|,|Proto-Oncogene Proteins B-raf|genetics|,|Thyroid Neoplasms|,|Thyroid Nodule|",,"Department of Translational and Precision Medicine\, ""Sapienza"" University of Rome\, Rome\, Italy.,Department of Translational and Precision Medicine\, ""Sapienza"" University of Rome\, Rome\, Italy.,Department of Translational and Precision Medicine\, ""Sapienza"" University of Rome\, Rome\, Italy.,Department of Translational and Precision Medicine\, ""Sapienza"" University of Rome\, Rome\, Italy.,0000-0002-0388-1283Department of Translational and Precision Medicine\, ""Sapienza"" University of Rome\, Rome\, Italy.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,
31585718,"Ullmann TM,Liang H,Moore MD,Al-Jamed I,Gray KD,Limberg J,Stefanova D,Buicko JL,Finnerty B,Beninato T,Zarnegar R,Min IM,Fahey TJ",Dual inhibition of BRAF and MEK increases expression of sodium iodide symporter in patient-derived papillary thyroid cancer cells in vitro.,"The majority of papillary thyroid cancers are driven by acquired mutations typically in the BRAF or RAS genes that aberrantly activate the mitogen-activated protein kinase pathway. This process leads to malignant transformation\, dedifferentiation\, and a decrease in the expression of the sodium-iodide symporter (NIS; SLC5A5)\, which results in resistance to radioactive iodine therapy. We sought to determine whether inhibition of aberrant mitogen-activated protein kinase-signaling can restore NIS expression.,We prospectively developed cultures of papillary thyroid cancers derived from operative specimens and applied drug treatments for 24 hours. Samples were genotyped to identify BRAF and RAS mutations. We performed quantitative PCR to measure NIS expression after treatment.,We evaluated 24 patient papillary thyroid cancer specimens; BRAFV600E mutations were identified in 18 out of 24 (75.0%); 1 patient tumor had an HRAS mutation\, and the remaining 5 were BRAF and RAS wildtype. Dual treatment with dabrafenib and trametinib increased NIS expression (mean fold change 4.01 ± 2.04\, P < .001)\, and single treatment with dabrafenib had no effect (mean fold change 0.98 ± 0.42\, P = .84). Tumor samples that had above-median NIS expression increases came from younger patients (39 vs 63 years\, P < .05).,Dual treatment with BRAF and MEK inhibitors upregulated NIS expression\, suggesting that this treatment regimen may increase tumor iodine uptake. The effect was greatest in tumor cells from younger patients.",Surgery,vol.167:1:56-63,2020,"Research Support, Non-U.S. Gov't","|Adult|,|Age Factors|,|Aged|,|Antineoplastic Combined Chemotherapy Protocols|pharmacology|therapeutic use|,|Chemoradiotherapy|methods|,|Female|,|Gene Expression Regulation\, Neoplastic|drug effects|genetics|,|Humans|,|Imidazoles|pharmacology|therapeutic use|,|Iodine Radioisotopes|administration & dosage|metabolism|,|MAP Kinase Signaling System|drug effects|genetics|,|Male|,|Middle Aged|,|Mitogen-Activated Protein Kinase Kinases|antagonists & inhibitors|,|Mutation|,|Oximes|pharmacology|therapeutic use|,|Primary Cell Culture|,|Prospective Studies|,|Protein Kinase Inhibitors|pharmacology|therapeutic use|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Pyridones|,|Pyrimidinones|,|Radiation Tolerance|drug effects|genetics|,|Symporters|metabolism|,|Thyroid Cancer\, Papillary|genetics|pathology|therapy|,|Thyroid Neoplasms|genetics|pathology|therapy|,|Tumor Cells\, Cultured|,|Up-Regulation|drug effects|",,"Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York.,Department of Surgery\, New York Presbyterian Hospital-Weill Cornell Medical Center\, New York. Electronic address: tjfahey@med.cornell.edu.","Imidazoles,Iodine Radioisotopes,Oximes,Protein Kinase Inhibitors,Pyridones,Pyrimidinones,Symporters,trametinib,sodium-iodide symporter,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Mitogen-Activated Protein Kinase Kinases,HRAS protein\, human,Proto-Oncogene Proteins p21(ras),dabrafenib",,,,
31589789,"Costigan DC,Dong F",The extended spectrum of RAS-MAPK pathway mutations in colorectal cancer.,"Current clinical guidelines recommend mutation analysis for select codons in KRAS and NRAS exons 2, 3, and 4 and BRAF V600E to guide therapy selection and prognostic stratification in advanced colorectal cancer. This study evaluates the impact of extended molecular testing on the detection of RAS-MAPK pathway mutations. Panel next-generation sequencing results of colorectal cancer specimens from 5795 individuals from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) were included. Mutations in RAS-MAPK pathway genes were analyzed and functionally annotated. Colorectal cancers had recurrent pathogenic pathway activating mutations in KRAS (44%), NRAS (4%), HRAS (<1%), BRAF (10%), MAP2K1 (1%), RAF1 (<1%), and PTPN11 (<1%). The proportion of colorectal cancers with pathogenic RAS pathway mutations was 37% when only KRAS codon 12 and 13 mutations were considered, 46% when also including select KRAS and NRAS exons 2, 3, and 4 mutations, 53% when including BRAF V600E mutations, and 56% when including all pathogenic mutations. Panel next-generation sequencing testing identifies additional RAS-MAPK pathway driver mutations beyond current guideline recommendations. These mutations have potential implications in treatment selection for patients with advanced colorectal cancer.","Genes, chromosomes & cancer",vol.59:3:152-159,2020,"Research Support, Non-U.S. Gov't","|Biomarkers\, Tumor|,|Colorectal Neoplasms|genetics|metabolism|pathology|,|Databases\, Genetic|,|Female|,|GTP Phosphohydrolases|genetics|,|Humans|,|Male|,|Membrane Proteins|genetics|,|Mitogen-Activated Protein Kinases|metabolism|,|Mutation|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Signal Transduction|,|ras Proteins|genetics|metabolism|",,"Department of Pathology\, Brigham and Women's Hospital\, Harvard Medical School\, Boston\, Massachusetts.,0000-0003-3769-0247Department of Pathology\, Brigham and Women's Hospital\, Harvard Medical School\, Boston\, Massachusetts.","Biomarkers\, Tumor,KRAS protein\, human,Membrane Proteins,Mitogen-Activated Protein Kinases,GTP Phosphohydrolases,NRAS protein\, human,HRAS protein\, human,Proto-Oncogene Proteins p21(ras),ras Proteins",,,,"BRAF,EGFR,KRAS,NRAS,colorectal cancer"
31594564,"Dong L,Wang X,Wang S,Du M,Niu C,Yang J,Li L,Zhang G,Fu B,Gao Y,Wang J",Interlaboratory assessment of droplet digital PCR for quantification of BRAF V600E mutation using a novel DNA reference material.,"Droplet digital PCR (ddPCR) has attracted much attention in the detection of genetic signatures of cancer present at low levels in circulating tumor DNA (ctDNA) in blood. A growing number of laboratory-developed liquid biopsy tests based on such technology have become commercially available for clinical settings. To obtain consistent and comparable results, an international standard is necessary for validation of the analytical performance. In this study, a novel and SI-traceable ""ctDNA"" reference material (RM) carrying BRAF V600E was prepared by gravimetrically mixing a 152 bp PCR amplicon and sonicated wild-type genomic DNA. The ddPCR performance was evaluated by analyzing serial ""ctDNA"" dilutions using a competitive MGB assay. The mutant frequency concordance (k) between ddPCR and the gravimetrical value was 1.03 in the range from 53.9% to 0.1%. The limit of blank (LoB), detection (LoD) and quantification (LoQ) of ddPCR assay were determined to be 0.01%, 0.02% and 0.1%, respectively. Results from the interlaboratory study, using challenging low levels of BRAF V600E ctDNA RMs, demonstrated that the participating laboratories had the appropriate technical competency to perform accurate ddPCR-based low level of ratio measurements. However, a systematic error caused by uncorrected droplet volume in Naica Crystal ddPCR platform was found by using the ctDNA RM. Between-laboratory consistency in copy number measurement was greatly improved when a correct droplet volume was applied for the ddPCR measurement by using the ctDNA RM. This confirms that the ""ctDNA"" RM is fit for the validation of ddPCR systems for ctDNA quantification. This would also support translation of tests for circulating tumor DNA by ddPCR into routine use.",Talanta,vol.207::120293,2020,Journal Article,"|Circulating Tumor DNA|genetics|,|DNA Mutational Analysis|standards|,|Laboratories|,|Polymerase Chain Reaction|standards|,|Proto-Oncogene Proteins B-raf|genetics|,|Reference Standards|,|Uncertainty|",,"Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China. Electronic address: donglh@nim.ac.cn.,Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China.,Nanjing Institute of Measurement and Testing Technology\, Nanjing\, 210049\, PR China.,Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis\, Beijing Center for Physical & Chemical Analysis\, Beijing\, 100093\, PR China.,Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China.,Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China.,Biotechnology Research Institute\, Chinese Academy of Agricultural Sciences\, Beijing\, 100081\, PR China.,Oncology Department\, Beijing Hospital of Traditional Chinese Medicine\, Capital Medical University\, Beijing\, 100069\, PR China.,Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China.,Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China.,Center for Advanced Measurement Science\, National Institute of Metrology\, Beijing\, 100013\, PR China. Electronic address: wj@nim.ac.cn.","Circulating Tumor DNA,Proto-Oncogene Proteins B-raf",,,,"BRAF V600E mutation,Circulating tumor DNA,Copy number concentration,Droplet digital PCR,Reference material,Traceability"
31595523,"Kang YJ,Killen J,Caruana M,Simms K,Taylor N,Frayling IM,Snowsill T,Huxley N,Coupe VM,Hughes S,Freeman V,Boussioutas A,Trainer AH,Ward RL,Mitchell G,Macrae FA,Canfell K",The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.,"To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia.,We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch)\, explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017\, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS\, we modelled ongoing colonoscopic surveillance.,Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages\, under 50/60/70 years) and of colonoscopic surveillance interval (one\, two years).,The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance\, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER]\, $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER\, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER\, $11 525-$32 153/LYS)\, and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted).,Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.",The Medical journal of Australia,vol.212:2:72-81,2020,"Research Support, Non-U.S. Gov't","|Aged|,|Australia|epidemiology|,|Colonoscopy|economics|statistics & numerical data|,|Colorectal Neoplasms\, Hereditary Nonpolyposis|diagnosis|economics|mortality|,|Cost-Benefit Analysis|statistics & numerical data|,|Female|,|Genetic Testing|economics|,|Humans|,|Immunohistochemistry|economics|,|Male|,|Middle Aged|",,"0000-0003-4045-1941Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,Institute of Medical Genetics\, University Hospital of Wales\, Cardiff\, United Kingdom.,University of Exeter Medical School\, Exeter\, United Kingdom.,Centre for Health Economics\, Monash Business School\, Monash University\, Melbourne\, VIC.,Amsterdam Public Health Research Institute\, VU University Medical Center\, Amsterdam\, The Netherlands.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.,University of Melbourne\, Melbourne\, VIC.,Parkville Familial Cancer Centre\, Peter MacCallum Cancer Institute\, Melbourne\, VIC.,University of Sydney\, Sydney\, NSW.,Parkville Familial Cancer Centre\, Peter MacCallum Cancer Institute\, Melbourne\, VIC.,Royal Melbourne Hospital\, Melbourne\, VIC.,Cancer Research Division\, Cancer Council New South Wales\, Sydney\, NSW.",,,,,"Cancer,Colonoscopy,Cost-benefit analysis,Digestive system neoplasms,Early detection of cancer,Genetic testing,Health policy,Neoplasms\, epidemiology,Preventive health services,Public health"
32664549,"Herbreteau G,Vallée A,Knol AC,Théoleyre S,Quéreux G,Frénard C,Varey E,Hofman P,Khammari A,Dréno B,Denis MG",Circulating Tumour DNA Is an Independent Prognostic Biomarker for Survival in Metastatic or -Mutated Melanoma Patients.,"Circulating tumour DNA (ctDNA) can be used to identify gene alterations. The purpose of this study was to determine whether the detection of ctDNA, based on the identification of BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma. In total, 68 BRAF or NRAS-mutated stage IV or unresectable stage III metastatic cutaneous melanoma patients were included and tested for the presence of BRAF and NRAS mutations in circulating DNA before treatment initiation, using the Cobas BRAF/NRAS Mutation Test (Roche). The expected mutation was detected in the plasma of 34/68 patients (50% sensitivity). ctDNA detection was associated with AJCC stage, along with the number and nature of metastases. ctDNA was less frequently detected in NRAS-mutated than in BRAF-mutated melanoma (36% and 66%, respectively). At initiation of first-line treatment, ctDNA detection was associated with poor prognosis in Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis (log-rank: p = 0.002 and p < 0.0001, respectively). In multivariate analysis, ctDNA detection was an independent factor of poor prognosis in OS, after adjustment for AJCC stage, number and nature of metastases and gender (HR = 4.384; 95% CI: (1.308; 14.699); p = 0.017).",Cancers,vol.12:7:,2020,Journal Article,,,"Department of Biochemistry\, CHU Nantes\, 44093 Nantes\, France.,Department of Biochemistry\, CHU Nantes\, 44093 Nantes\, France.,Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) Inserm 1232\, Centre Hospitalier Universitaire de Nantes (CHU Nantes)\, 44093 Nantes\, France.,Department of Biochemistry\, CHU Nantes\, 44093 Nantes\, France.,Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) Inserm 1232\, Centre Hospitalier Universitaire de Nantes (CHU Nantes)\, 44093 Nantes\, France.,Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) Inserm 1232\, Centre Hospitalier Universitaire de Nantes (CHU Nantes)\, 44093 Nantes\, France.,Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) Inserm 1232\, Centre Hospitalier Universitaire de Nantes (CHU Nantes)\, 44093 Nantes\, France.,Laboratory of Clinical and Experimental Pathology\, Pasteur Hospital\, University Côte d'Azur\, 06000 Nice\, France.,0000-0001-9328-8004Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) Inserm 1232\, Centre Hospitalier Universitaire de Nantes (CHU Nantes)\, 44093 Nantes\, France.,Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) Inserm 1232\, Centre Hospitalier Universitaire de Nantes (CHU Nantes)\, 44093 Nantes\, France.,0000-0001-5865-3248Department of Biochemistry\, CHU Nantes\, 44093 Nantes\, France.",,Roche,,No number,"BRAF,NRAS,circulating tumour DNA,melanoma,mutation,prognosis"
32665205,"Lapthanasupkul P,Laosuk T,Ruangvejvorachai P,Aittiwarapoj A,Kitkumthorn N",Frequency of BRAF V600E mutation in a group of Thai patients with ameloblastomas.,"BRAF V600E mutation has recently been reported in a high proportion of ameloblastomas. This study was conducted to investigate the frequency of this mutation in ameloblastoma and unicystic ameloblastoma. The correlation between clinicopathologic data and BRAF V600E mutation was also analyzed.,A total of 51 archival samples of ameloblastomas and 22 cases of unicystic ameloblastomas were examined for BRAF V600E mutation by using anti-BRAF V600E (clone VE1) immunohistochemistry.,Positivity for anti-BRAF V600E antibody was detected in 72.5% (37 of 51) of ameloblastomas\, but the mutation showed no significant correlation with the clinicopathologic parameters. With regard to unicystic ameloblastoma\, 95.5% (21) of the 22 cases exhibited positive immunostaining for BRAF V600E\, whereas only 1 case showed the mural subtype of wild-type BRAF.,A high frequency of BRAF V600E mutation was detected in a group of Thai patients with ameloblastomas\, suggesting the future use of BRAF-targeted therapy in patients with BRAF-mutated ameloblastoma. However\, no significant association between BRAF V600E mutation and the clinicopathologic characteristics of ameloblastomas was found in our study.","Oral surgery, oral medicine, oral pathology and oral radiology",vol.::,2020,Journal Article,,,"Department of Oral and Maxillofacial Pathology\, Faculty of Dentistry\, Mahidol University\, Bangkok\, Thailand.,Department of Biochemistry\, Faculty of Science\, Chulalongkorn University\, Bangkok\, Thailand.,Department of Pathology\, Faculty of Medicine\, Chulalongkorn University\, Bangkok\, Thailand.,Department of Oral and Maxillofacial Pathology\, Faculty of Dentistry\, Mahidol University\, Bangkok\, Thailand.,Department of Oral Biology\, Faculty of Dentistry\, Mahidol University\, Bangkok\, Thailand. Electronic address: Nakarinkit@gmail.com.",,,,,
32665850,"Li QH,Wang YZ,Tu J,Liu CW,Yuan YJ,Lin R,He WL,Cai SR,He YL,Ye JN",Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.,"Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.",Gastroenterology report,vol.8:3:179-191,2020,Review,,,"Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Musculoskeletal Oncology\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,0000-0001-5786-4377Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Radiology\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.,Department of Gastrointestinal Surgery\, the First Affiliated Hospital of Sun Yat-sen University\, Guangzhou\, Guangdong\, P. R. China.",,,,,"EGFR,cetuximab,drug resistance,metastatic colorectal cancer,panitumumab"
32665851,"Li ZN,Zhao L,Yu LF,Wei MJ"," and mutations in metastatic colorectal cancer: future perspectives for personalized therapy.","Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.",Gastroenterology report,vol.8:3:192-205,2020,Review,,,"Department of Pharmacology\, School of Pharmacy\, China Medical University\, Shenyang\, Liaoning\, P. R. China.,Department of Pharmacology\, School of Pharmacy\, China Medical University\, Shenyang\, Liaoning\, P. R. China.,Department of Pharmacology\, School of Pharmacy\, China Medical University\, Shenyang\, Liaoning\, P. R. China.,Department of Pharmacology\, School of Pharmacy\, China Medical University\, Shenyang\, Liaoning\, P. R. China.",,,,,"BRAF mutation,KRAS mutation,epidermal growth factor receptor,metastatic colorectal cancer,personalized therapy"
32668867,"Takahashi S,Hanaka J,Takahashi M,Goya T",[Transverse Colon Cancer with Peritoneal Metastasis Successfully Treated with mFOLFOX6 plus Bevacizumab-A Case Report].,"A male patient in his 80s, diagnosed with rectal cancer, underwent transverse colon resection(pT3, pN0, cM0, and pStage Ⅱa, RAS wild-type, BRAF-mutant). However, 19 months later, intraperitoneal metastasis was detected and the patient received 8 courses of mFOLFOX6 plus bevacizumab. Following the observation of an allergic reaction that was attributable to oxaliplatin, the regimen was changed to a total of 7 courses of sLV5FU2 plus bevacizumab. Subsequently, a marked decrease was observed in intraperitoneal metastasis. The patient completed sLV5FU2 plus bevacizumab chemotherapy. At 1 year after the marked decrease, the metastatic recurrence was not exacerbated.",Gan to kagaku ryoho. Cancer & chemotherapy,vol.47:7:1125-1127,2020,Journal Article,"|Aged\, 80 and over|,|Antineoplastic Combined Chemotherapy Protocols|therapeutic use|,|Bevacizumab|,|Colon\, Transverse|,|Colonic Neoplasms|drug therapy|,|Fluorouracil|,|Humans|,|Leucovorin|,|Male|,|Organoplatinum Compounds|,|Peritoneal Neoplasms|",,"Dept. of Surgery\, Koyama Memorial Hospital.,,,","Organoplatinum Compounds,Bevacizumab,Leucovorin,Fluorouracil",,,,
32669268,"Tung JK,Neishaboori N,Haraldsdottir S,Suarez CJ",An amino-terminal deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer.,"Although combination therapy with RAF and EGFR inhibitors has improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating mutations in RASgenes, MAP2K mutations, and amplifications in BRAF, RAS genes, and EGFR In this report, we describe a patient with BRAF-mutated CRC who acquired an amino-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. Amino-terminal BRAF deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC for which there is only one prior report in the literature.",Cold Spring Harbor molecular case studies,vol.6:4:,2020,Journal Article,,,"Department of Pathology\, Stanford University School of Medicine\, Stanford\, California 94305\, USA.,Adaptive Biotechnologies\, Seattle\, Washington 98102\, USA.,Department of Oncology\, Dana-Farber Cancer Institute\, Boston\, Massachusetts 02215\, USA.,0000-0002-4531-9723Department of Pathology\, Stanford University School of Medicine\, Stanford\, California 94305\, USA.",,,,,"neoplasm of the gastrointestinal tract,neoplasm of the large intestine"
32669928,"Landego I,Hewitt D,Hibbert I,Dhaliwal D,Pieterse W,Grenier D,Wong R,Johnston J,Banerji V",PD-1 inhibition in malignant melanoma and lack of clinical response in chronic lymphocytic leukemia in the same patients: a case series.,"Chronic lymphocytic leukemia (cll) is the most common adult leukemia in the Western world. Unfortunately, affected patients are often immunosuppressed and at increased risk of infection and secondary malignancy. Previous meta-analysis has found that patients with cll have a risk of melanoma that is increased by a factor of 4 compared with the general population. Recent advances in the understanding of the PD receptor pathway have led to immunotherapies that target cancer cells. The use of PD-1 inhibitors is now considered first-line treatment for BRAF wild-type metastatic melanoma. Interestingly, early preclinical data suggest that inhibition of that pathway could also be used in the treatment of cll; however, recent clinical data did not support the effectiveness of that approach. In this case series, we highlight 2 cases in which patients with cll and concurrent malignant melanoma underwent treatment with PD-1 inhibitors and were found to experience reductions in their white blood cell counts without improvement in their hemoglobin. Those cases further illustrate that treatment of cll with PD-1 inhibitors is ineffective.","Current oncology (Toronto, Ont.)",vol.27:3:169-172,2020,Case Reports,,,"Department of Internal Medicine\, Rady College of Medicine\, Max Rady Faculty of Health Sciences\, University of Manitoba\, Winnipeg\, MB.,Research Institute of Oncology and Hematology\, CancerCare Manitoba and the University of Manitoba\, Winnipeg\, MB.,Department of Nursing\, CancerCare Manitoba\, Winnipeg\, MB.,Section of Hematology and Oncology\, Rady College of Medicine\, Max Rady Faculty of Health Sciences\, University of Manitoba\, Winnipeg\, MB.,Russell Health Centre\, Community Oncology Program\, Winnipeg\, MB.,Section of Hematology and Oncology\, Rady College of Medicine\, Max Rady Faculty of Health Sciences\, University of Manitoba\, Winnipeg\, MB.,Section of Hematology and Oncology\, Rady College of Medicine\, Max Rady Faculty of Health Sciences\, University of Manitoba\, Winnipeg\, MB.,Research Institute of Oncology and Hematology\, CancerCare Manitoba and the University of Manitoba\, Winnipeg\, MB.,Research Institute of Oncology and Hematology\, CancerCare Manitoba and the University of Manitoba\, Winnipeg\, MB.",,,,,"Immunotherapy,chronic lymphocytic leukemia,cll,melanoma"
32670650,"Myrdal CN,Sundararajan S",Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy.,"Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.",Case reports in oncological medicine,vol.2020::4392562,2020,Case Reports,,,"https://orcid.org/0000-0002-5723-5535University of Arizona College of Medicine\, Tucson\, AZ\, USA.,Hematology and Oncology\, Texas Oncology\, Houston\, TX\, USA.",,,,,
32671653,"Chin PD,Zhu CY,Sajed DP,Fishbein GA,Yeh MW,Leung AM,Livhits MJ",Correlation of ThyroSeq Results with Surgical Histopathology in Cytologically Indeterminate Thyroid Nodules.,"The ThyroSeq next-generation sequencing test refines the risk of malignancy in cytologically indeterminate thyroid nodules. Specific genetic alterations have distinct cancer probabilities and clinical phenotypes. There is limited data on the association between specific genetic alterations and histopathologic features. The aim of this study was to evaluate specific ThyroSeq alterations in prognosticating high-risk histopathologic characteristics. We performed a retrospective single-institution study of all patients diagnosed with indeterminate thyroid nodules (May 2016-December 2019) who had a mutation identified with ThyroSeq v2 or v3 and underwent surgical resection. Specific genetic alterations were correlated with surgical histopathology. The main outcomes were risk of malignancy and structural recurrence risk based on histopathologic features and the 2015 American Thyroid Association (ATA) risk stratification. Of the 78 nodules, 50 (64%) were thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on surgical histopathology. Nodules with high-risk TERT or TP53 combination mutations (TERT/TP53) and those with BRAF-like mutations were associated with a 100% probability of cancer and higher rates of extrathyroidal extension and regional nodal involvement than nodules with RAS-like mutations. Among nodules with RAS-like mutations, there was an even distribution between benign, NIFTP, and malignant results, the latter of which were all ATA low risk for structural disease recurrence. Overall, TERT/TP53 and BRAF-like ThyroSeq mutations are associated with an increased cancer probability and risk of recurrence defined by histopathologic features, while RAS-like mutations are associated with lower cancer probability and indolent disease. Individualized management, including extent of surgery, should be considered based on specific genetic alterations found in cytologically indeterminate thyroid nodules.",Endocrine pathology,vol.31:4:377-384,2020,Journal Article,,,"Section of Endocrine Surgery\, University of California Los Angeles David Geffen School of Medicine\, 10833 Le Conte Ave\, Suite 72-228 CHS\, Los Angeles\, CA\, 90095\, USA.,Section of Endocrine Surgery\, University of California Los Angeles David Geffen School of Medicine\, 10833 Le Conte Ave\, Suite 72-228 CHS\, Los Angeles\, CA\, 90095\, USA.,Division of Anatomic Pathology\, Department of Pathology and Laboratory Medicine\, University of California Los Angeles David Geffen School of Medicine\, Los Angeles\, CA\, USA.,Division of Anatomic Pathology\, Department of Pathology and Laboratory Medicine\, University of California Los Angeles David Geffen School of Medicine\, Los Angeles\, CA\, USA.,Section of Endocrine Surgery\, University of California Los Angeles David Geffen School of Medicine\, 10833 Le Conte Ave\, Suite 72-228 CHS\, Los Angeles\, CA\, 90095\, USA.,Department of Medicine\, Division of Endocrinology\, Diabetes\, and Metabolism\, University of California Los Angeles David Geffen School of Medicine\, Los Angeles\, CA\, USA.,Section of Endocrine Surgery\, University of California Los Angeles David Geffen School of Medicine\, 10833 Le Conte Ave\, Suite 72-228 CHS\, Los Angeles\, CA\, 90095\, USA. mlivhits@mednet.ucla.edu.",,,,,"Histopathology,Indeterminate FNA,Molecular alterations,Prognostication,ThyroSeq,Thyroid nodule"
32673997,"Bisschop C,de Heer EC,Brouwers AH,Hospers GAP,Jalving M",Rational use of F-FDG PET/CT in patients with advanced cutaneous melanoma: A systematic review.,"18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used in patients with advanced melanoma. Immune checkpoint inhibitors and BRAF/MEK-targeted therapy have transformed the therapeutic landscape of metastatic melanoma. Consequently, a need for markers predicting (early) response to treatment and for monitoring treatment (toxicity) has arisen. This systematic review appraises the current literature evidence for rational use of 18F-FDG PET/CT scans in staging, clinical decision-making, treatment monitoring and follow-up in advanced melanoma. 18F-FDG PET/CT has high overall accuracy for detection of distant metastases and is, combined with cerebral MRI, the preferred imaging strategy for staging metastatic melanoma. In contrast, strong evidence supporting the standard use of 18F-FDG PET/CT for predicting and monitoring therapy response and toxicity is currently lacking. Essential for determining the position of 18F-FDG PET/CT during treatment course in advanced melanoma are well-designed studies with standardized scanning protocols, incorporation of clinical parameters and comparison with contrast-enhanced CT alone.",Critical reviews in oncology/hematology,vol.153::103044,2020,Systematic Review,"|Fluorodeoxyglucose F18|,|Humans|,|Melanoma|,|Neoplasm Staging|,|Positron Emission Tomography Computed Tomography|,|Positron-Emission Tomography|,|Radiopharmaceuticals|,|Skin Neoplasms|drug therapy|",,"University of Groningen\, University Medical Center Groningen\, Department of Medical Oncology\, Groningen\, the Netherlands.,University of Groningen\, University Medical Center Groningen\, Department of Medical Oncology\, Groningen\, the Netherlands.,University of Groningen\, University Medical Center Groningen\, Department of Nuclear Medicine and Molecular Imaging\, Groningen\, the Netherlands.,University of Groningen\, University Medical Center Groningen\, Department of Medical Oncology\, Groningen\, the Netherlands.,University of Groningen\, University Medical Center Groningen\, Department of Medical Oncology\, Groningen\, the Netherlands. Electronic address: m.jalving@umcg.nl.","Radiopharmaceuticals,Fluorodeoxyglucose F18",,,,"(18)F-FDG,(18)F-fluorodeoxyglucose,BRAF(/MEK) inhibition,Imaging,Immunotherapy,Melanoma,PET/CT,Positron emission tomography"
32674932,"Lièvre A,de la Fouchardière C,Samalin E,Benoist S,Phelip JM,André T,Lledo G",[BRAF V600E-mutant colorectal cancers: Where are we?],"The BRAFV600E mutation, observed in 8 % of colorectal cancers (CRC), introduces a particular phenotype and a poor prognosis at the localized or metastatic stage. BRAF mutant CRCs are more often localized in the right colon, poorly differentiated and mucinous. They affect an older population (more often female) and are associated with a more frequent metastatic lymph node and peritoneal evolution. The BRAFV600E mutation is associated with a sporadic microsatellite instability (MSI) status in 20 to 40% of cases. In localized colon cancer, it does not imply any modification of the adjuvant treatment. In metastatic CRC, the first action must be the systematic search for an MSI phenotype, given its frequent association with the presence of a BRAF mutation, in order to propose immunotherapy that has been demonstrated to be very effective in MSI metastatic CRC. In non-MSI CRC, a first-line trichimiotherapy associated with bevacizumab is an option to be favored in patients in good general condition but the association with an anti-EGFR can be discussed, especially when the objective is tumor response. At the same time, surgical resection must be systematically discussed in the case of resectable hepatic metastases since the presence of a BRAFV600E mutation is not a risk factor for recurrence and that prolonged survival may be observed after surgery. In the second or third line, the triplet encorafenib, binimetinib and cetuximab, as well as the doublet encorafenib and cetuximab are superior to the association of irinotecan plus cetuximab in terms of response and survival (phase III study BEACON) and represent a new therapeutic standard. Their use on the front line is under study.",Bulletin du cancer,vol.107:9:881-895,2020,Review,"|Colorectal Neoplasms|genetics|therapy|,|Decision Trees|,|Humans|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|",,"Service des maladies de l'appareil digestif\, CHU Pontchaillou\, université Rennes 1\, Rennes\, France. Electronic address: astrid.lievre@chu-rennes.fr.,Département d'oncologie\, centre Léon-Bérard\, Lyon\, France.,Département d'oncologie\, institut du cancer de Montpellier (ICM)\, University Montpellier\, Montpellier et institut de génomique fonctionnelle\, CNRS\, inserm\, university Montpellier\, Montpellier\, France.,service de chirurgie digestive et oncologique\, CHU Bicêtre\, AP-HP\, université Paris-Saclay\, Le Kremlin Bicêtre\, France.,Service de gastroentérologie\, CHU Saint-Étienne\, Saint-Etienne\, France.,Département d'oncologie médicale\, Sorbonne université\, hôpital Saint-Antoine\, AP-HP\, 7512 Paris\, France.,Centre hospitalier Lyon Sud\, Lyon\, France.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"Anti-EGFR,BRAF mutation,Bevacizumab,Cancer colorectal métastatique,Encorafenib,Instabilité des microsatellites,Metastatic colorectal cancer,Microsatellite instability,Mutation de BRAF"
32675393,"Zhou DL,Liu Q,Xu BH,Li Y,Su X,Ye ZL,Zhang X,Peng JL,Deng L,Tang T,Shao Q,Ma JJ,Yang XH,He CY",lncRNA GAS8-AS1 genetic alterations in papillary thyroid carcinoma and their clinical significance.,"The long non-coding RNA (lncRNA) GAS8-AS1 is the second-most frequently altered gene, following the BRAF gene, in papillary thyroid carcinoma (PTC). We aimed to study the specificity and significance of genetic alterations in GAS8-AS1 in PTC. In this study, we reported the prevalence of genetic alterations of GAS8-AS1 in tissues of 48 nodular goiter, 573 papillary thyroid cancer, 95 colorectal cancer, 101 non-small cell lung cancer, 92 glioma, and 69 gastrointestinal stromal tumor patients, and in peripheral white blood cells of 286 healthy volunteers. We observed that the genomic sequence of GAS8-AS1 had a high frequency of genetic alterations in addition to the previously reported c.713A>G/714T>C substitution. Substitution of c.713A>G was completely linked with four other loci at c.714T>C, c.728A>G, c.737G>A, and c.752G>A. Two novel substitutions at c.749G>A and c.826A>G were also found. Interestingly, evidence from different samples indicated that these variations were not unique variants for PTC; they were also found in other malignant tissues and white blood cells of healthy volunteers. The c.713A>G substitution was associated with the T stage of PTC, while c.749G>A was more likely to occur in younger patients with PTC. PTC patients carrying heterozygous variants at the c.749 and c.826 loci had a higher risk of developing multiple lesions. These associations were also observed in patients with PTC and concomitant benign thyroid disease. Notably, the rare homozygous GG at the c.826 site conferred a higher risk of developing T2 PTC without benign thyroid disease, and a lower risk of developing T2 PTC with benign thyroid disease. Alterations of c.749G>A and c.826A>G had higher levels of serum TSH (thyroid stimulating hormone) in PTC subjects. Our study provides evidence that the detection of GAS8-AS1 genetic alterations would be useful in diagnostic screening and prognostic assessment of PTC.",Cancer biomarkers : section A of Disease markers,vol.29:2:255-264,2020,Journal Article,,,"Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Head and Neck\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.,Department of Molecular Diagnostics\, Sun Yat-Sen University Cancer Center\, State Key Laboratory of Oncology in South China\, Collaborative Innovation Center for Cancer Medicine\, Guangzhou\, Guangdong\, China.",,,,,"Papillary thyroid carcinoma,genetic variation,lncRNA,thyroid function"
32677947,"Xiong W,Du H,Ding W,Sun J,Xu M,Guo X",The association between pulmonary embolism and the cancer-related genomic alterations in patients with NSCLC.,"To date, the association between the acute pulmonary embolism (PE) and the currently existing cancer-related genomic alterations in patients with non-small cell lung cancer (NSCLC) has been understudied. We reviewed patients with a confirmed histopathological diagnosis of NSCLC who underwent computed tomography pulmonary angiography (CTPA) and molecular tests including ALK, ROS1, EGFR, BRAF V600E as well as PD-L1 during the diagnosis of NSCLC, to explore the association between the genomic alterations and PE. The results showed that, for the patients with positive results of genomic alterations, the proportion of positive ALK (13.6%vs8.5%, P<0.001) and PD-L1 (24.7%vs19.9%, P = 0.001) in PE group were more than those in Non-PE group. The patients with positive ALK and PD-L1 had the most (19.0%) and second most (15.4%) incidence of PE among all the patients being studied. A multivariate Logistic regression analysis showed that the positive ALK [1.685(1.065-2.215)(P<0.001)] and PD-L1[1.798(1.137-2.201)(P<0.001)] were correlated with the occurrence of PE. The positive results of ALK and PD-L1 genomic alterations may indicate an increased risk of pulmonary embolism in patients with NSCLC.",Respiratory research,vol.21:1:185,2020,Letter,,,"Department of Respiratory Medicine\, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine\, No. 1665\, Kongjiang Road\, Shanghai\, 200092\, Yangpu District\, China. xiongwei@xinhuamed.com.cn.,Department of Oncology\, Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine\, Shanghai\, China.,Department of Pulmonary and Critical Care Medicine\, Punan Hospital\, Pudong New District\, Shanghai\, China.,Department of Respiratory Medicine\, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine\, No. 1665\, Kongjiang Road\, Shanghai\, 200092\, Yangpu District\, China.,Department of General Practice\, North Bund Community Health Center\, Shanghai\, Hongkou District\, China. 15026472812@163.com.,Department of Respiratory Medicine\, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine\, No. 1665\, Kongjiang Road\, Shanghai\, 200092\, Yangpu District\, China. guoxuejun@xinhuamed.com.cn.",,,,,"Association,Genomic alterations,NSCLC,Pulmonary embolism"
32679231,"Gassenmaier M,Rentschler M,Fehrenbacher B,Eigentler TK,Ikenberg K,Kosnopfel C,Sinnberg T,Niessner H,Bösmüller H,Wagner NB,Schaller M,Garbe C,Röcken M","Expression of DNA Methyltransferase 1 Is a Hallmark of Melanoma, Correlating with Proliferation and Response to B-Raf and Mitogen-Activated Protein Kinase Inhibition in Melanocytic Tumors.","Aberrant DNA methylation is an epigenetic hallmark of melanoma, but the expression of DNA methyltransferase (Dnmt)-1 in melanocytic tumors is unknown. Dnmt1 expression was analyzed in primary melanocytes, melanoma cell lines, and 83 melanocytic tumors, and its associations with proliferation, mutational status, and response to B-Raf and mitogen-activated protein kinase kinase (MEK) inhibition were explored. Dnmt1 expression was increased incrementally from nevi [mean fluorescence intensity (MFI), 48.1; interquartile range, 41.7 to 59.6] to primary melanomas (MFI, 68.8; interquartile range, 58.4 to 77.0) and metastatic melanomas (MFI, 87.5; interquartile range, 77.1 to 114.5) (P < 0.001). Dnmt1 expression was correlated with Ki-67 expression (Spearman correlation, 0.483; P < 0.001) and was independent of BRAF mutation status (P = 0.55). In BRAF-mutant melanoma, Dnmt1 was down-regulated during response to B-Raf and MEK inhibition and was again up-regulated on drug resistance in vitro and in vivo. Degradation of Dnmt1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid was associated with decreased cell viability in B-Raf inhibitor-sensitive and -resistant cell lines. This study demonstrates that Dnmt1 expression is correlated with proliferation in melanocytic tumors, is increased with melanoma progression, and is associated with response to B-Raf and MEK inhibition. Given its strong expression in metastatic melanoma, Dnmt1 may be a promising target for combined epigenetic and immunotherapy.",The American journal of pathology,vol.190:10:2155-2164,2020,"Research Support, Non-U.S. Gov't","|Cell Line\, Tumor|,|Cell Proliferation|drug effects|,|DNA|drug effects|metabolism|,|Histone Deacetylase Inhibitors|therapeutic use|,|Humans|,|Melanocytes|drug effects|metabolism|,|Melanoma|genetics|metabolism|pathology|,|Mitogen-Activated Protein Kinase Kinases|metabolism|,|Mitogen-Activated Protein Kinases|drug effects|metabolism|,|Protein Kinase Inhibitors|pharmacology|,|Proto-Oncogene Proteins B-raf|genetics|metabolism|,|Skin Neoplasms|genetics|metabolism|,|Vorinostat|pharmacology|",,"Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany. Electronic address: maximilian.gassenmaier@med.uni-tuebingen.de.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Institute of Pathology and Molecular Pathology\, University Hospital Zurich\, Zurich\, Switzerland.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Institute of Pathology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Cantonal Hospital St. Gallen\, St. Gallen\, Switzerland.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.,Department of Dermatology\, Eberhard Karls University of Tübingen\, Tübingen\, Germany.","Histone Deacetylase Inhibitors,Protein Kinase Inhibitors,Vorinostat,DNA,Proto-Oncogene Proteins B-raf,Mitogen-Activated Protein Kinases,Mitogen-Activated Protein Kinase Kinases",,,,
31576556,"Chui MH,Shih IM",Oncogenic BRAF and KRAS mutations in endosalpingiosis.,"Endosalpingiosis, a microscopic lesion composed of ectopic Fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian serous borderline tumour or low-grade serous carcinoma, but its pathogenic significance remains unclear. Using laser-capture microdissection and droplet digital PCR, we investigated whether endosalpingiosis harbours the driver mutations in BRAF and KRAS that characterise ovarian low-grade serous neoplasms. Somatic mutations were detected in 14 (33%) of 43 endosalpingiotic lesions analysed. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low-grade serous tumour, mutations were identified in endosalpingiotic lesions from 11 (52%) women, with most cases (10/11, 91%) demonstrating identical mutations in both tumour and endosalpingiosis. In contrast, of 13 cases of endosalpingiosis not associated with an ovarian tumour, only one harboured a KRAS mutation. The proliferative activity as assessed by Ki-67 immunohistochemistry was lower in endosalpingiosis than in low-grade serous tumours, and endosalpingiosis with either a BRAF or KRAS mutation had a significantly lower Ki-67 index than those without. Ectopic expression of KRASG12V in Fallopian tube epithelial cells led to ERK phosphorylation, p21 induction, growth arrest and cellular senescence. In conclusion, we demonstrate that endosalpingiosis represents an interesting example of cancer driver mutations in deceptively normal-appearing cells, which may be prone to neoplastic transformation upon bypass of endogenous oncosuppressive mechanisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",The Journal of pathology,vol.250:2:148-158,2020,"Research Support, Non-U.S. Gov't","|Cell Proliferation|genetics|,|Cell Transformation\, Neoplastic|,|Cells\, Cultured|,|Choristoma|genetics|pathology|,|Cystadenocarcinoma\, Serous|genetics|,|Epithelial Cells|pathology|,|Fallopian Tubes|,|Female|,|Humans|,|Laser Capture Microdissection|methods|,|Lymphatic Diseases|genetics|pathology|,|Mutation|,|Ovarian Neoplasms|genetics|,|Peritoneal Diseases|genetics|pathology|,|Precancerous Conditions|genetics|pathology|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|",,"0000-0002-7220-3996Department of Pathology\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.,Department of Gynecology and Obstetrics\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.","Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)",CIHR,Canada,,"endosalpingiosis,low-grade serous carcinoma,mutation,precursor lesion,serous borderline tumour"
33110363,"Karakurt S,AbuŞoĞlu G,Arituluk ZC",Comparison of anticarcinogenic properties of Viburnum opulus and its active compound p-coumaric acid on human colorectal carcinoma.,"Resistance to therapeutic agents and the highly toxic side effects of synthetic drugs has spurred new research in the treatment of colon cancer, which has high morbidity and mortality ratios. This study aims to clarify the molecular mechanisms of the anticarcinogenic properties of methanol extract of Viburnum opulus L. (EVO)and its main active compound, trans-p -coumaric acid ( p -CA), on human colon cancer cells (DLD-1, HT-29, SW-620, Caco-2) and healthy colon epithelial cells (CCD-18Co). The effects of EVO on controlled cell death (apoptosis) and the cell division cycle were determined by flow cytometry. Alteration in mRNA and protein expressions of switch genes in colorectal carcinoma (APC, MLH1, TP53, SMAD4, KRAS, and BRAF) were determined by qRT-PCR and Western blot, respectively. Our results show that EVO possesses a strong reducing capacity and free-radical scavenging activity. HPLC analyses prove that p -CAis the main compound of EVO. EVO and p -CA inhibit the proliferation of human colon cancer cells DLD-1 and HT-29 in a dose-dependent manner. EVO increases apoptosis of DLD-1 cells and halts the cell cycle in the G2 stage in HT-29 cells. mRNA and protein expressions of p53 and SMAD-4 are upregulated, while BRAFs are downregulated. The results were directly proportional to p -CA. EVO and p -CA up- and downregulate switch genes and protein expressions of DLD-1 cells, which alter the expression of 186 other genes. This is the first study of pharmacological exploration of V.opulus in human colon cancer. Its antiproliferative effects may be due to the presence of p -CA.",Turkish journal of biology = Turk biyoloji dergisi,vol.44:5:252-263,2020,Journal Article,,,"https://orcid.org/0000-0002-4449-6103Department of Biochemistry\, Faculty of Science\, Selçuk University\, Konya Turkey.,https://orcid.org/0000-0003-1630-1257Department of Medical Laboratory Techniques\, Vocational School of Health\, Selçuk University\, Konya Turkey.,https://orcid.org/0000-0003-3986-4909Department of Pharmaceutical Botany\, Faculty of Pharmacy\, Hacettepe University\, Ankara Turkey.",,,,,"BRAF,Colorectal carcinoma,TP53,Viburnum opulus,apoptosis,cell cycle,p-coumaric acid"
33115526,"Luchini C,Paolino G,Mattiolo P,Piredda ML,Cavaliere A,Gaule M,Melisi D,Salvia R,Malleo G,Shin JI,Cargnin S,Terrazzino S,Lawlor RT,Milella M,Scarpa A",KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities.,"Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.",Journal of experimental & clinical cancer research : CR,vol.39:1:227,2020,Review,,,"Department of Diagnostics and Public Health\, Section of Pathology\, University of Verona\, 37134\, Verona\, Italy.,Department of Diagnostics and Public Health\, Section of Pathology\, University of Verona\, 37134\, Verona\, Italy.,Department of Diagnostics and Public Health\, Section of Pathology\, University of Verona\, 37134\, Verona\, Italy.,ARC-Net Research Center\, University and Hospital Trust of Verona\, 37134\, Verona\, Italy.,Section of Oncology\, Department of Medicine\, University and Hospital Trust of Verona\, Piazzale L.A. Scuro 10\, 37134\, Verona\, VR\, Italy.,Section of Oncology\, Department of Medicine\, University and Hospital Trust of Verona\, Piazzale L.A. Scuro 10\, 37134\, Verona\, VR\, Italy.,Section of Oncology\, Department of Medicine\, University and Hospital Trust of Verona\, Piazzale L.A. Scuro 10\, 37134\, Verona\, VR\, Italy.,Department of Surgery\, University of Verona\, 37134\, Verona\, Italy.,Department of Surgery\, University of Verona\, 37134\, Verona\, Italy.,Yonsei University College of Medicine\, 03722\, Seoul\, Republic of Korea.,Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF)\, University of Piemonte Orientale\, 28100\, Novara\, Italy.,Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF)\, University of Piemonte Orientale\, 28100\, Novara\, Italy.,ARC-Net Research Center\, University and Hospital Trust of Verona\, 37134\, Verona\, Italy.,http://orcid.org/0000-0002-3826-5237Section of Oncology\, Department of Medicine\, University and Hospital Trust of Verona\, Piazzale L.A. Scuro 10\, 37134\, Verona\, VR\, Italy. michele.milella@univr.it.,Department of Diagnostics and Public Health\, Section of Pathology\, University of Verona\, 37134\, Verona\, Italy.",,"Associazione Italiana per la Ricerca sul Cancro,Fondazione Cariverona: Oncology Biobank Project ""Antonio Schiavi""",",","12182,203885/2017","BRAF,KRAS,MSI,dMMR,fusion genes,pancreatic cancer"
33116270,"Yoshitake R,Saeki K,Eto S,Shinada M,Nakano R,Sugiya H,Endo Y,Fujita N,Nishimura R,Nakagawa T",Author Correction: Aberrant expression of the COX2/PGE axis is induced by activation of the RAF/MEK/ERK pathway in BRAF canine urothelial carcinoma.,An amendment to this paper has been published and can be accessed via a link at the top of the paper.,Scientific reports,vol.10:1:18820,2020,Published Erratum,,,"Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.,http://orcid.org/0000-0001-7432-660XLaboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan. kohei.saeki.1987@gmail.com.,Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.,http://orcid.org/0000-0001-5639-8087Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.,http://orcid.org/0000-0003-0255-6347Laboratory of Veterinary Biochemistry\, Department of Veterinary Medicine\, Nihon University College of Bioresource Sciences\, 1866 Kameino\, Fujisawa\, Kanagawa\, 252-0880\, Japan.,Laboratory of Veterinary Biochemistry\, Department of Veterinary Medicine\, Nihon University College of Bioresource Sciences\, 1866 Kameino\, Fujisawa\, Kanagawa\, 252-0880\, Japan.,Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.,http://orcid.org/0000-0001-7815-2192Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.,Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.,Laboratory of Veterinary Surgery\, Graduate School of Agricultural and Life Sciences\, University of Tokyo\, 1-1-1\, Yayoi\, Bunkyo-ku\, Tokyo\, 113-8657\, Japan.",,,,,
33116365,"Gkiala A,Palioura S","Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies.","To present the molecular mechanisms involved in the pathogenesis of conjunctival melanoma (CM) and review the existing literature on targeted molecular inhibitors as well as immune checkpoint inhibitors for the management of locally advanced and metastatic disease.,A comprehensive review of the literature was performed using the keywords ""conjunctival melanoma""\, ""immune checkpoint inhibitors""\, ""BRAF inhibitors""\, ""MEK inhibitors""\, ""CTLA4 inhibitors""\, ""PD1 inhibitors""\, ""c-KIT mutations""\, ""BRAF mutations""\, ""NRAS mutations""\, ""dabrafenib""\, ""trametinib""\, ""vemurafenib""\, ""ipilimumab""\, ""pembrolizumab""\, and ""nivolumab"". A total of 250 articles were reviewed and 120 were included in this report.,Mutations of mediators in the MAP kinase pathway\, such as RAS\, BRAF\, MEK and ERK\, and mutations of the PI3K/AKT/mTOR pathway play a major role in the pathogenesis of conjunctival melanoma. In addition\, alterations of c-KIT\, NF1\, TERT\, chemokine receptors as well as chromosomal copy number alterations and micro RNAs are thought to have a causative association with CM development. Targeted molecular inhibitors\, such as BRAF and MEK inhibitors\, are currently being implemented in the therapy of BRAF-mutated CM. Furthermore\, immune checkpoint PD-1 and CTLA4 inhibitors with favorable clinical outcomes in the treatment of cutaneous melanoma have increased recurrence-free survival and reduced metastatic spread in CM cases.,The complex molecular mechanisms that contribute to the development of CM can be targeted both by molecular inhibitors of oncogenic pathways as well as immune checkpoint inhibitors in order to halt progression of the disease and increase survival.","Clinical ophthalmology (Auckland, N.Z.)",vol.14::3137-3152,2020,Review,,,"National and Kapodistrian University of Athens School of Medicine\, Athens\, Greece.,Athens Vision Eye Institute\, Athens\, Greece.",,,,,"BRAF inhibitors,BRAF mutations,CTLA4 inhibitors,MEK inhibitors,NRAS mutations,PD1 inhibitors,c-KIT mutations,dabrafenib,immune checkpoint inhibitors,ipilimumab,nivolumab,pembrolizumab,trametinib,vemurafenib"
33117675,"Qin C,Long W,Zhang C,Xie Y,Wu C,Li Y,Xiao Q,Ji N,Liu Q",Multidisciplinary Therapy Managed Recurrent Glioblastoma in a BRAF-V600E Mutant Pregnant Female: A Case Report and Review of the Literature.,"Background: Glioblastoma (GBM) is the most malignant intracranial tumor in adults. However, the overall management of GBM in pregnancy is rarely reported. How to balance the therapeutic benefits to the mother and risks to the fetus remains hugely challenging for clinicians. The application of specific targeting therapy combined with conventional treatment sheds light on a longer lifetime for the patients suffering from GBM. Case Presentation: We present a pregnant female at 20 weeks gestation diagnosed with GBM. Surgical resection was initially performed without adjuvant therapy, and the tumor recurred de novo 2 months later. A secondary craniotomy and cesarean section were performed simultaneously at 32 weeks gestation, both the patient and infant were survived. She was subsequently treated with traditional chemo-radiotherapy. No other identified genetic alterations indicating an optimistic prognosis were detected except for BRAF V600E mutation. Thus, the BRAF inhibitor was placed on her with achieving a good clinical outcome of more than 2-year survival without recurrence. Conclusion: Personalized multidisciplinary therapy should be considered when GBMs occur in pregnancy. Response to the therapy in this presenting case suggests that BRAF V600E mutation is a favorable biomarker for GBM. The mortality of GBM might be reduced through genetic testing and targeted treatment. However, more studies must be conducted to confirm our observation.",Frontiers in oncology,vol.10::522816,2020,Case Reports,,,"Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.,Department of Neurosurgery in Beijing Tiantan Hospital\, Capital Medical University\, Beijing\, China.,Department of Neurosurgery in Xiangya Hospital\, Central South University\, Changsha\, China.",,,,,"BRAF V600E,glioblastoma (GBM),multidisciplinary therapy (MDT),pregnancy,vemurafenib"
33117686,"Luo Y,Jiang H,Xu W,Wang X,Ma B,Liao T,Wang Y","Clinical, Pathological, and Molecular Characteristics Correlating to the Occurrence of Radioiodine Refractory Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis.","Background: Recently, radioiodine refractory differentiated thyroid cancer (RR-DTC) has received increasing attention due to its poor prognosis. The roles of clinical, pathological, and molecular features in the development of RR-DTC remain controversial and require additional investigation. This study aimed to evaluate the association between these risk factors and the occurrence of RR-DTC. Methods: We performed a systematic search for relevant literature following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in PubMed, EMBASE, Medline, SCOPUS, and Web of Science up to the July 15, 2020. Observational studies that investigated the risk factors for RR-DTC were included. Fixed- or random-effects models were used to calculate pooled odds ratios (ORs) or mean differences (MD) with corresponding 95% confidence intervals. Results: We included 13 eligible studies incorporating 1,431 cases, of which 603 were patients with RR-DTC. The pooled analysis indicated that four parameters significantly increased the risk of RR-DTC: extrathyroidal extension (ETE) (OR: 2.28, 95% CI: 1.43-3.64, I 2 = 14%), BRAF V600E mutation (OR: 3.60, 95% CI: 1.74-7.46, I 2 = 69%), TERT promoter mutation (OR: 9.84, 95% CI: 3.60-26.89, I 2 = 61%) and high-risk histological subtype (OR: 1.94, 95% CI: 1.15-3.27, I 2 = 15%), including tall cell variant papillary thyroid carcinoma (PTC), sclerosing diffuse PTC, hobnail variant PTC, follicular thyroid carcinoma (FTC) (including Hürthle cell), and poorly differentiated thyroid carcinoma (PDTC). However, there was no statistical significance regarding sex, age, tumor size, multifocality, or lateral lymph node metastasis. Subgroup and sensitivity analyses were conducted to further confirm the robustness of the results. Conclusions: Histological subtype, ETE, BRAF V600E mutation, and TERT promoter mutation could be considered clinicopathological factors and biomarkers. They could assist in risk stratification, prognostic prediction, and individual therapy options for RR-DTC.",Frontiers in oncology,vol.10::549882,2020,Systematic Review,,,"Department of Head and Neck Surgery\, Fudan University Shanghai Cancer Center\, Fudan University\, Shanghai\, China.,Department of Head and Neck Surgery\, Fudan University Shanghai Cancer Center\, Fudan University\, Shanghai\, China.,Department of Head and Neck Surgery\, Fudan University Shanghai Cancer Center\, Fudan University\, Shanghai\, China.,Department of Head and Neck Surgery\, Fudan University Shanghai Cancer Center\, Fudan University\, Shanghai\, China.,Department of Head and Neck Surgery\, Fudan University Shanghai Cancer Center\, Fudan University\, Shanghai\, China.,Department of Oncology\, Shanghai Medical College\, Fudan University\, Shanghai\, China.,Department of Head and Neck Surgery\, Fudan University Shanghai Cancer Center\, Fudan University\, Shanghai\, China.",,,,,"meta-analysis,poorly differentiated thyroid cancer,radioactive iodine refractory (RAIR),risk factors,thyroid cancer"
33120354,"Santana NO,Lerario AM,Schmerling CK,Marui S,Alves VAF,Hoff AO,Kopp P,Danilovic DLS",Molecular profile of Hürthle cell carcinomas: recurrent mutations in the Wnt/β-catenin pathway.,"Genomic alterations in Hürthle cell carcinomas (HCC) include chromosomal losses\, mitochondrial DNA mutations\, and changes in the expression profile of the PI3K-AKT-mTOR and Wnt/β-catenin pathways. This study aimed at characterizing the mutational profile of HCC.,Next-generation sequencing (NGS) of 40 HCC using a 102-gene panel including\, among others\, the MAPK\, PI3K-AKT-mTOR\, Wnt/β-catenin\, and Notch pathways. HCC was widely invasive in 57.5%\, and lymph node and distant metastases were diagnosed in 5% and 7.5% of cases. During follow-up\, 10% of patients presented with persistent/recurrent disease\, but there were no cancer-related deaths.,Genetic alterations were identified in 47.5% of HCC and comprised 190 single-nucleotide variants and 5 insertions/deletions. The Wnt/β-catenin pathway was most frequently affected (30%)\, followed by MAPK (27.5%) and PI3K-AKT-mTOR (25%). FAT1 and APC were the most frequently mutated genes and present in 17.5%. RAS mutations were present in 12.5% but no BRAF mutation was found. There was no association between the mutational profile and clinicopathological features.,This series of HCC presents a wide range of mutations in the Wnt/β-catenin\, MAPK and PI3K-AKT-mTOR pathways. The recurrent involvement of Wnt/β-catenin pathway\, particularly mutations in APC and FAT1\, are of particular interest. The data suggest that mutated FAT1 may represent a potential novel driver in HCC tumorigenesis and that the Wnt/β-catenin pathway plays a critical role in this distinct thyroid malignancy.",European journal of endocrinology,vol.183:6:647-656,2020,Journal Article,"|Adenoma\, Oxyphilic|genetics|,|Adenomatous Polyposis Coli Protein|genetics|,|Aged|,|Cadherins|genetics|,|Female|,|Gene Expression Regulation\, Neoplastic|genetics|,|High-Throughput Nucleotide Sequencing|,|Humans|,|Male|,|Middle Aged|,|Polymorphism\, Single Nucleotide|,|Retrospective Studies|,|Thyroid Neoplasms|genetics|,|Wnt Signaling Pathway|genetics|,|beta Catenin|genetics|",,"Laboratorio de Endocrinologia Celular e Molecular (LIM25)\, Hospital das Clinicas HCFMUSP\, Faculdade de Medicina\, Universidade de Sao Paulo\, Sao Paulo\, Brazil.,Division of Metabolism\, Endocrinology and Diabetes\, Department of Internal Medicine\, University of Michigan\, Ann Arbor\, Michigan\, USA.,Pathology\, Hospital das Clinicas HCFMUSP\, Faculdade de Medicina\, Universidade de Sao Paulo\, Sao Paulo\, Brazil.,Laboratorio de Endocrinologia Celular e Molecular (LIM25)\, Hospital das Clinicas HCFMUSP\, Faculdade de Medicina\, Universidade de Sao Paulo\, Sao Paulo\, Brazil.,Pathology\, Hospital das Clinicas HCFMUSP\, Faculdade de Medicina\, Universidade de Sao Paulo\, Sao Paulo\, Brazil.,Endocrinology\, Instituto do Cancer do Estado de Sao Paulo\, Faculdade de Medicina\, Universidade de Sao Paulo\, Sao Paulo\, Brazil.,Division of Endocrinology\, Diabetes and Metabolism\, University of Lausanne\, Lausanne\, Switzerland.,Laboratorio de Endocrinologia Celular e Molecular (LIM25)\, Hospital das Clinicas HCFMUSP\, Faculdade de Medicina\, Universidade de Sao Paulo\, Sao Paulo\, Brazil.","APC protein\, human,Adenomatous Polyposis Coli Protein,CTNNB1 protein\, human,Cadherins,FAT1 protein\, human,beta Catenin",,,,
33120984,"Rangel-Pozzo A,Sisdelli L,Cordioli MIV,Vaisman F,Caria P,Mai S,Cerutti JM",Genetic Landscape of Papillary Thyroid Carcinoma and Nuclear Architecture: An Overview Comparing Pediatric and Adult Populations.,"Thyroid cancer is a rare malignancy in the pediatric population that is highly associated with disease aggressiveness and advanced disease stages when compared to adult population. The biological and molecular features underlying pediatric and adult thyroid cancer pathogenesis could be responsible for differences in the clinical presentation and prognosis. Despite this, the clinical assessment and treatments used in pediatric thyroid cancer are the same as those implemented for adults and specific personalized target treatments are not used in clinical practice. In this review, we focus on papillary thyroid carcinoma (PTC), which represents 80-90% of all differentiated thyroid carcinomas. PTC has a high rate of gene fusions and mutations, which can influence the histologic subtypes in both children and adults. This review also highlights telomere-related genomic instability and changes in nuclear organization as novel biomarkers for thyroid cancers.",Cancers,vol.12:11:,2020,Review,,,"Cell Biology\, Research Institute of Oncology and Hematology\, University of Manitoba\, CancerCare Manitoba\, Winnipeg\, MB R3E 0V9\, Canada.,Genetic Bases of Thyroid Tumors Laboratory\, Division of Genetics\, Department of Morphology and Genetics\, Universidade Federal de São Paulo/EPM\, São Paulo SP 04039-032\, Brazil.,Genetic Bases of Thyroid Tumors Laboratory\, Division of Genetics\, Department of Morphology and Genetics\, Universidade Federal de São Paulo/EPM\, São Paulo SP 04039-032\, Brazil.,Instituto Nacional do Câncer\, Rio de Janeiro RJ 22451-000\, Brazil.,Department of Biomedical Sciences\, University of Cagliari\, 09042 Cagliari\, Italy.,0000-0002-5797-2201Cell Biology\, Research Institute of Oncology and Hematology\, University of Manitoba\, CancerCare Manitoba\, Winnipeg\, MB R3E 0V9\, Canada.,Genetic Bases of Thyroid Tumors Laboratory\, Division of Genetics\, Department of Morphology and Genetics\, Universidade Federal de São Paulo/EPM\, São Paulo SP 04039-032\, Brazil.",," CIHR,Fundação de Amparo à Pesquisa do Estado de São Paulo","Canada,","o,2014/06570-6","AGK-BRAF,BRAFV600E,Papillary thyroid carcinoma,RET/PTC,genomic instability,nuclear architecture,pediatric"
33120998,"Swami U,Chennamadhavuni A,Borcherding N,Bossler AD,Mott SL,Garje R,Zakharia Y,Milhem M",Multivariable Analysis of 169 Cases of Advanced Cutaneous Melanoma to Evaluate Antibiotic Exposure as Predictor of Survival to Anti-PD-1 Based Immunotherapies.,"Recently antibiotic exposure has been associated with worse outcomes in patients undergoing treatment with antibodies directed against programmed cell death protein-1 (PD-1). We reviewed data of 1264 patients enrolled at Melanoma Skin and Ocular Tissue Repositories at University of Iowa Hospitals and Clinic. Reviewed data included patient demographics, prior medical history, baseline hematologic and disease parameters and outcomes including progression-free survival (PFS) and overall survival (OS). Cox regression models were used to determine predictive markers. Overall, 169 patients with advanced cutaneous melanoma received anti-PD-1 based therapies. Median follow up was 18.46 (range 0.89 to 62.52) months. On multivariable analysis brain metastasis, higher absolute neutrophil count (ANC) and lower absolute lymphocyte count were associated with poorer PFS while brain and liver metastasis and lower albumin were associated with poorer OS. Prior antibiotics, radiation as well as age, gender, basal metabolic index (BMI), smoking status, BRAF mutation, line of therapy (first or latter), prior treatments (ipilimumab or BRAF inhibitors), hemoglobin, neutrophil-to-lymphocyte ratio, white blood cell, platelet and eosinophil counts were not associated with PFS or OS in multivariable analysis. Contrary to some prior studies BMI, radiation, and antibiotics were not associated with PFS or OS.","Antibiotics (Basel, Switzerland)",vol.9:11:,2020,Journal Article,,,"0000-0003-3518-0411Department of Internal Medicine\, Division of Oncology\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, UT 84112\, USA.,0000-0002-8730-4343Holden Comprehensive Cancer Center\, University of Iowa\, Iowa City\, IA 52242\, USA.,Holden Comprehensive Cancer Center\, University of Iowa\, Iowa City\, IA 52242\, USA.,Department of Pathology\, University of Iowa Hospitals and Clinics\, 200 Hawkins Dr.\, Iowa City\, IA 52242\, USA.,Holden Comprehensive Cancer Center\, University of Iowa\, Iowa City\, IA 52242\, USA.,0000-0002-7244-5602Holden Comprehensive Cancer Center\, University of Iowa\, Iowa City\, IA 52242\, USA.,Holden Comprehensive Cancer Center\, University of Iowa\, Iowa City\, IA 52242\, USA.,Holden Comprehensive Cancer Center\, University of Iowa\, Iowa City\, IA 52242\, USA.",,"NCI NIH HHS,NIGMS NIH HHS","United States,United States","P30 CA086862,T32 GM007337","PD-1,antibiotics,melanoma,microbiome,microbiota"
33122190,"Echejoh G,Liu Y,Chung-Faye G,Charlton J,Moorhead J,Clark B,Davidson P,Sarker D,Ross P,Ooft ML",Validity of whole genomes sequencing results in neoplasms in precision medicine.,"To compare the whole genomes sequencing (WGS) results in the 100K Genomes project with the results of routine molecular diagnostics in precision medicine.,We analysed 374 cancers including a high tumour mutational burden (TMB-high) subgroup\, defined as >10 non-synonymous single nucleotide variations per megabase. Colon cancers were evaluated for microsatellite instability (MSI)\, mismatch repair (MMR) genes and NRAS\, KRAS and BRAF mutations using routine molecular diagnostics. Fluorescence in-situ hybridisation/immunohistochemistry was used to evaluate the Her2Neu status in breast cancers.,There was high correlation between WGS and routine diagnostic testing results irrespective of TMB status in colon cancers. Her2Neu status was discordant in 3 out of the 5 TMB-high breast cancers (p=0.049). The presence of ductal carcinoma in-situ correlated significantly with discordance (p=0.04). There were 3 (5%) discordant colorectal cases\, all in the KRAS gene\, 2 of which were from the non-invasive adenomatous component (p=0.0058). Of the 374 cases we identified 24 tumours with a TMB >10; comprising (colorectal carcinomas (CRCs) n=16\, breast carcinomas n=5\, bladder urothelial cell cancers n=3). Of the 16 TMB-high colorectal adenocarcinomas\, 13 had MSI-high status. The same 13 had defective MMR protein expression. TMB-high colorectal cancers had 100% concordant results between WGS and NGS testing for KRAS\, BRAF and NRAS (16/16).,The microsatellite and mutational status of colorectal cancers evaluated by WGS seem to correlate well with the routine diagnostic testing if it is ensured that the invasive component is sequenced. Evaluation of WGS results need to be carefully correlated with histomorphology\, as tumour heterogeneity/contamination with pre-malignant components needs to be taken into account.",Journal of clinical pathology,vol.::,2020,Journal Article,,,"http://orcid.org/0000-0002-3944-9302Department of Histopathology\, King's College Hospital\, King's College\, London\, UK.,Department of Histopathology\, King's College Hospital\, King's College\, London\, UK.,Department of Gastroenterology\, King's College Hospital\, London\, UK.,Precision Medicine\, King's College Hospital\, London\, UK.,Department of Histopathology\, King's College Hospital\, King's College\, London\, UK.,Precision Medicine\, King's College Hospital\, London\, UK.,Precision Medicine\, King's College Hospital\, London\, UK.,Department of Medical Oncology\, Guy's and St Thomas' NHS Trust\, London\, UK.,Department of Medical Oncology\, Guy's and St Thomas' NHS Trust\, London\, UK.,Department of Histopathology\, King's College Hospital\, King's College\, London\, UK m.ooft@nhs.net.",,,,,"erbB-2,genes,genetics,molecular,neoplasm,pathology"
33122997,"Taylor SS,Kaila-Sharma P,Weng JH,Aoto P,Schmidt SH,Knapp S,Mathea S,Herberg FW",Kinase Domain Is a Dynamic Hub for Driving LRRK2 Allostery.,"Protein kinases and GTPases are the two major molecular switches that regulate much of biology, and both of these domains are embedded within the large multi-domain Leucine-Rich Repeat Kinase 2 (LRRK2). Mutations in LRRK2 are the most common cause of familial Parkinson's disease (PD) and are also implicated in Crohn's disease. The recent Cryo-Electron Microscopy (Cryo-EM) structure of the four C-terminal domains [ROC COR KIN WD40 (RCKW)] of LRRK2 includes both of the catalytic domains. Although the important allosteric N-terminal domains are missing in the Cryo-EM structure this structure allows us to not only explore the conserved features of the kinase domain, which is trapped in an inactive and open conformation but also to observe the direct allosteric cross-talk between the two domains. To define the unique features of the kinase domain and to better understand the dynamic switch mechanism that allows LRRK2 to toggle between its inactive and active conformations, we have compared the LRRK2 kinase domain to Src, BRaf, and PKA. We also compare and contrast the two canonical glycine-rich loop motifs in LRRK2 that anchor the nucleotide: the G-Loop in protein kinases that anchors ATP and the P-Loop in GTPases that anchors GTP. The RCKW structure also provides a template for the cross-talk between the kinase and GTPase domains and brings new mechanistic insights into the physiological function of LRRK2 and how the kinase domain, along with key phosphorylation sites, can serve as an allosteric hub for mediating conformational changes.",Frontiers in molecular neuroscience,vol.13::538219,2020,Journal Article,,,"Department of Pharmacology\, University of California\, San Diego\, San Diego\, CA\, United States.,Department of Pharmacology\, University of California\, San Diego\, San Diego\, CA\, United States.,Department of Pharmacology\, University of California\, San Diego\, San Diego\, CA\, United States.,Department of Pharmacology\, University of California\, San Diego\, San Diego\, CA\, United States.,Department of Biochemistry\, Institute for Biology\, University of Kassel\, Kassel\, Germany.,Institute of Pharmaceutical Chemistry\, Goethe-University Frankfurt\, Frankfurt\, Germany.,Institute of Pharmaceutical Chemistry\, Goethe-University Frankfurt\, Frankfurt\, Germany.,Department of Biochemistry\, Institute for Biology\, University of Kassel\, Kassel\, Germany.",,,,,"GTPase,Walker motifs,allostery,hydrophobic cores,leucin rich repeat kinase 2 (LRRK2),protein kinase (PK)"
33123389,"Čepulytė R,Žučenka A,Pečeliūnas V",Combination of Dabrafenib and Trametinib for the Treatment of Relapsed and Refractory Multiple Myeloma Harboring BRAF V600E Mutation.,"Multiple myeloma (MM) is an incurable plasma cell neoplasia characterized by relapsed and/or refractory (R/R) disease course, which poses a major therapeutic challenge. New therapies, including BRAF V600E mutation targeting, may become a new treatment option for R/R MM. In combination with mitogen-activated protein kinase inhibitors (MEKi), BRAF inhibitors (BRAFi) could provide better tailored clinical management, although experience in this field is lacking. To this date, there is only one case describing R/R MM treatment with BRAFi vemurafenib and MEKi cobimetinib. This is the first case presenting a R/R MM patient treated with BRAFi dabrafenib and MEKi trametinib.",Case reports in hematology,vol.2020::8894031,2020,Case Reports,,,"https://orcid.org/0000-0002-7589-9036Vilnius University Hospital Santaros Klinikos\, Center of Hematology\, Oncology and Transfusion Medicine\, Santariškių 2\, Vilnius 08661\, Lithuania.,https://orcid.org/0000-0002-5520-1534Vilnius University Hospital Santaros Klinikos\, Center of Hematology\, Oncology and Transfusion Medicine\, Santariškių 2\, Vilnius 08661\, Lithuania.,https://orcid.org/0000-0001-8232-8381Vilnius University Hospital Santaros Klinikos\, Center of Hematology\, Oncology and Transfusion Medicine\, Santariškių 2\, Vilnius 08661\, Lithuania.",,,,,
33127831,"van Ipenburg JA,Naus NC,Dubbink HJ,van Ginderdeuren R,Missotten GS,Paridaens D,Verdijk RM",Prognostic value of promoter mutations in conjunctival melanomas in addition to clinicopathological features.,"To evaluate the prognostic value of clinical\, histopathological and molecular features and to relate different treatment modalities to clinical outcome in conjunctival melanomas (CM).,Retrospective review of clinical\, histopathological and BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutation status and treatment modalities\, correlated to recurrence and metastasis in 79 patients with CM\, diagnosed between 1987 and 2015 in three tertiary referral centres in the Netherlands and Belgium.,Out of 78 evaluable patients\, recurrences occurred in 16 patients and metastasis in 12 patients (median follow-up time 35 months (0-260 months)). Tumour thickness >2 mm\, pT status\, the presence of epithelioid cells\, ulceration and mitoses was significantly correlated with metastasis (p value 0.046\, 0.01\, 0.02\, 0.001 and 0.003\, respectively). Furthermore\, CM frequently harbour BRAF V600E and TERT promoter mutations (29% and 43%\, respectively). TERT promoter mutations were correlated to shorter metastasis-free survival (p value 0.002). No significant correlation was found for clinical parameters and metastatic disease. Palpebral\, forniceal and caruncular melanomas were more prone to develop recurrences (p value: 0.03). Most CM were treated with excision with adjuvant therapy.,In line with the recommendations in the Eighth Edition of the American Joint Committee on Cancer Staging for CM\, the pathology report should include information about pT status\, tumour thickness\, presence of epithelioid cells\, ulceration and mitoses. Furthermore\, information about the presence of a TERT promoter mutation and BRAF V600E mutation is of interest for therapeutic decision making. The presence of a TERT promoter mutation is correlated to metastatic disease.",The British journal of ophthalmology,vol.::,2020,Journal Article,,,"http://orcid.org/0000-0001-5029-1983Pathology\, Erasmus MC\, Rotterdam\, Netherlands.,Ophthalmology\, Erasmus MC\, Medical Centre\, Rotterdam\, Netherlands.,Erasmus Medical Center\, Rotterdam\, Zuid-Holland\,Netherlands.,Department of Ophthalmology and Pathology\, University Hospital Leuven\, Leuven\, Belgium.,Ophthalmology\, KU Leuven University Hospitals Leuven Gasthuisberg Campus Hospital Pharmacy\, Leuven\, Flanders\, Belgium.,Rotterdam Eye Hospital\, Rotterdam\, Netherlands.,http://orcid.org/0000-0003-1437-214XPathology\, Erasmus University Medical Center\, Rotterdam\, Netherlands r.verdijk@erasmusmc.nl/ j.vanipenburg@erasmusmc.nl.",,,,,"Conjunctiva,Diagnostic tests/Investigation,Neoplasia,Pathology"
33128316,"Ma VT,Daignault-Newton S,Waninger JJ,Journey S,Chopra Z,Tezel A,Redman BG,Fecher LA,Green MD,Alva AS,Lao CD",The impact of BRAF mutation status on clinical outcomes with anti-PD-1 monotherapy versus combination ipilimumab/nivolumab in treatment-naïve advanced stage melanoma.,"Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for advanced stage melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens based on BRAF mutation status. We retrospectively analyzed a cohort of metastatic or unresectable melanoma patients who were treated with combination ipilimumab/nivolumab (ipi/nivo) or anti-PD-1 monotherapy, nivolumab, or pembrolizumab, as first-line treatment. 235 previously untreated patients were identified in our study. Our univariate analysis showed no statistical difference in progression-free survival (PFS) or overall survival (OS) with ipi/nivo versus anti-PD-1 monotherapy in the BRAF V600 mutant cohort, but there was improved PFS [HR: 0.48, 95% CI, 0.28-0.80] and OS [HR: 0.50, 95% CI, 0.26-0.96] with ipi/nivo compared to anti-PD-1 monotherapy in the BRAF WT group. After adjusting for known prognostic variables in our multivariable analysis, the BRAF WT cohort continued to show PFS and OS benefit with ipi/nivo compared to anti-PD-1 monotherapy. Our single-institution analysis suggests ipi/nivo should be considered over anti-PD-1 monotherapy as the initial immunotherapy regimen for metastatic melanoma patients regardless of BRAF mutation status, but possibly with greater benefit in BRAF WT.",Pigment cell & melanoma research,vol.::,2020,Journal Article,,,"https://orcid.org/0000-0002-8417-2787Division of Hematology and Oncology\, Department of Internal Medicine\, University of Michigan\, Ann Arbor\, MI\, USA.,Department of Biostatistics\, University of Michigan\, Ann Arbor\, MI\, USA.,Michigan Center for Translational Pathology\, University of Michigan\, Ann Arbor\, MI\, USA.,Department of Medical Education\, University of Michigan\, Ann Arbor\, MI\, USA.,Department of Medical Education\, University of Michigan\, Ann Arbor\, MI\, USA.,Department of Medical Education\, University of Michigan\, Ann Arbor\, MI\, USA.,Division of Hematology and Oncology\, Department of Internal Medicine\, University of Michigan\, Ann Arbor\, MI\, USA.,Division of Hematology and Oncology\, Department of Internal Medicine\, University of Michigan\, Ann Arbor\, MI\, USA.,Department of Radiation Oncology\, University of Michigan\, Ann Arbor\, MI\, USA.,Division of Hematology and Oncology\, Department of Internal Medicine\, University of Michigan\, Ann Arbor\, MI\, USA.,Division of Hematology and Oncology\, Department of Internal Medicine\, University of Michigan\, Ann Arbor\, MI\, USA.",,,,,"BRAF mutation,anti-CTLA-4 inhibitor,anti-PD-1 inhibitor,immune checkpoint inhibitor,melanoma"
33132786,"Karki S,Umar S,Kasi A",Treating Colorectal Cancer with Immunotherapy: Implications for Single versus Combination Therapy.,"Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States\, with most metastatic cases subsequently turning refractory to standard chemotherapy. One of the promising current interventions is immunotherapy that relies on harnessing the body's immune mechanisms to kill the cancer cells. The aim of this review is to highlight the implications of single versus combination immunotherapy and identify the molecular features and mutations that enhance or deter responsiveness.,Based on current findings\, responsiveness is associated with deficiency of mismatch repair (dMMR) genes or presence of microsatellite instability (MSI-high)\, with high immunoscore and tumor-mutational burden contributing to better efficacy while BRAF mutation conferring no significant effect. Combination immunotherapy demonstrates better efficacy in treating MSI-high CRC compared to single agent immunotherapy or chemotherapy.,Given improved responsiveness and overall survival\, there is potential for immunotherapy to change the standard of care for metastatic CRC. Furthermore\, stratifying the patients by their molecular features and mutation status is critical for establishing care.",Current colorectal cancer reports,vol.16:5:107-117,2020,Journal Article,,,"Department of Medicine\, University of Kansas School of Medicine\, Kansas City\, KS\, U.S.A.,Department of Medicine\, Division of Surgery\, Kansas University Medical Center\, Kansas City\, KS\, U.S.A.,Department of Medicine\, Division of Medical Oncology\, Kansas University Medical Center\, Kansas City\, KS\, U.S.A.",,NCI NIH HHS,United States,R01 CA185322,"Colorectal Cancer,Immunotherapy,Microsatellite Instability,Mismatch-repair,Nivolumab,Pembrolizumab"
32989177,"Kim Y,Park SS,Min CK,Lee GD,Son J,Jo SJ,Han E,Han K,Kim M",", , and mutations in plasma cell myeloma at a single Korean institute.","Plasma cell myeloma (PCM) is a genetically heterogeneous disease. The genetic spectrum of PCM has been expanded to mutations such as KRAS\, NRAS\, and BRAF genes in the RAS-RAF-MAPK pathway. In this study\, we have evaluated the frequency of these mutations and their significance\, including baseline characteristics and clinical outcomes.,We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at a single Korean institute. Clinical and laboratory parameters were gathered through careful review of medical records. Mutation analysis was carried out using DNA from the bone marrow at the time of diagnosis. Pyrosequencing was performed to detect KRAS G12V\, KRAS G13D\, and NRAS G61R. BRAF V600E was analyzed by allele-specific real- time PCR. Comparison of clinical and laboratory parameters was carried out according to those mutations.,We identified 14 patients (28%) with activating mutations in the RAS-RAF-MAPK pathway (RAS/RAF mutations): KRAS (N=3)\, NRAS (N=4)\, BRAF (N=7)\, and both KRAS and BRAF (N=1). RAS/RAF mutations were more frequently observed in patients with complex karyotypes and showed poorer progression free survival (PFS). Specifically\, the BRAF V600E mutation had a significantly negative impact on median PFS.,We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome\, as well as its potential as a therapeutic target.",Blood research,vol.55:3:159-168,2020,Journal Article,,,"Department of Laboratory Medicine\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Department of Hematology\, Leukemia Research Institute\, Seoul St. Mary's Hematology Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Department of Hematology\, Leukemia Research Institute\, Seoul St. Mary's Hematology Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Catholic Genetic Laboratory Center\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Catholic Genetic Laboratory Center\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Department of Laboratory Medicine\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Department of Laboratory Medicine\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Department of Laboratory Medicine\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.,Department of Laboratory Medicine\, Seoul St. Mary's Hospital\, College of Medicine\, The Catholic University of Korea\, Seoul\, Korea.",,,,,"BRAF,KRAS,NRAS,Plasma cell myeloma"
32990852,"Kachko VA,Vanushko VE,Platonova NM,Abrosimov AY,Mel'nichenko GA","Somatic Mutations in the BRAF, KRAS, NRAS, EIF1AX, and TERT Genes: Diagnostic Value in Thyroid Neoplasms.","The feasibility of using molecular genetic markers associated with thyroid neoplasms and more aggressive course of the disease is now actively studied. We analyzed the diagnostic value of somatic mutations in the hot spots of BRAF, KRAS, KRAS, EIF1AX, and TERT genes in histological material from 153 patients with thyroid gland neoplasms. BRAF mutations (exon 15, codon area 600-601) were found in 54 patients, NRAS mutations (exon 3, codon 61) were detected in 12 patients; mutations KRAS, TERT, and EIF1AX genes were not detected.",Bulletin of experimental biology and medicine,vol.169:5:669-672,2020,Journal Article,,,"National Medical Research Center of Endocrinology\, Ministry of Health of Russian Federation\, Moscow\, Russia. veraf246@gmail.com.,National Medical Research Center of Endocrinology\, Ministry of Health of Russian Federation\, Moscow\, Russia.,National Medical Research Center of Endocrinology\, Ministry of Health of Russian Federation\, Moscow\, Russia.,National Medical Research Center of Endocrinology\, Ministry of Health of Russian Federation\, Moscow\, Russia.,National Medical Research Center of Endocrinology\, Ministry of Health of Russian Federation\, Moscow\, Russia.",,,,,"KRAS,NRAS,TERT,and EIF1AX mutations,thyroid neoplasms; BRAF"
32999736,"Daniel EB,Ney DE,Levy JMM",MEK inhibition with trametinib is a successful therapy in ganglioglioma.,"Gangliogliomas are predominantly low-grade primary brain tumors comprised of neuronal and glial components that are found in both pediatric and young adult populations. In the majority of cases, surgical resection of these tumors is curative. However, tumor location in eloquent centers of the brain can make surgical intervention inappropriate. Additionally, a subset of tumors progress to anaplastic ganglioglioma which carries a poor prognosis, despite resection. Activating mutations in the MAPK pathway, such as BRAF V600E, have been identified in many of these tumors. Tumors carrying such mutations have demonstrated susceptibility to MEK inhibition therapy. However, there remains a subset of ganglioglioma that do not contain a known mutation in the MAPK pathway and thus have not been targeted with MEK inhibition therapy. Here, we present a young adult ganglioglioma patient without identified MAPK pathway activation mutations who demonstrated a significant and sustained response to MEK inhibition with trametinib.",Clinical case reports and reviews,vol.6:2:,2020,Journal Article,,,"Department of Pediatrics\, University of Colorado Denver\, Aurora\, USA.,Departments of Neurology and Neurosurgery\, University of Colorado School of Medicine\, Aurora\, USA.,Department of Pediatrics\, University of Colorado Denver\, Aurora\, USA.",,NCI NIH HHS,United States,K08 CA193982,"BRAF,MEK inhibitor,Trametinib,ganglioglioma,low-grade-glioma"
33000894,"Vido MJ,Rock J,Aplin AE",Role of serine 365 in BRAF V600E sensitivity to RAF inhibition.,"The serine-threonine kinase, BRAF, is an upstream regulator of the MEK-ERK1/2 pathway and is commonly mutated in cancer. 14-3-3 proteins bind to two sites in BRAF, N-terminal S365, and C-terminal S729. 14-3-3 binding modulates the activity and dimerization of both wild-type and non-V600 mutant forms of BRAF. In BRAF V600E mutants, the C-terminal S729 site affects dimerization of truncated splice variants. The N-terminal, S365, is removed in BRAF V600E splice variants but its importance in full-length BRAF V600 mutants remains uncertain. We tested the role of S365 in dimerization and RAF inhibitor resistance in full-length BRAF V600E. Mutating BRAF S365 site to an alanine (S365A) reduced 14-3-3 association and increased BRAF V600E homodimerization. BRAF V600E S365A displayed reduced sensitivity to RAF inhibitor at the level of MEK-ERK1/2 signaling, cell growth, and cell viability. These data suggest that alteration or removal of the S365 14-3-3 binding site may contribute to RAF inhibitor resistance.",Pigment cell & melanoma research,vol.::,2020,Journal Article,,,"Department of Cancer Biology\, Thomas Jefferson University\, Philadelphia\, PA\, USA.,Department of Cancer Biology\, Thomas Jefferson University\, Philadelphia\, PA\, USA.,https://orcid.org/0000-0002-2734-3244Department of Cancer Biology\, Thomas Jefferson University\, Philadelphia\, PA\, USA.",,"NIH HHS,NIH HHS,NIH HHS,Medical Research Foundation","United States,United States,United States,","F30-CA203314,CA182635,CA160495","14-3-3,BRAF inhibitor,phosphorylation,resistance,targeted therapy"
33003444,"De Martino E,Brunetti D,Canzonieri V,Conforti C,Eisendle K,Mazzoleni G,Nobile C,Rao F,Zschocke J,Jukic E,Jaschke W,Weinlich G,Zelger B,Schmuth M,Stanta G,Zanconati F,Zalaudek I,Bonin S",The Association of Residential Altitude on the Molecular Profile and Survival of Melanoma: Results of an Interreg Study.,"Cutaneous melanoma (CM) incidence is rising worldwide and is the primary cause of death from skin disease in the Western world. Personal risk factors linked to environmental ultraviolet radiation (UVR) are well-known etiological factors contributing to its development. Nevertheless, UVR can contribute to the development of CM in different patterns and to varying degrees. The present study aimed at investigating whether altitude of residence can contribute to the development of specific types of CM and/or influence its progression. To this aim, 306 formalin-fixed and paraffin-embedded (FFPE) tissues from primary CM diagnosed in different geographical areas were submitted to B-RAF proto-oncogene serine/threonine kinase (BRAF) and N-RAS proto-oncogene GTPase (NRAS) mutational status detection and mRNA and miRNA profiling by qPCR. Genes were chosen for their functions in specific processes, such as immune response (CD2, PDL1, or CD274) and pigmentation (MITF, TYRP1, and TRPM1). Furthermore, four microRNAs, namely miR-150-5p, miR-155-5p, miR-204-5p, and miR-211-5p, were included in the profiling. Our results highlight differences in the gene expression profile of primary CM with respect to the geographical area and the altitude of residence. Melanoma-specific survival was influenced by the gene expression of mRNA and miRNAs and varied with the altitude of patients' residence. In detail, TYRP1 and miR-204-5p were highly expressed in patients living at higher altitudes, unlike miR-150-5p, miR-155-5p, and miR-211-5p. Since miRNAs are highly regulated by reactive oxygen species, it is possible that different regulatory mechanisms characterize CMs at different altitudes due to the different environment and UVR intensity.",Cancers,vol.12:10:,2020,Journal Article,,,"0000-0003-0733-7231DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,0000-0001-6010-0976DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,0000-0002-8234-9964Azienda Sanitaria dell'Alto Adige\, 39100 Bolzano\, Italy.,Azienda Sanitaria dell'Alto Adige\, 39100 Bolzano\, Italy.,Azienda Sanitaria dell'Alto Adige\, 39100 Bolzano\, Italy.,Pathology Unit\, IRCCS CRO Aviano-National Cancer Institute\, 33081 Aviano\, Italy.,Institute for Human Genetics\, Medical University of Innsbruck\, 6020 Innsbruck\, Austria.,0000-0001-6909-7005Institute for Human Genetics\, Medical University of Innsbruck\, 6020 Innsbruck\, Austria.,Department of Dermatology\, Venereology and Allergology\, Medical University of Innsbruck\, 6020 Innsbruck\, Austria.,Department of Dermatology\, Venereology and Allergology\, Medical University of Innsbruck\, 6020 Innsbruck\, Austria.,Department of Dermatology\, Venereology and Allergology\, Medical University of Innsbruck\, 6020 Innsbruck\, Austria.,0000-0002-4064-1334Department of Dermatology\, Venereology and Allergology\, Medical University of Innsbruck\, 6020 Innsbruck\, Austria.,DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.,0000-0002-7349-0296DSM-Department of Medical Sciences\, University of Trieste\, 34149 Trieste\, Italy.",,Interreg,,ITAT1018,"altitude,cutaneous melanoma,miRNA,molecular profiling"
33003483,"Proietti I,Skroza N,Bernardini N,Tolino E,Balduzzi V,Marchesiello A,Michelini S,Volpe S,Mambrin A,Mangino G,Romeo G,Maddalena P,Rees C,Potenza C",Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review.,"This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of 'escape routes', so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.",Cancers,vol.12:10:,2020,Review,,,"0000-0003-3795-3190Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,0000-0002-8950-9780Department of Medico-Surgical Sciences and Biotechnologies\, Sapienza University of Rome\, 00185 Rome\, Italy.,Department of Medico-Surgical Sciences and Biotechnologies\, Sapienza University of Rome\, 00185 Rome\, Italy.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.,Springer Healthcare\, Auckland 0627\, New Zealand.,Dermatology Unit ""Daniele Innocenzi""\, Department of Medical-Surgical Sciences and Bio-Technologies\, Sapienza University of Rome\, Fiorini Hospital\, Polo Pontino\, 04019 Terracina\, Italy.",,,,,"BRAF inhibitors,melanoma,metastasis,microenvironment,resistance,therapy"
33005299,"Guan JL,Liu JH,Wang Q,Cong YW,Chen YX,Huang KF,Huang ML,Huang L",Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report.,"Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments\, which have been shown to be effective in HER2-positive metastatic CRC patients\, single-agent anti-HER2 therapy is rarely used to treat CRC.,Herein\, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently\, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover\, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However\, a high level of HER2 amplification was detected again at the time of disease progression. Finally\, a phosphatidylinositol-4\,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression\, which may explain the acquired resistance to lapatinib.,This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.",World journal of gastrointestinal oncology,vol.12:9:1065-1072,2020,Case Reports,,,"Department of Oncology\, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences\, Guangzhou 510655\, Guangdong Province\, China.,Department of Oncology\, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences\, Guangzhou 510655\, Guangdong Province\, China.,The Medical Department\, 3D Medicines Inc.\, Shanghai 201114\, China.,The Medical Department\, 3D Medicines Inc.\, Shanghai 201114\, China.,The Medical Department\, 3D Medicines Inc.\, Shanghai 201114\, China.,The Bioinformatic Department\, 3D Medicines Inc.\, Shanghai 201114\, China.,The Medical Department\, 3D Medicines Inc.\, Shanghai 201114\, China.,Department of Oncology\, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences\, Guangzhou 510655\, Guangdong Province\, China. 13710351111@139.com.",,,,,"Case report,Circulating tumor DNA,Colorectal cancer,Human epidermal growth factor receptor 2,Lapatinib"
33005620,"van Ipenburg JA,Damman J,Paridaens D,Verdijk RM",Histopathological and Molecular Features of a Conjunctival Caruncular Deep Penetrating Nevus.,"We describe the first presentation of a deep penetrating nevus (DPN) on the lacrimal caruncle. This lesion was seen in an 18-year-old woman presenting with hemorrhage of a long-standing pigmented mass on the caruncle. Histology showed a combined melanocytic neoplasm that consisted of two different melanocytic components. The differential diagnosis, based on histological examination, was a conventional melanocytic nevus, a Spitz nevus, or a combined melanocytic nevus. On the molecular level, one of the components revealed a mutation in the CTNNB1 gene encoding the β-catenin protein, while both components harbored a BRAF V600E mutation, without molecular features of a malignant melanocytic lesion. This presentation of a DPN of the lacrimal caruncle emphasizes the similarities of the caruncle with the skin.",Ocular oncology and pathology,vol.6:4:293-296,2020,Case Reports,,,"Section of Ophthalmic Pathology\, Department of Pathology\, Erasmus MC - University Medical Center\, Rotterdam\, The Netherlands.,Section of Ophthalmic Pathology\, Department of Pathology\, Erasmus MC - University Medical Center\, Rotterdam\, The Netherlands.,The Rotterdam Eye Hospital\, Rotterdam\, The Netherlands.,Section of Ophthalmic Pathology\, Department of Pathology\, Erasmus MC - University Medical Center\, Rotterdam\, The Netherlands.",,,,,"BRAF,Caruncle,Conjunctiva,Deep penetrating nevus,β-Catenin"
33007097,"Cuccurullo V,Di Stasio GD,Cascini GL",PET/CT in thyroid cancer - the importance of BRAF mutations.,"Thyroid cancer (TC) represents less than 1% of all newly diagnosed malignancies. In some selected cases, with a high clinical suspicion for disease but negative I-131 scan, positron emission tomography/computed tomography (PET) with F-18-Fluorodeoxyglucose (FDG) could be helpful in the detection of disease and the definition of its extent. FDG PET/CT, better if performed after TSH stimulation analogously to patient preparation done for radioiodine scintigraphy, could be useful mainly in the detection of metastatic and recurrent disease since the uptake and diagnostic sensitivity of FDG are increased by TSH stimulation. Recently, the role of oncogenic mutations in the tumorigenesis of TCs has become clearer. Among such mutations, BRAFV600E represents the most common genetic alteration. Mutated BRAF may define a more aggressive papillary carcinoma with poorer prognosis and therefore its analysis has been extensively studied as a rule-in test for thyroid carcinoma. In this paper, we try to outline the possible role of FDG PET/CT in the management of patients with TC and positive BRAF mutations and the impact that it could have on their therapeutic algorithm, in terms of thyroidectomy and radioactive iodine (RAI) therapy.",Nuclear medicine review. Central & Eastern Europe,vol.23:2:97-102,2020,Journal Article,,,"0000-0003-0474-7163Università della Campania\, p.zza Miraglia\,2\, 80138 Napoli\, Italy. vincenzo.cuccurullo@unicampania.it.,Università della Campania\, p.zza Miraglia\,2\, 80138 Napoli\, Italy.,Università Magna Graecia\, Catanzaro\, Catanzaro\, Italy.",,,,,"BRAF mutation,fluorodeoxyglucose F18,positron emission tomography,thyroid neoplasms"
33014052,"Xu SF,Guo Y,Zhang X,Zhu XD,Fan N,Zhang ZL,Ren GB,Rao W,Zang YJ",Somatic Mutation Profiling of Intrahepatic Cholangiocarcinoma: Comparison between Primary and Metastasis Tumor Tissues.,"Intrahepatic cholangiocarcinoma (ICC) exhibited increasing incidence and mortality around the world\, with a 35% five-year survival rate. In this study\, the genetic alteration of primary ICC and metastasis ICC was exhibited to discover novel personalized treatment strategies to improve the clinical prognosis.,Based on 153 primary and 49 metastasis formalin-fixed paraffin-embedded ICC samples\, comprehensive genomic profiling was carried out.,In primary tumor samples (PSs) and metastasis tumor samples (MSs)\, the top alteration genes were TP53 (41.8% vs 36.7%)\, KRAS (30.7% vs 36.7%)\, and ARID1A (22.2% vs 14.2%). In the top 20 most frequent alteration genes\, BRAF showed lower mutation frequency in MSs as compared to PSs (0 vs 11.1%\, P=0.015)\, while LRP1B exhibited opposed trend (22.4% vs 10.4%\, P=0.032). In PSs\, patients with MSI-H showed all PDL1 negative\, and patients with PDL1 positive exhibited MSS both in PSs and MSs. It was found that the Notch pathway had more alteration genes in MSI-H patients (P=0.027). Furthermore\, the patients with mutated immune genes in PSs were more than that in MSs (28.8% vs 8.2%\, P=0.003\, odd ratio = 0.2). Interestingly\, the platinum drug resistance pathway was only enriched by mutated genes of MSs.,In this study\, the identification of two meaningful mutated genes\, BRAF and LRP1B\, highly mutated immune gene harbored by primary ICC patients. Both in PSs and MSs\, no patients with MSI-H showed PDL1 positive. The Notch pathway had more alteration genes in patients with MSI-H. And the enrichment of the platinum drug resistance pathway in MSs might offer reference for the novel therapeutic strategy of ICC.",Journal of oncology,vol.2020::5675020,2020,Journal Article,,,"Shandong Provincial Hospital Affiliated to Shandong First Medical University\, Shandong\, China.,Liver Disease Center\, The Affiliated Hospital of Qingdao University\, Qingdao\, China.,Origimed\, Shanghai\, China.,Organ Transplant Center\, The Affiliated Hospital of Qingdao University\, Qingdao\, China.,Liver Disease Center\, The Affiliated Hospital of Qingdao University\, Qingdao\, China.,Department of Hepatobiliary Surgery\, Fourth Hospital of Hebei Medical University\, Shijiazhuang\, China.,Oncology Department\, Armed Police Characteristic Medical Center\, Tianjin\, China.,https://orcid.org/0000-0002-6559-583XDivision of Hepatology\, Liver Disease Center\, Organ Transplantation Center\, The Affiliated Hospital of Qingdao University\, Qingdao\, China.,https://orcid.org/0000-0002-2028-1562Organ Transplant Center\, The Affiliated Hospital of Qingdao University\, Qingdao\, China.",,,,,
31469305,"Shah S,Raskin L,Cohan D,Freeman M,Hamid O",Treatment patterns of malignant melanoma in the United States from 2011 to 2016: a retrospective cohort study.,"Background: Since 2011, the approval of several new agents has improved treatment options for malignant melanoma. We describe treatment patterns for malignant melanoma in the United States from the MarketScan database from 2011 to 2016.Methods: Treatments used for patients aged >18 years diagnosed with malignant melanoma after January 1, 2011 and enrolled in the Truven MarketScan database were analyzed. Patient data were collected for the 12-month period from the date of the first melanoma diagnosis to either death, the pre-specified study end date (August 31, 2016), or date of termination of health insurance. Treatment patterns from 2011-2013 and 2014-2016 were analyzed according to agent, year of drug administration, and line of therapy.Results: From 2011 to 2016, use of cytokines (63.8; 13.3%) and chemotherapy (19.6; 12.9%) decreased, and use of checkpoint inhibitors increased (2.0; 49.9%). Checkpoint inhibitor use also increased across all lines of therapy from 2011-2013 and 2014-2016. Use of BRAF/MEK inhibitors remained relatively stable from 2011 to 2016 (6.5-12.5%); however, the use of vemurafenib monotherapy decreased (6.5; 0.8%), and treatment with combination regimens increased (0; 10.9%) from 2011-2016. BRAF/MEK inhibitor use only increased in the first line setting from 2011-2013 (9.7%) to 2014-2016 (11.2%).Conclusion: With the approval of immune checkpoint inhibitors, BRAF/MEK inhibitors, and targeted therapies, the therapeutic landscape for the treatment of metastatic melanoma has shifted dramatically away from cytokines and chemotherapy. Treatment patterns will likely continue to evolve as scientific advances are made.",Current medical research and opinion,vol.36:1:63-72,2020,"Research Support, Non-U.S. Gov't","|Adolescent|,|Adult|,|Aged|,|Cohort Studies|,|Female|,|Humans|,|Immunotherapy|methods|,|Male|,|Melanoma|drug therapy|pathology|,|Middle Aged|,|Molecular Targeted Therapy|,|Protein Kinase Inhibitors|therapeutic use|,|Retrospective Studies|,|United States|,|Young Adult|",,"Global Health Economics\, Amgen Inc.\, Thousand Oaks\, CA\, USA.,Center for Observational Research\, Amgen Inc.\, Thousand Oaks\, CA\, USA.,Medical Affairs\, Amgen Inc.\, Thousand Oaks\, CA\, USA.,City of Hope\, Duarte\, CA\, USA.,The Angeles Clinic and Research Institute\, Los Angeles\, CA\, USA.",Protein Kinase Inhibitors,,,,"Malignant melanoma,claims analysis,immunotherapy,targeted therapy"
31475312,"Goud KI,Matam K,Madasu AM,Ali Khan I",Positive Correlation Between Somatic Mutations in RAS Gene and Colorectal Cancer in Telangana Population: Hospital-Based Study in a Cosmopolitan City.,"Colorectal cancer (CRC) ranks among the most prevalent cancer types in both men and women. Screening of RAS (Kirsten rat sarcoma viral oncogene homolog (KRAS), neuro-blastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF)) somatic mutations is necessary prior to considering anti-epidermal growth factor receptor (EGFR) therapies in CRC patients. Next-generation sequencing studies have confirmed that RAS gene panels could be used while developing treatment strategies for patients with CRC. The present study explored genetic mutations in KRAS, NRAS, and BRAF in CRC patients in the Telangana state of India. Patients with confirmed CRC (n = 100) who visited the Apollo hospitals were evaluated. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissues, and pyrosequencing analysis was performed. Patient DNA samples were screened for 54 different KRAS, NRAS, and BRAF mutations, which revealed 34 somatic mutations. Exon 11 of BRAF possessed 4 mutations with highest individuals documented with G469A mutation. Pyrosequencing, a reliable method for analyzing somatic mutations present in RAS, could aid in taking treatment decisions for patients with CRC.",Applied biochemistry and biotechnology,vol.190:2:703-711,2020,Journal Article,"|Case-Control Studies|,|Cities|,|Colorectal Neoplasms|genetics|,|Genes\, ras|,|Genetic Predisposition to Disease|,|Humans|,|India|,|Mutation|",,"Department of Molecular Biology and Cytogenetics\, Apollo Hospitals\, Hyderabad\, India.,Department of Molecular Biology and Cytogenetics\, Apollo Hospitals\, Hyderabad\, India.,http://orcid.org/0000-0002-2006-5501Department of Molecular Biology and Cytogenetics\, Apollo Hospitals\, Hyderabad\, India.,http://orcid.org/0000-0002-9746-5300Department of Clinical Laboratory Sciences\, College of Applied Medical Sciences\, King Saud University\, PO Box-10219\, Riyadh\, 11433\, Kingdom of Saudi Arabia. imkhan@ksu.edu.sa.",,,,,"BRAF,Colorectal cancer,KRAS,NRAS,RAS"
31449665,"Alegría-Landa V,Jo-Velasco M,Santonja C,Eraña I,Vergara-Sanchez A,Kutzner H,Requena L",Syringocystadenoma papilliferum associated with verrucous carcinoma of the skin in the same lesion: Report of four cases.,"The association of syringocystadenoma papilliferum (SCAP) with verrucous carcinoma (VC) of the skin in the same lesion is a rare, but well-documented event. Although human papillomaviruses (HPV) have been proposed to have an etiologic role in the development of the verrucous proliferations associated with SCAP, most of the immunohistochemical and molecular studies have failed to show the presence of their genomic material in these lesions. We report a series of four cases of SCAP associated with VC in anogenital lesions. In two of the cases, we demonstrated the presence of the BRAF V600E mutation by polymerase chain reaction and immunohistochemistry, both in the glandular and in the squamous component. No HPV-related histopathologic changes were found, nor could the presence of viral DNA be showed.",Journal of cutaneous pathology,vol.47:1:12-16,2020,Journal Article,"|Aged|,|Aged\, 80 and over|,|Amino Acid Substitution|,|Carcinoma\, Verrucous|genetics|metabolism|pathology|,|Humans|,|Male|,|Middle Aged|,|Mutation\, Missense|,|Neoplasms\, Second Primary|genetics|metabolism|pathology|,|Proto-Oncogene Proteins B-raf|genetics|metabolism|,|Sweat Gland Neoplasms|genetics|metabolism|pathology|,|Tubular Sweat Gland Adenomas|genetics|metabolism|pathology|",,"https://orcid.org/0000-0003-4585-8070Department of Dermatology\, Fundación Jiménez Díaz\, Universidad Autónoma\, Madrid\, Spain.,Department of Pathology\, Fundación Jiménez Díaz\, Universidad Autónoma\, Madrid\, Spain.,https://orcid.org/0000-0002-1335-0339Department of Pathology\, Fundación Jiménez Díaz\, Universidad Autónoma\, Madrid\, Spain.,Department of Pathology\, Hospital de Guadalajara\, Universidad de Alcalá de Henares\, Guadalajara\, Spain.,Department of Dermatology\, Hospital de Guadalajara\, Universidad de Alcalá de Henares\, Guadalajara\, Spain.,Dermatopathologie Laboratory\, Friedrichshafen\, Germany.,https://orcid.org/0000-0002-1347-3507Department of Dermatology\, Fundación Jiménez Díaz\, Universidad Autónoma\, Madrid\, Spain.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"\nBRAF\nV600E mutation,human papillomaviruses,syringocystadenoma papilliferum,verrucous carcinoma of the skin"
32024448,"Nieminen TT,Walker CJ,Olkinuora A,Genutis LK,O'Malley M,Wakely PE,LaGuardia L,Koskenvuo L,Arola J,Lepistö AH,Brock P,Yilmaz AS,Eisfeld AK,Church JM,Peltomäki P,de la Chapelle A","Thyroid Carcinomas That Occur in Familial Adenomatous Polyposis Patients Recurrently Harbor Somatic Variants in , , and .","Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic ""second-hit"" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic ""second-hits"" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.",Thyroid : official journal of the American Thyroid Association,vol.30:3:380-388,2020,"Research Support, Non-U.S. Gov't",,,"Department of Cancer Biology and Genetics\, The Ohio State University Comprehensive Cancer Center\, Columbus\, Ohio.,Department of Cancer Biology and Genetics\, The Ohio State University Comprehensive Cancer Center\, Columbus\, Ohio.,Department of Medical and Clinical Genetics\, Biomedicum Helsinki\, University of Helsinki\, Helsinki\, Finland.,Department of Cancer Biology and Genetics\, The Ohio State University Comprehensive Cancer Center\, Columbus\, Ohio.,Department of Colorectal Surgery\, Cleveland Clinical\, Lakewood\, Ohio.,Department of Pathology\, The Ohio State University Wexner Medical Center\, Columbus\, Ohio.,Department of Colorectal Surgery\, Cleveland Clinical\, Lakewood\, Ohio.,Department of Gastrointestinal Surgery\, Abdominal Center\, Helsinki University Hospital\, University of Helsinki\, Helsinki\, Finland.,Department of Pathology\, HUSLAB\, University of Helsinki\, Helsinki\, Finland.,Department of Gastrointestinal Surgery\, Abdominal Center\, Helsinki University Hospital\, University of Helsinki\, Helsinki\, Finland.,Division of Human Genetics\, Department of Internal Medicine\, The Ohio State University Wexner Medical Center\, Columbus\, Ohio.,Department of Biomedical Informatics\, The Ohio State University\, Columbus\, Ohio.,Department of Cancer Biology and Genetics\, The Ohio State University Comprehensive Cancer Center\, Columbus\, Ohio.,Department of Colorectal Surgery\, Cleveland Clinical\, Lakewood\, Ohio.,Department of Medical and Clinical Genetics\, Biomedicum Helsinki\, University of Helsinki\, Helsinki\, Finland.,Department of Cancer Biology and Genetics\, The Ohio State University Comprehensive Cancer Center\, Columbus\, Ohio.",,,,,"APC,cribriform–morular variant,familial adenomatous polyposis,papillary thyroid cancer,whole-genome sequencing"
32024680,Smalley KSM,Two Worlds Collide: Unraveling the Role of the Immune System in BRAF-MEK Inhibitor Responses.,"Although BRAF-MEK inhibition can enhance the immune recognition of melanoma cells, the mechanisms that underlie this remain poorly defined. In this issue of Cancer Discovery, Erkes and colleagues present new data showing that BRAF-MEK inhibition activates pyroptosis in melanoma cells through gasdermin E cleavage, leading to T-cell infiltration and improved therapy responses in vivo.See related article by Erkes et al., p. 254.",Cancer discovery,vol.10:2:176-178,2020,Comment,"|Humans|,|Melanoma|,|Protein Kinase Inhibitors|,|Proto-Oncogene Proteins B-raf|,|Pyroptosis|,|T-Lymphocytes|,|Tumor Microenvironment|",,"The Department of Tumor Biology and the Department of Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, Tampa, Florida. keiran.smalley@moffitt.org.","Protein Kinase Inhibitors,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,
32026754,"Kozak K,Kowalik A,Gos A,Wasag B,Lugowska I,Jurkowska M,Krawczynska N,Kosela-Paterczyk H,Switaj T,Teterycz P,Klimczak A,Siedlecki JA,Chlopek M,Kalisz J,Limon J,Rutkowski P",Cell-free DNA V600E measurements during BRAF inhibitor therapy of metastatic melanoma: long-term analysis.,"We assessed the status of the BRAF V600E mutation in cell-free circulating tumor DNA (cfDNA) isolated from the plasma of patients with metastatic melanoma treated with the BRAF inhibitor vemurafenib\, collected at different time points during therapy to evaluate the sensitivity and specificity of quantitative polymerase chain reaction and droplet digital polymerase chain reaction (ddPCR) and the correlation between the level of plasma cfDNA p.V600E and the long-term clinical outcome.,cfDNA in patients with BRAF-mutated melanoma (n = 62) was analyzed at baseline and at 4-8 weeks from the start of vemurafenib therapy. BRAF mutations were assessed using tumor tissue-derived DNA and circulating cfDNA from plasma samples. Quantification of BRAF V600E was performed in cfDNA using ddPCR.,cfDNA V600E was detected in the plasma of 48/62 (77%) patients at baseline and in 18/62 (29%) patients after 4-8 weeks of treatment. Patients positive for BRAF mutations in cfDNA at baseline had shorter progression-free survival (PFS) and overall survival (OS) compared with patients with undetectable cfDNA BRAF mutations. Undetectable cfDNA p.V600E at baseline and after 4-8 weeks of therapy was associated with the best prognosis. When treated as a continuous variable\, the log-transformed concentration of baseline cfDNA p.V600E was significantly associated with both PFS and OS. This effect was retained in the multivariate OS Cox model adjusted for Eastern Cooperative Oncology Group performance status\, the presence of brain metastases\, patient age\, and previous systemic treatment.,Monitoring of plasma BRAF p.V600E cfDNA concentrations in patients with metastatic melanoma on targeted therapy may have prognostic value. Undetectable cfDNA p.V600E before and during treatment was associated with a favorable prognosis.",Tumori,vol.::300891619900928,2020,Journal Article,,,"https://orcid.org/0000-0002-3225-422XDepartment of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Molecular Diagnostics\, Holy Cross Cancer Centre\, Kielce\, Poland.,Department of Molecular and Translational Oncology\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Molecular Biology\, Medical University of Gdansk\, Gdansk\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Genomed Health Care Centre\, Warsaw\, Poland.,Department of Molecular Biology\, Medical University of Gdansk\, Gdansk\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Molecular and Translational Oncology\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.,Department of Molecular Diagnostics\, Holy Cross Cancer Centre\, Kielce\, Poland.,Department of Molecular Diagnostics\, Holy Cross Cancer Centre\, Kielce\, Poland.,Department of Molecular Biology\, Medical University of Gdansk\, Gdansk\, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma\, Maria Sklodowska-Curie Institute Oncology Center\, Warsaw\, Poland.",,,,,"cfDNA,melanoma,targeted therapy"
32026770,"Mahmoud A,Elkhalifa D,Alali F,Al Moustafa AE,Khalil A",Novel Polymethoxylated Chalcones as Potential Compounds Against KRAS-Mutant Colorectal Cancers.,"KRAS-mutant colorectal cancers (CRC) are tumors that are associated with poor prognosis. However\, no effective treatments are available to target them. Therefore\, we designed and synthesized novel chalcone analogs\, small organic molecules\, to investigate their effects on KRAS-mutant CRC cells.,Fourteen new chalcone analogs were synthesized\, optimized\, characterized\, and tested against two KRAS-mutant CRC cell lines (HCT-116 and LoVo)\, one p-53 and BRAF mutant CRC cell line (HT-29) and one normal immortalized colon cells (NCE-1 E6/E7). Effects on cell viability\, apoptosis\, cell cycle\, migration\, colony formation\, EMT\, and angiogenesis were investigated.,Compounds 3 and 14 were the most effective. Compound 3 showed potent activity against HCT-116 and LoVo cell lines (GI50 of 6.10 μM and 7.00 μM\, respectively). While compound 14 showed GI50 of 8.60 μM and 8.80 μM on HCT-116 and LoVo cell lines\, respectively. Both compounds were approximately 2-3 times more selective toward cancer cells rather than normal colon cells. Compound 3 was effective in inducing apoptosis in HCT-116 cells via Bax upregulation and Bcl-2 downregulation. Invasion and metastasis of KRAS-mutant cells were modulated by compounds 3 and 14 through significant inhibition of cell migration and the prevention of colony formation. In addition\, they reversed EMT by downregulation of EMT markers (vimentin\, fascin\, and β- catenin) and upregulation of cell-cell adhesion marker\, E-cadherin. Furthermore\, compounds 3 and 14 had significantly inhibited angiogenesis in ovo.,Compounds 3 and 14 represent potent and selective leads for KRAS-mutant CRC cells\, thus\, further in vitro and in vivo studies are necessary to confirm their effect on KRAS-mutant CRCs.",Current pharmaceutical design,vol.26:14:1622-1633,2020,"Research Support, Non-U.S. Gov't","|Apoptosis|,|Cell Line\, Tumor|,|Cell Movement|,|Cell Proliferation|,|Chalcones|pharmacology|,|Colorectal Neoplasms|drug therapy|genetics|,|Epithelial-Mesenchymal Transition|,|Humans|,|Proto-Oncogene Proteins p21(ras)|chemistry|genetics|",,"College of Pharmacy\, QU Health\, Qatar University\, Doha\, Qatar.,College of Pharmacy\, QU Health\, Qatar University\, Doha\, Qatar.,College of Pharmacy\, QU Health\, Qatar University\, Doha\, Qatar.,College of Medicine\, QU Health\, Qatar University\, Doha\, Qatar.,College of Pharmacy\, QU Health\, Qatar University\, Doha\, Qatar.","Chalcones,KRAS protein\, human,Proto-Oncogene Proteins p21(ras)",,,,"Chalcone,KRAS mutation,analogs,colorectal cancer,epithelial-mesenchymal transition (EMT),metastasis."
32027186,"Huijberts SC,van Geel RM,Bernards R,Beijnen JH,Steeghs N","Encorafenib, binimetinib and cetuximab combined therapy for patients with mutant metastatic colorectal cancer.","Approximately 10-15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.","Future oncology (London, England)",vol.16:6:161-173,2020,Review,"|Antineoplastic Combined Chemotherapy Protocols|therapeutic use|,|Benzimidazoles|pharmacology|therapeutic use|,|Carbamates|pharmacology|therapeutic use|,|Cetuximab|pharmacology|therapeutic use|,|Colorectal Neoplasms|drug therapy|genetics|pathology|,|Humans|,|Molecular Targeted Therapy|,|Mutation|,|Neoplasm Metastasis|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|,|Signal Transduction|drug effects|,|Sulfonamides|pharmacology|therapeutic use|,|Treatment Outcome|",,"Department of Clinical Pharmacology\, The Netherlands Cancer Institute\, Amsterdam\, 1066 CX\, The Netherlands.,Department of Clinical Pharmacy & Toxicology\, Maastricht University Medical Centre\, Maastricht\, 6229 HX\, The Netherlands.,Division of Molecular Carcinogenesis\, Oncode Institute\, The Netherlands Cancer Institute\, Amsterdam\, 1066 CX\, The Netherlands.,Department of Clinical Pharmacology\, The Netherlands Cancer Institute\, Amsterdam\, 1066 CX\, The Netherlands.,Department of Clinical Pharmacology\, The Netherlands Cancer Institute\, Amsterdam\, 1066 CX\, The Netherlands.","Benzimidazoles,Carbamates,Sulfonamides,binimetinib,encorafenib,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Cetuximab",,,,"BRAF inhibitor,BRAFV600E mutation,EGFR inhibitor,MEK inhibitor,binimetinib,cetuximab,colorectal cancer,encorafenib,metastatic"
32027303,"Fan ZQ,Pan YZ,Liu P,Fan WJ,Bai H",[Reaserch Advance on Langerhans Cell Histiocytosis Review].,"Abstract  Langerhans cell histiocytosis (LCH) is a disease originated from bone marrow dendritic cells, and classified as a tumor by the discovery of a recurrent somatic BRAF-V600E point mutation in the RAS-RAF-MEK-ERK signaling pathway. The clinical manifestations of LCH are mainly granulomatous lesions composed of clonal pathological tissue cells. According to the lesions and invasive risk organs, it is divided into single system diseases, multi-system diseases with risk-free organ infiltration and multi-system diseases with risk organ infiltration. The diagnosis was based on immunohistochemical pathological dendritic cell-specific markers CD1α++and/or CD207+,therefore, according to risk stratification, the regiment and intensity of combination chemotherapy and targeted therapy are drawn up. Prognosis is associates with risk organ infiltration, initial treatment response, and BRAF mutations. Due to the low incidence and lack of systematic knowledge, the clinical understanding of this disease is insufficient, thus the rates of misdiagnosis and therapeutic error are high. In this review, the pathogenesis, clinical manifestations, diagnostic and treatment are summarized. So on to provide a theroretical basis for clinical diagnosis and treatment of the diseases.",Zhongguo shi yan xue ye xue za zhi,vol.28:1:354-358,2020,Review,"|Dendritic Cells|,|Histiocytosis\, Langerhans-Cell|,|Humans|,|MAP Kinase Signaling System|,|Mutation|,|Proto-Oncogene Proteins B-raf|,|Signal Transduction|",,"Department of Hematology\, The 94 Hospital of the People's Liberation Army Joint Service Support Force\, Lanzhou 730050\, Gansu Province\, China\,Gansu Traditional Chinese Medicine University\, Lanzhou 730000\, Gansu Province\, China.,Department of Hematology\, The 94 Hospital of the People's Liberation Army Joint Service Support Force\, Lanzhou 730050\, Gansu Province\, China.,Department of Hematology\, The 94 Hospital of the People's Liberation Army Joint Service Support Force\, Lanzhou 730050\, Gansu Province\, China\,Gansu Traditional Chinese Medicine University\, Lanzhou 730000\, Gansu Province\, China.,Department of Hematology\, The 94 Hospital of the People's Liberation Army Joint Service Support Force\, Lanzhou 730050\, Gansu Province\, China.,Department of Hematology\, The 94 Hospital of the People's Liberation Army Joint Service Support Force\, Lanzhou 730050\, Gansu Province\, China\,E-mail:baihai98@tom.com.",Proto-Oncogene Proteins B-raf,,,,
32028967,"Hibiya T,Tanaka M,Matsumura M,Aoki A,Ikegami T,Okudela K,Kawano N,Ohashi K",An NRAS mutation in primary malignant melanoma of the lung: a case report.,"Primary malignant melanoma of the lung (PML) is extremely rare. No precursor lesions of PML have been identified\, and little is known about the genetic mutations associated with the disease. Typically\, 15-20% of malignant melanomas possess NRAS gene mutations\, but no cases of NRAS-mutated PML have been reported in the English literature. We present a case of PML involving an NRAS mutation.,Clinical summary A 74-year-old Japanese female presented with worsening dyspnea and was admitted to hospital. Computed tomography (CT) revealed a right lung (S10) mass and pleural dissemination. Cytology of the pleural effusion in the right lung was performed\, and malignant melanoma or clear cell sarcoma was suspected. A dermatological examination and gallium scintigraphy were conducted to determine the primary tumor site\, but no suspicious lesions\, expect for the right lung mass\, were found. After admission\, CT showed complicating bilateral pneumonia\, and an antibiotic drug was administered\, but the pleural effusion got worse. About 2 weeks later\, the patient died of respiratory failure and cardiac arrest. An autopsy was performed to determine the histological diagnosis. Autopsy findings A 26x15x20-mm black and pale yellow mass was found in the right lower lobe. Many disseminated nodules were found in the right lobe. The tumor had invaded the right diaphragm. Subcarinal lymph node metastasis was also detected. Immunohistochemically\, the tumor cells exhibited positivity for S-100 and HMB45 staining. The patient was diagnosed with malignant melanoma. Sanger sequencing of the tumor detected an NRAS mutation.,We found an NRAS D54N mutation in PML\, which has not been reported previously anywhere in the world. Previous reports indicated that most cases of PML can be classified into the triple-wild-type\, but BRAF mutation status was only analyzed in a few cases. We should analyze the mutation patterns of PML to determine whether any subtypes other than the triple-wild-type exist. PML might be a form of de novo cancer.",Diagnostic pathology,vol.15:1:11,2020,Journal Article,"|Aged|,|Female|,|GTP Phosphohydrolases|genetics|,|Humans|,|Lung Neoplasms|genetics|,|Melanoma|diagnosis|genetics|pathology|,|Membrane Proteins|genetics|,|Mutation|genetics|,|Proto-Oncogene Proteins B-raf|genetics|",,"http://orcid.org/0000-0001-6243-139XDepartment of Pathology\, Yokohama City University Hospital\, 3-9 Fukuura\, Kanazawa-ku\, Yokohama\, 236-0004\, Japan. hibiya-cib@umin.ac.jp.,Department of Pathology\, Graduate School of Medicine\, Yokohama City University\, 3-9 Fukuura\, Kanazawa-ku\, Yokohama\, 236-0004\, Japan.,Department of Pathology\, Graduate School of Medicine\, Yokohama City University\, 3-9 Fukuura\, Kanazawa-ku\, Yokohama\, 236-0004\, Japan.,Department of Respiratory Medicine\, Yokohama Minami Kyousai Hospital\, 1-21-1 Mutsuura-higashi\, Kanazawa-ku\, Yokohama\, 236-0037\, Japan.,Department of Diagnostic Radiology\, Kanagawa Dental University Hospital\, 1-23 Ogawacho\, Yokosuka\, 238-8570\, Japan.,Department of Pathology\, Graduate School of Medicine\, Yokohama City University\, 3-9 Fukuura\, Kanazawa-ku\, Yokohama\, 236-0004\, Japan.,Department of Pathology\, Yokohama Minami Kyousai Hospital\, 1-21-1 Mutsuura-higashi\, Kanazawa-ku\, Yokohama\, 236-0037\, Japan.,Department of Pathology\, Yokohama City University Hospital\, 3-9 Fukuura\, Kanazawa-ku\, Yokohama\, 236-0004\, Japan.","Membrane Proteins,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human",,,,"Autopsy,NRAS mutation,Primary malignant melanoma of the lung,Sanger sequencing"
32005716,"Kim YJ,Tsang T,Anderson GR,Posimo JM,Brady DC",Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAF-Driven Melanoma.,"The principal unmet need in BRAFV600E-positive melanoma is lack of an adequate therapeutic strategy capable of overcoming resistance to clinically approved targeted therapies against oncogenic BRAF and/or the downstream MEK1/2 kinases. We previously discovered that copper (Cu) is required for MEK1 and MEK2 activity through a direct Cu-MEK1/2 interaction. Repurposing the clinical Cu chelator tetrathiomolybdate (TTM) is supported by efficacy in BRAFV600E-driven melanoma models, due in part to inhibition of MEK1/2 kinase activity. However, the antineoplastic activity of Cu chelators is cytostatic. Here, we performed high-throughput small-molecule screens to identify bioactive compounds that synergize with TTM in BRAFV600E-driven melanoma cells. Genetic perturbation or pharmacologic inhibition of specific members of the BCL2 family of antiapoptotic proteins (BCL-W, BCL-XL, and MCL1) selectively reduced cell viability when combined with a Cu chelator and induced CASPASE-dependent cell death. Further, in BRAFV600E-positive melanoma cells evolved to be resistant to BRAF and/or MEK1/2 inhibitors, combined treatment with TTM and the clinically evaluated BCL2 inhibitor, ABT-263, restored tumor growth suppression and induced apoptosis. These findings further support Cu chelation as a therapeutic strategy to target oncogene-dependent tumor cell growth and survival by enhancing Cu chelator efficacy with chemical inducers of apoptosis, especially in the context of refractory or relapsed BRAFV600E-driven melanoma. SIGNIFICANCE: This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAFV600E mutation-positive melanoma.",Cancer research,vol.80:7:1387-1400,2020,"Research Support, Non-U.S. Gov't","|Aniline Compounds|pharmacology|therapeutic use|,|Animals|,|Antineoplastic Combined Chemotherapy Protocols|pharmacology|therapeutic use|,|Apoptosis|drug effects|,|Cell Line\, Tumor|,|Cell Survival|drug effects|genetics|,|Chelating Agents|pharmacology|therapeutic use|,|Copper|metabolism|,|Drug Repositioning|,|Drug Resistance\, Neoplasm|drug effects|genetics|,|Drug Synergism|,|HEK293 Cells|,|High-Throughput Screening Assays|,|Humans|,|Melanoma|drug therapy|genetics|pathology|,|Mice|,|Molybdenum|pharmacology|therapeutic use|,|Protein Kinase Inhibitors|pharmacology|therapeutic use|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|,|Proto-Oncogene Proteins c-bcl-2|antagonists & inhibitors|genetics|,|Skin Neoplasms|drug therapy|genetics|pathology|,|Sulfonamides|pharmacology|therapeutic use|,|Xenograft Model Antitumor Assays|",,"Department of Cancer Biology\, Perelman School of Medicine\, University of Pennsylvania\, Philadelphia\, Pennsylvania.,Cell and Molecular Biology Graduate Group\, Perelman School of Medicine\, University of Pennsylvania\, Philadelphia\, Pennsylvania.,Department of Pharmacology and Cancer Biology\, Duke University Medical Center\, Durham\, North Carolina.,0000-0002-9793-3792Department of Cancer Biology\, Perelman School of Medicine\, University of Pennsylvania\, Philadelphia\, Pennsylvania.,0000-0002-2786-2802Department of Cancer Biology\, Perelman School of Medicine\, University of Pennsylvania\, Philadelphia\, Pennsylvania. bradyd@pennmedicine.upenn.edu.","Aniline Compounds,Chelating Agents,Protein Kinase Inhibitors,Proto-Oncogene Proteins c-bcl-2,Sulfonamides,Copper,Molybdenum,tetrathiomolybdate,BRAF protein\, human,Proto-Oncogene Proteins B-raf,navitoclax","NCI NIH HHS,NCI NIH HHS,NCI NIH HHS","United States,United States,United States","F31 CA243294,K00 CA222728,P50 CA174523",
32007138,"Dummer R,Brase JC,Garrett J,Campbell CD,Gasal E,Squires M,Gusenleitner D,Santinami M,Atkinson V,Mandalà M,Chiarion-Sileni V,Flaherty K,Larkin J,Robert C,Kefford R,Kirkwood JM,Hauschild A,Schadendorf D,Long GV","Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial.","Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected\, BRAFV600-mutant\, stage III melanoma in the phase 3 COMBI-AD trial. This prespecified exploratory biomarker analysis aimed to evaluate potential prognostic or predictive factors and mechanisms of resistance to adjuvant targeted therapy.,COMBI-AD is a randomised\, double-blind\, placebo-controlled\, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm)\, IIIB\, or IIIC cutaneous melanoma\, per American Joint Committee on Cancer 7th edition criteria\, with a BRAFV600E or BRAFV600K mutation. Patients were randomly assigned (1:1) to the two treatment groups by an interactive voice response system\, stratified by mutation type and disease stage. Patients\, physicians\, and the investigators who analysed data were masked to treatment allocation. The primary outcome was relapse-free survival\, defined as the time from randomisation to disease recurrence or death from any cause. Biomarker assessment was a prespecified exploratory outcome of the trial. We assessed intrinsic tumour genomic features by use of next-generation DNA sequencing and characteristics of the tumour microenvironment by use of a NanoString RNA assay\, which might provide prognostic and predictive information. This trial is registered with ClinicalTrials.gov\, number NCT01682083\, and is ongoing but no longer recruiting participants.,Between Jan 31\, 2013\, and Dec 11\, 2014\, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30\, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB\, top third; hazard ratio [HR] 0·56\, 95% CI 0·37-0·85\, p=0·0056)\, but not in the dabrafenib plus trametinib group (0·83\, 95% CI 0·53-1·32\, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49\, 95% CI 0·35-0·68\, p<0·0001). However\, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75\, 95% CI 0·44-1·26\, p=0·27)\, especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93]\, p=0·74).,Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted.,Novartis Pharmaceuticals.",The Lancet. Oncology,vol.21:3:358-372,2020,"Research Support, Non-U.S. Gov't","|Adolescent|,|Adult|,|Aged|,|Aged\, 80 and over|,|Antineoplastic Combined Chemotherapy Protocols|therapeutic use|,|Double-Blind Method|,|Drug Resistance\, Neoplasm|drug effects|,|Female|,|Follow-Up Studies|,|Humans|,|Imidazoles|administration & dosage|,|Male|,|Melanoma|drug therapy|genetics|pathology|,|Middle Aged|,|Mutation|,|Neoplasm Metastasis|,|Neoplasm Recurrence\, Local|drug therapy|genetics|pathology|,|Oximes|administration & dosage|,|Prognosis|,|Proto-Oncogene Proteins B-raf|genetics|,|Pyridones|administration & dosage|,|Pyrimidinones|administration & dosage|,|Salvage Therapy|,|Skin Neoplasms|drug therapy|genetics|pathology|,|Survival Rate|,|Young Adult|",,"University Hospital Zürich Skin Cancer Center\, Zürich\, Switzerland. Electronic address: reinhard.dummer@usz.ch.,Novartis Pharma\, Basel\, Switzerland.,Novartis Institutes for BioMedical Research\, Cambridge\, MA\, USA.,Novartis Institutes for BioMedical Research\, Cambridge\, MA\, USA.,Novartis Pharmaceuticals\, East Hanover\, NJ\, USA.,Novartis Pharma\, Basel\, Switzerland.,Novartis Institutes for BioMedical Research\, Cambridge\, MA\, USA.,Fondazione IRCCS Istituto Nazionale dei Tumori\, Milan\, Italy.,Princess Alexandra Hospital\, Gallipoli Medical Research Foundation\, University of Queensland\, Brisbane\, QLD\, Australia.,Papa Giovanni XXIII Cancer Center Hospital\, Bergamo\, Italy.,Melanoma Oncology Unit\, Veneto Institute of Oncology IOV-IRCCS\, Padova\, Italy.,Massachusetts General Hospital Cancer Center and Harvard Medical School\, Boston\, MA\, USA.,Royal Marsden NHS Foundation Trust\, London\, UK.,Gustave Roussy and Paris-Sud-Paris-Saclay University\, Villejuif\, France.,Macquarie University and Westmead Hospital\, Sydney\, NSW\, Australia; Melanoma Institute Australia and The University of Sydney\, Sydney\, NSW\, Australia.,Melanoma Program\, UPMC Hillman Cancer Center\, University of Pittsburgh\, Pittsburgh\, PA\, USA.,University Hospital Schleswig-Holstein\, Kiel\, Germany.,University Hospital Essen\, Essen\, Germany; German Cancer Consortium\, Heidelberg\, Germany.,Melanoma Institute Australia and The University of Sydney\, Sydney\, NSW\, Australia; Royal North Shore and Mater Hospitals\, Sydney\, NSW\, Australia.","Imidazoles,Oximes,Pyridones,Pyrimidinones,trametinib,BRAF protein\, human,Proto-Oncogene Proteins B-raf,dabrafenib",,,,
32007245,"Zheng R,Shen Q,Mardekian S,Solomides C,Wang ZX,Evans NR",Molecular profiling of key driver genes improves staging accuracy in multifocal non-small cell lung cancer.,"Multifocal non-small cell lung cancer has historically been separated into synchronous primary lung cancers or intrapulmonary metastases with the use of histopathology. We hypothesize that using targeted next-generation sequencing of key driver mutations in multifocal non-small cell lung cancer will improve our ability to differentiate intrapulmonary metastases from synchronous primary lung cancers.,We identified patients who underwent surgery for non-small cell lung cancer between 2013 and 2018 with multifocal tumors. Archived specimens were reviewed with a 4-gene next-generation sequencing panel identifying mutations of EGFR\, KRAS\, BRAF\, and NRAS. Synchronous primary lung cancers were classified as lesions with different histopathologic subtypes or driver mutations. Tests of hypotheses were performed with the Fisher exact test. Calculations were performed in Stata (v13.0; StataCorp LLC\, College Station\, Tex).,A total of 18 patients had non-small cell lung cancer tumor specimens (n = 41) available from 2 or more sites. The pathologic diagnosis was predominantly adenocarcinoma (39/41 specimens). We detected a driver mutation in 68.3% (28/41) of all tumors. The most common mutations observed were in KRAS (n = 17/41) and EGFR (n = 7/41). Eleven patients had synchronous primary lung cancers\, and 4 patients had intrapulmonary metastases based on combined histopathologic and molecular profiling results. Three lacked driver mutations in either lesion. Eight synchronous primary lung cancers (8/18\, 44%) were downstaged when compared with their original diagnosis (P = .08). Of these\, 4 patients received adjuvant chemotherapy unnecessarily in hindsight.,Molecular non-small cell lung cancer profiling using a 4-gene next-generation sequencing panel allows for better distinction between synchronous primary lung cancers and intrapulmonary metastases than histopathology alone. Routine use of next-generation sequencing for multifocal lesions prevents unnecessary adjuvant treatment for patients with histologically similar synchronous primary lung cancers.",The Journal of thoracic and cardiovascular surgery,vol.160:2:e71-e79,2020,Video-Audio Media,"|Aged|,|Aged\, 80 and over|,|Biomarkers\, Tumor|genetics|,|Carcinoma\, Non-Small-Cell Lung|genetics|secondary|therapy|,|Chemotherapy\, Adjuvant|,|Clinical Decision-Making|,|DNA Mutational Analysis|,|ErbB Receptors|genetics|,|Female|,|GTP Phosphohydrolases|genetics|,|Gene Expression Profiling|,|High-Throughput Nucleotide Sequencing|,|Humans|,|Lung Neoplasms|genetics|pathology|therapy|,|Male|,|Membrane Proteins|genetics|,|Middle Aged|,|Mutation|,|Neoplasm Staging|,|Neoplasms\, Multiple Primary|genetics|pathology|therapy|,|Pneumonectomy|,|Predictive Value of Tests|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Reproducibility of Results|,|Retrospective Studies|,|Transcriptome|",,"Department of Surgery\, Sidney Kimmel Medical College\, Thomas Jefferson University\, Philadelphia\, Pa.,Department of Pathology\, Sidney Kimmel Medical College\, Thomas Jefferson University\, Philadelphia\, Pa.,Department of Pathology\, Sidney Kimmel Medical College\, Thomas Jefferson University\, Philadelphia\, Pa.,Department of Pathology\, Sidney Kimmel Medical College\, Thomas Jefferson University\, Philadelphia\, Pa.,Department of Pathology\, Sidney Kimmel Medical College\, Thomas Jefferson University\, Philadelphia\, Pa.,Department of Surgery\, Sidney Kimmel Medical College\, Thomas Jefferson University\, Philadelphia\, Pa. Electronic address: Nathaniel.Evans@jefferson.edu.","Biomarkers\, Tumor,KRAS protein\, human,Membrane Proteins,EGFR protein\, human,ErbB Receptors,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human,Proto-Oncogene Proteins p21(ras)",,,,"lung cancer staging,molecular profiling,multifocal lung cancer,next-generation sequencing"
32009180,"Rassidakis GZ,Stromberg O,Xagoraris I,Jatta K,Sonnevi K",Trametinib and Dabrafenib in histiocytic sarcoma transdifferentiated from chronic lymphocytic leukemia with a K-RAS and a unique BRAF mutation.,,Annals of hematology,vol.99:3:649-651,2020,Letter,"|Aged|,|Antineoplastic Combined Chemotherapy Protocols|administration & dosage|,|Cell Transdifferentiation|,|Head and Neck Neoplasms|diagnostic imaging|drug therapy|genetics|pathology|,|Histiocytic Sarcoma|diagnostic imaging|drug therapy|genetics|pathology|,|Humans|,|Imidazoles|administration & dosage|,|Leukemia\, Lymphocytic\, Chronic\, B-Cell|diagnostic imaging|drug therapy|genetics|pathology|,|Male|,|Oximes|administration & dosage|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Pyridones|administration & dosage|,|Pyrimidinones|administration & dosage|",,"http://orcid.org/0000-0002-9082-4091Department of Pathology and Cytology\, Karolinska University Hospital\, Stockholm\, Sweden. georgios.rassidakis@ki.se.,Department of Hematology\, Karolinska University Hospital\, Stockholm\, Sweden.,Department of Oncology & Pathology\, Karolinska Institutet\, Stockholm\, Sweden.,Department of Pathology and Cytology\, Karolinska University Hospital\, Stockholm\, Sweden.,Department of Hematology\, Karolinska University Hospital\, Stockholm\, Sweden.","Imidazoles,KRAS protein\, human,Oximes,Pyridones,Pyrimidinones,trametinib,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras),dabrafenib",,,,
32011515,"Nagaishi M,Nakae R,Fujii Y,Inoue Y,Sugiura Y,Takano I,Tanaka Y,Suzuki K",Rare clinical presentations of pleomorphic xanthoastrocytoma with a high proliferative index: Two case reports.,"Pleomorphic xanthoastrocytomas (PXA) are rare\, typically benign\, slow-growing tumors that commonly occur in the cerebral hemispheres. We describe two cases of clinically aggressive PXA with uncommon locations; one was in the tectal plate\, and the other had simultaneous multicentric lesions.,The both cases presented with severe headache with no significant past medical history.,PXA World Health Organization grade II were histopathologically diagnosed from surgically resected specimens\, and immunohistochemical and sequence analysis revealed a high Ki-67 proliferative index and BRAF V600E mutation in both the cases.,The first case presented with multicentric lesions and underwent partial resection\, whereas the second case presented with a tectal plate tumor that was managed by gross total surgical resection. Strong 5-aminolevulinic acid (5-ALA)-induced fluorescence was observed in both the lesions. Postoperative radiotherapy plus concomitant and adjuvant temozolomide was administered to both the patients.,Despite completing adjuvant chemo-radiotherapy\, both the patients had local tumor recurrence at 2 and 5 months after the operation\, respectively.,The progressive clinical courses in our cases suggest that additional postoperative therapy should be considered during the treatment of PXA with a high Ki67 index\, and that temozolomide with radiotherapy\, followed by temozolomide maintenance therapy\, may not prevent recurrence in such tumors. Importantly\, our experience implies that unlike other subtypes of low grade gliomas\, 5-ALA fluorescence is useful for intraoperative visualization of PXA.",Medicine,vol.99:3:e18880,2020,Journal Article,"|Astrocytoma|diagnostic imaging|genetics|pathology|therapy|,|Brain Neoplasms|diagnostic imaging|genetics|pathology|therapy|,|Combined Modality Therapy|,|Diagnosis\, Differential|,|Disease Progression|,|Female|,|Humans|,|Ki-67 Antigen|genetics|,|Middle Aged|,|Neoplasm Grading|,|Neoplasm Recurrence\, Local|,|Neoplasm\, Residual|diagnostic imaging|genetics|therapy|,|Proto-Oncogene Proteins B-raf|genetics|,|Young Adult|",,",,,,,,,","Ki-67 Antigen,Proto-Oncogene Proteins B-raf",,,,
32012328,"Vela V,Juskevicius D,Gerlach MM,Meyer P,Graber A,Cathomas G,Dirnhofer S,Tzankov A",High throughput sequencing reveals high specificity of TNFAIP3 mutations in ocular adnexal marginal zone B-cell lymphomas.,"The majority of ocular adnexal (OA) lymphomas (OAL) are extranodal marginal zone lymphomas (MZL). First high throughput sequencing (HTS) studies on OA-MZL showed inconsistent results and the distribution of mutations in reactive lymphoid lesions of this anatomic region has not yet been sufficiently addressed. We characterized OAL and lymphoid lesions of the OA by targeted HTS. The study included 34 OA-MZL, 11 chronic conjunctivitis, five mature small cell B-cell lymphomas spreading to the OA, five diseases with increase of IgG4+ plasma cells, three Burkitt lymphomas (BL), three diffuse large B-cell lymphomas (DLBCL), three mantle cell lymphomas, three idiopathic orbital inflammations/orbital pseudo tumors (PT), and three OA lymphoid hyperplasia. All cases were negative for Chlamydia. The mutational number was highest in BL and lowest in PT. The most commonly (and exclusively) mutated gene in OA-MZL was TNFAIP3 (10 of 34 cases). Altogether, 20 out of 34 patients harbored mutually exclusive mutations of either TNFAIP3, BCL10, MYD88, ATM, BRAF, or NFKBIE, or nonexclusive mutations of IRF8, TNFRSF14, KLHL6, and TBL1XR1, all encoding for NK-κB pathway compounds or regulators. Thirteen patients (38%) had, to a great part, mutually exclusive mutations of chromatin modifier-encoding genes: KMT2D, CREBBP, BCL7A, DNMT3A, EP300, or HIST1H1E. Only four patients harbored co-occurring mutations of genes encoding for NK-κB compounds and chromatin modifiers. Finally, PTEN, KMT2D, PRDM1, and HIST1H2BK mutations were observable in reactive lymphoid lesions too, while such instances were devoid of NF-κB compound mutations and/or mutations of acetyltransferase-encoding genes. In conclusion, 80% of OA-MZL display mutations of either NK-κB compounds or chromatin modifiers. Lymphoid lesions of the OA bearing NF-κB compound mutations and/or mutations of acetyltransferase-encoding genes highly likely represent lymphomas.",Hematological oncology,vol.38:3:284-292,2020,Journal Article,"|Adolescent|,|Adult|,|Aged|,|Aged\, 80 and over|,|Biomarkers\, Tumor|genetics|,|Child|,|Combined Modality Therapy|,|Eye Neoplasms|genetics|pathology|therapy|,|Female|,|Follow-Up Studies|,|High-Throughput Nucleotide Sequencing|methods|,|Humans|,|Lymphoma\, B-Cell\, Marginal Zone|genetics|pathology|therapy|,|Male|,|Middle Aged|,|Mutation|,|Prognosis|,|Tumor Necrosis Factor alpha-Induced Protein 3|genetics|,|Young Adult|",,"Institute of Medical Genetics and Pathology\, University Hospital Basel\, Basel\, Switzerland.,Institute of Medical Genetics and Pathology\, University Hospital Basel\, Basel\, Switzerland.,Institute of Medical Genetics and Pathology\, University Hospital Basel\, Basel\, Switzerland.,Institute of Medical Genetics and Pathology\, University Hospital Basel\, Basel\, Switzerland.,Cantonal Institute of Pathology\, Liestal\, Switzerland.,Cantonal Institute of Pathology\, Liestal\, Switzerland.,Institute of Medical Genetics and Pathology\, University Hospital Basel\, Basel\, Switzerland.,https://orcid.org/0000-0002-1100-3819Institute of Medical Genetics and Pathology\, University Hospital Basel\, Basel\, Switzerland.","Biomarkers\, Tumor,TNFAIP3 protein\, human,Tumor Necrosis Factor alpha-Induced Protein 3",Stiftung zur Krebsbekämpfung Zürich,,460,"BCL10,MYD88,NF-κB,TNFAIP3,high throughput sequencing,marginal zone B-cell lymphoma,ocular adnexa"
32015690,"Fanelli GN,Dal Pozzo CA,Depetris I,Schirripa M,Brignola S,Biason P,Balistreri M,Dal Santo L,Lonardi S,Munari G,Loupakis F,Fassan M",The heterogeneous clinical and pathological landscapes of metastatic -mutated colorectal cancer.,"Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the ""serrated"" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.",Cancer cell international,vol.20::30,2020,Review,,,"1Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.,1Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.,2Department of Oncology\, Veneto Institute of Oncology IOV-IRCCS\, Padua\, Italy.,2Department of Oncology\, Veneto Institute of Oncology IOV-IRCCS\, Padua\, Italy.,1Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.,2Department of Oncology\, Veneto Institute of Oncology IOV-IRCCS\, Padua\, Italy.,1Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.,1Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.,2Department of Oncology\, Veneto Institute of Oncology IOV-IRCCS\, Padua\, Italy.,1Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.,2Department of Oncology\, Veneto Institute of Oncology IOV-IRCCS\, Padua\, Italy.,0000-0001-6515-54821Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, via Gabelli 61\, 35121 Padua\, Italy.",,,,,"BRAF mutation,Colorectal cancer,Personalized medicine,Sequencing"
32016676,"Chen J,Chen QL,Wang WH,Chen XL,Hu XQ,Liang ZQ,Cao YB,Cao YM,Su SB",Prognostic and predictive values of CXCL10 in colorectal cancer.,"The role of CXCL10 in progression and prognosis of colorectal cancer (CRC) has been studied for years\, yet results remain controversial.,This study aims to explore the relationship between CXCL10 and CRC progression and prognosis.,We evaluated plasma CXCL10 in CRC patients using ELISA. We also performed a meta-analysis of the associations between CXCL10 and overall survival (OS)\, disease-free survival (DFS)\, disease-specific survival (DSS)\, relapse-free survival (RFS)\, and clinicopathological features. Finally\, correlations between CXCL10 and methylation or immune infiltration were performed using TCGA data.,ELISA analysis showed that CXCL10 was associated with age\, red blood cells\, blood platelets\, and blood urea nitrogen. A separate analysis of 3\,763 patients from 24 studies revealed that there were significant associations between low CXCL10 expression and OS (HR 1.25\, 95% CI 1.01-1.53)\, DFS (HR 1.65\, 95% CI 1.17-2.34)\, and RFS (HR 1.43\, 95% CI 1.20-1.71) in CRC. Additionally\, downregulated CXCL10 expression was significantly correlated with age [odds ratio (OR) 1.31\, 95% CI 1.13-1.52]\, metastasis (OR 1.34\, 95% CI 1.11-1.63)\, recurrence (OR 1.46\, 95% CI 1.16-1.83)\, tumor location (OR 1.88\, 95% CI 1.58-2.24)\, differentiation (OR 0.57\, 95% CI 0.35-0.93)\, microsatellite instability (OR 0.23\, 95% CI 0.15-0.35)\, BRAF mutation (OR 1.62\, 95% CI 1.25-2.08)\, p53 mutation (OR 0.28\, 95% CI 0.16-0.47)\, and CIMP (OR 0.27\, 95% CI 0.17-0.43). Furthermore\, significant associations were observed between CXCL10 and methylation and immune infiltration.,The study suggests that CXCL10 might be a potential target for the treatment of CRC.,NCT03189992. Registered 4 June 2017\, https://www.clinicaltrials.gov/ct2/show/study/NCT03189992?term=NCT03189992&rank=1 .",Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico,vol.22:9:1548-1564,2020,Journal Article,,,"Shanghai TCM-Integrated Hospital\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 200082\, China.,Research Center for Traditional Chinese Medicine Complexity System\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 201203\, China.,Department of Medical Oncology\, Shuguang Hospital Affiliated Baoshan Branch\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 201901\, China.,Research Center for Traditional Chinese Medicine Complexity System\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 201203\, China.,Research Center for Traditional Chinese Medicine Complexity System\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 201203\, China.,Shanghai TCM-Integrated Hospital\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 200082\, China.,Shanghai TCM-Integrated Hospital\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 200082\, China.,Shanghai TCM-Integrated Hospital\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 200082\, China.,http://orcid.org/0000-0002-7635-314XResearch Center for Traditional Chinese Medicine Complexity System\, Shanghai University of Traditional Chinese Medicine\, Shanghai\, 201203\, China. shibingsu17@163.com.",,,,,"CXCL10,Colorectal cancer,Immune infiltration,Meta-analysis,Methylation,Prognosis"
32017841,"Dika E,Veronesi G,Altimari A,Riefolo M,Ravaioli GM,Piraccini BM,Lambertini M,Campione E,Gruppioni E,Fiorentino M,Melotti B,Ferracin M,Patrizi A","BRAF, KIT, and NRAS Mutations of Acral Melanoma in White Patients.","Malignant acral melanoma (AM) is relatively infrequent in white patients. Molecular investigations have returned variable results regarding the mutational pattern. We sought to describe the mutation profile and clinicopathologic features of AM.,We investigated BRAF\, KIT\, and NRAS mutational status in a series of 31 AM samples from white patients.,Nodular melanoma was the most common histopathologic subtype (48.4%)\, followed by acral lentiginous melanoma (25.8%) and superficial spreading melanoma (25.8%). BRAF\, KIT\, and NRAS mutational rates were 12.9%\, 17.2%\, and 30.0%\, respectively. We observed significant associations between KIT mutational status and a thinner Breslow thickness compared with wild-type (WT) status (P = .002)\, NRAS mutation status and younger age compared with WT. In patients presenting at least one mutation\, triple-WT patients presented metastases most frequently.,Although these data represent preliminary results\, better knowledge of tumor biology and prognosis of AM can support the clinical approach and follow-up.",American journal of clinical pathology,vol.153:5:664-671,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|DNA Mutational Analysis|,|European Continental Ancestry Group|,|Female|,|GTP Phosphohydrolases|genetics|,|Humans|,|Male|,|Melanoma|genetics|pathology|,|Membrane Proteins|genetics|,|Middle Aged|,|Mutation|,|Prognosis|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins c-kit|genetics|,|Skin Neoplasms|genetics|pathology|",,"Dermatology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Dermatology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Laboratory of Oncologic and Transplantation Molecular Pathology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Laboratory of Oncologic and Transplantation Molecular Pathology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Dermatology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Dermatology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Dermatology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Department of Experimental Medicine\, University of Rome Tor Vergata\, Rome\, Italy.,Laboratory of Oncologic and Transplantation Molecular Pathology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Laboratory of Oncologic and Transplantation Molecular Pathology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.,Medical Oncology Unit\, Sant'Orsola Malpighi Hospital\, Bologna\, Italy.,Department of Experimental\, Diagnostic and Specialty Medicine (DIMES)\, University of Bologna\, Bologna\, Italy.,Dermatology\, Department of Experimental\, Diagnostic and Specialty Medicine\, University of Bologna\, Italy.","Membrane Proteins,KIT protein\, human,Proto-Oncogene Proteins c-kit,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human",,,,"\n BRAF\n ,\n KIT\n ,\n NRAS\n ,Acral lentiginous melanoma,Genetic,Melanoma,Metastases,Mutations,Pathology,Prognosis"
32020225,"Kasajima R,Yamaguchi R,Shimizu E,Tamada Y,Niida A,Tremmel G,Kishida T,Aoki I,Imoto S,Miyano S,Uemura H,Miyagi Y",Variant analysis of prostate cancer in Japanese patients and a new attempt to predict related biological pathways.,"There are regional and/or ethnic differences in tumorigenic pathways among several types of cancer, including prostate cancer (PCa). However, information on genome‑wide gene alterations and the transcriptome is currently only available for PCa patients from Western countries. In order to profile the genetic alterations in Japanese patients with PCa, new panels were created to examine nucleotide sequence variations in 71 selected PCa‑related genes (KCC71) and to detect all fusion RNA transcripts known in PCa (PCaFusion). An analysis of 21 Japanese PCa cases identified 33 different somatic variants in 24 genes in the KCC71 panel, including 2 in SPOP (F102V and F133L), 2 in BRCA2 (I1859fs and R2318ter, resulting in premature termination of the polypeptide), and 1 each in BRAF (K601E), CDH1 (E880K) and RB1 (R621S), as pathogenic alterations. Unexpectedly, the TMPRSS2‑ERG fusion transcript was detected in only 1 case, although the SLC45A3‑ELK4 and USP9Y‑TTTY15 fusion transcripts, known as transcription‑mediated chimeric RNAs, were detected in all examined cases. A new pathway analysis with The Cancer Network Galaxy (TCNG), a cancer gene regulatory network database, was also applied in an attempt to predict molecular pathways implicated in PCa in the Japanese population. Based on the 24 genes having somatic variants identified by the panel analysis as initial seed genes, a putative core network was finally established, including 5 identified genes, namely TNK2, SOX9, CDH1, FOXA1 and TP53, with high commonality from TCNG datasets. These genes are expected to be involved in tumor development, as revealed by the results of an enrichment analysis with Gene Ontology terms. This analysis must be further extended to include more cases in order to verify this method and also to elucidate the characteristics of PCa in Japanese patients.",Oncology reports,vol.43:3:943-952,2020,Journal Article,"|Gene Expression Profiling|,|Gene Expression Regulation\, Neoplastic|genetics|,|Gene Ontology|,|Gene Regulatory Networks|genetics|,|Humans|,|Japan|epidemiology|,|Male|,|Monosaccharide Transport Proteins|genetics|,|Prostatic Neoplasms|genetics|pathology|,|Protein-Tyrosine Kinases|genetics|,|Serine Endopeptidases|genetics|,|Signal Transduction|genetics|,|Transcriptome|genetics|",,"Molecular Pathology and Genetics Division\, Kanagawa Cancer Center Research Institute\, Yokohama\, Kanagawa 241‑8515\, Japan.,Laboratory of DNA Information Analysis\, Human Genome Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Laboratory of DNA Information Analysis\, Human Genome Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Laboratory of DNA Information Analysis\, Human Genome Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Division of Health Medical Computational Science\, Health Intelligence Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Laboratory of DNA Information Analysis\, Human Genome Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Department of Urology\, Kanagawa Cancer Center Hospital\, Yokohama\, Kanagawa 241‑8515\, Japan.,Niwa Hospital Pathology Section\, Odawara\, Kanagawa 205‑0042\, Japan.,Division of Health Medical Data Science\, Health Intelligence Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Laboratory of DNA Information Analysis\, Human Genome Center\, Institute of Medical Science\, University of Tokyo\, Tokyo 108‑8639\, Japan.,Department of Urology and Renal Transplantation\, Yokohama City University Medical Center\, Yokohama\, Kanagawa 236‑0027\, Japan.,Molecular Pathology and Genetics Division\, Kanagawa Cancer Center Research Institute\, Yokohama\, Kanagawa 241‑8515\, Japan.","Monosaccharide Transport Proteins,SLC45a3 protein\, human,Protein-Tyrosine Kinases,TNK2 protein\, human,Serine Endopeptidases,TMPRSS2 protein\, human",,,,
32020654,"Li X,Li E,Du J,Wang J,Zheng B",The Authors' Reply: Comment on: BRAF mutation analysis by ARMS-PCR refines thyroid nodule management.,,Clinical endocrinology,vol.92:5:483-485,2020,Comment,"|Humans|,|Mutation|,|Polymerase Chain Reaction|,|Proto-Oncogene Proteins B-raf|genetics|,|Thyroid Neoplasms|,|Thyroid Nodule|",,"Department of Head and Neck Surgery\, Renji Hospital\, School of Medicine\, Shanghai Jiaotong University\, Shanghai\, China.,Department of Laboratory Medicine\, Renji Hospital\, School of Medicine\, Shanghai Jiaotong University\, Shanghai\, China.,Department of Ultrasonography\, Renji Hospital\, School of Medicine\, Shanghai Jiaotong University\, Shanghai\, China.,Department of Head and Neck Surgery\, Renji Hospital\, School of Medicine\, Shanghai Jiaotong University\, Shanghai\, China.,Department of Laboratory Medicine\, Renji Hospital\, School of Medicine\, Shanghai Jiaotong University\, Shanghai\, China.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,
32021277,"Yu Z,Yu H,Zou Q,Huang Z,Wang X,Tang G,Bai L,Zhou C,Zhuang Z,Xie Y,Wang H,Xu G,Chen Z,Fu X,Huang M,Luo Y",Nomograms for Prediction of Molecular Phenotypes in Colorectal Cancer.,"Colorectal cancer (CRC) patients with different molecular phenotypes\, including microsatellite instability (MSI)\, CpG island methylator phenotype (CIMP)\, and somatic mutations in BRAF and KRAS gene\, vary in treatment response and prognosis. However\, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes.,Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI\, CIMP\, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype.,The incidences of MSI\, CIMP\, BRAF mutation and KRAS mutation were 25.3% (72/285)\, 2.5% (7/270)\, 3.4% (10/293)\, and 34.8% (96/276) respectively. In the multivariate Logistic analysis\, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation\, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation\, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation\, proximal tumor\, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI\, CIMP\, BRAF mutation and KRAS mutation were developed based on these independent predictors\, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%)\, 95.57% (95% CI: 95.20-95.94%)\, 83.56% (95% CI: 81.54-85.58%)\, and 69.12% (95% CI: 68.30-69.94%) respectively.,We established four nomograms using easily accessible variables that could well predict the presence of MSI\, CIMP\, BRAF mutation and KRAS mutation in CRC patients.",OncoTargets and therapy,vol.13::309-321,2020,Journal Article,,,"0000-0002-2306-5590Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0001-8357-1615Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0003-3625-315XGuangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0002-3911-6911Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0002-8395-5712Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0002-2338-7258Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0003-1821-2995Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,Guangdong Institute of Gastroenterology\, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.,0000-0002-5200-3997Department of Colorectal Surgery\, The Sixth Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, Guangdong 510655\, People's Republic of China.",,,,,"BRAF,CpG island methylator phenotype,KRAS,colorectal cancer,microsatellite instability,nomogram,prediction of molecular subtypes"
32021565,"Li K,Zhao S,Long J,Su J,Wu L,Tao J,Zhou J,Zhang J,Chen X,Peng C",A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products.,"Melanoma is one of the most aggressive tumors with the remarkable characteristic of resistance to traditional chemotherapy and radiotherapy. Although targeted therapy and immunotherapy benefit advanced melanoma patient treatment\, BRAFi (BRAF inhibitor) resistance and the lower response rates or severe side effects of immunotherapy have been observed\, therefore\, it is necessary to develop novel inhibitors for melanoma treatment.,We detected the cell proliferation of lj-1-59 in different melanoma cells by CCK 8 and colony formation assay. To further explore the mechanisms of lj-1-59 in melanoma\, we performed RNA sequencing to discover the pathway of differential gene enrichment. Western blot and Q-RT-PCR were confirmed to study the function of lj-1-59 in melanoma.,We found that lj-1-59 inhibits melanoma cell proliferation in vitro and in vivo\, induces cell cycle arrest at the G2/M phase and promotes apoptosis in melanoma cell lines. Furthermore\, RNA-Seq was performed to study alterations in gene expression profiles after treatment with lj-1-59 in melanoma cells\, revealing that this compound regulates various pathways\, such as DNA replication\, P53\, apoptosis and the cell cycle. Additionally\, we validated the effect of lj-1-59 on key gene expression alterations by Q-RT-PCR. Our findings showed that lj-1-59 significantly increases ROS (reactive oxygen species) products\, leading to DNA toxicity in melanoma cell lines. Moreover\, lj-1-59 increases ROS levels in BRAFi -resistant melanoma cells\, leading to DNA damage\, which caused G2/M phase arrest and apoptosis.,Taken together\, we found that lj-1-59 treatment inhibits melanoma cell growth by inducing apoptosis and DNA damage through increased ROS levels\, suggesting that this compound is a potential therapeutic drug for melanoma treatment.",Cancer cell international,vol.20::36,2020,Journal Article,,,"1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,4Department of Dermatology\, Affiliated Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, China.,5Department of Plastic Surgery of Third Xiangya Hospital\, Central South University\, Changsha\, China.,1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,1The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.,0000-0001-7104-54901The Department of Dermatology\, Xiangya Hospital\, Central South University\, 87 Xiangya Road\, Changsha\, Hunan China.",,,,,"Chalcone,DNA damage,Melanoma,P53,ROS (reactive oxygen species)"
32021610,"Sanri A,Gurkan H,Demir S",Cardiofaciocutaneous Syndrome Phenotype in a Case with de novo Pathogenic Variant.,"Cardiofaciocutaneous (CFC) syndrome is one of the developmental disorders caused by a dysregulation of the Ras/mitogen-activated protein kinase (MAPK) pathway. RASopathies share overlapping clinical features, making the diagnosis challenging, especially in the newborn period. The majority of CFC syndrome cases arise by a mutation in the BRAF, MAP2K1, MAP2K2, or (rarely) KRAS genes. Germline KRAS mutations are identified in a minority of CFC and Noonan syndrome cases. Here, we describe a patient with a KRAS mutation presenting with a CFC syndrome phenotype. The female patient was referred for genetic testing because of congenital exophthalmos. Her facial appearance is distinctive with a coarse face, exophthalmos, ptosis, downslanting palpebral fissures, hypertelorism, deep philtrum, downturned corners of the mouth, and a short neck. She suffered from feeding difficulties, poor weight gain, and developmental delay. The sequencing of the genes involved in the MAPK pathway (PTPN11, SOS1, RAF1, KRAS, NRAS, MAP2K1, SHOC2, CBL, and SPRED1) identified a heterozygous de novo NM_004985.4:c.173C>T (p.Thr58Ile) in the KRAS gene. Germline KRAS mutations have been identified in approximately 2% of the reported NS cases and less than 5% of the reported CFC syndrome cases. Because CFC and Noonan syndrome share clinical overlapping features, the phenotype caused by KRAS mutations is often difficult to assign to one of the 2 entities. The mutation that we detected in our patient was previously reported in a patient with an Noonan syndrome phenotype. However, our patient predominantly exhibits CFC clinical features. In our case, coarse facial appearance and severe developmental delay help discriminate CFC from Noonan syndrome. Thus, patient follow-up, especially for delayed motor milestones suspected from RASopathies, is important for the discrimination of overlapping conditions as in the abovementioned syndromes.",Molecular syndromology,vol.10:6:344-347,2020,Journal Article,,,"Department of Pediatric Genetics\, Samsun Training and Research Hospital\, Samsun\, Turkey.,Department of Medical Genetics\, Faculty of Medicine\, Trakya University\, Edirne\, Turkey.,Department of Medical Genetics\, Faculty of Medicine\, Trakya University\, Edirne\, Turkey.",,,,,"Cardiofaciocutaneous syndrome,KRAS,Noonan syndrome,RASopathies"
31496327,"Cornejo KM,Cosar EF,Paner GP,Yang P,Tomaszewicz K,Meng X,Mehta V,Sirintrapun SJ,Barkan GA,Hutchinson L",Mutational Profile Using Next-Generation Sequencing May Aid in the Diagnosis and Treatment of Urachal Adenocarcinoma.,"Objectives. The rare urachal adenocarcinoma (UAC) of the bladder has striking morphologic and immunohistochemical overlap with colorectal adenocarcinoma (CAC) and bladder adenocarcinoma (BAC). To date, the mutational status in UAC and BAC has not been well investigated. Methods. We retrospectively evaluated 34 UACs (mucinous, n = 9; intestinal, n = 3; signet ring cell, n = 1; not otherwise specified, n = 21) and 4 BACs (n = 4). Next-generation sequencing analysis of 50 cancer ""hotspot"" gene mutations using the Ampliseq Cancer Hotspot Panel v2 was performed. Two UAC cases did not have adequate DNA quality with poor sequencing coverage and were excluded from the study. Results. RAS mutations were identified in 16 of 32 (50%) UACs (15 KRAS; 1 NRAS) and none of the BACs (0%). TP53 mutations were found in both UACs (18/32; 56%) and BACs (4/4; 100%). GNAS (n = 4), SMAD4 (n = 3), and BRAF (n = 1) mutations were only found in UACs. In contrast, APC (n = 2) mutations were only found in BACs. The mucinous subtype of UAC contained a SMAD4 mutation in 33% of cases (3/9), which was not identified in any other subtype (0/23; 0%) (P = .0169). The only BRAF mutation was identified in the single signet ring cell subtype of UAC. There were no other differences in the mutation profile when comparing histologic subtypes of UAC. Conclusions. In summary, UAC and BAC have overlapping but distinct mutation profiles and these differences may aid in separating these 2 entities. Next-generation sequencing to identify therapeutic targets or resistance markers may aid treatment decisions.",International journal of surgical pathology,vol.28:1:51-59,2020,Journal Article,"|Adenocarcinoma|diagnosis|genetics|pathology|therapy|,|Biomarkers\, Tumor|genetics|,|Clinical Decision-Making|,|Diagnosis\, Differential|,|High-Throughput Nucleotide Sequencing|,|Humans|,|Molecular Targeted Therapy|,|Mutation|,|Retrospective Studies|,|Urinary Bladder Neoplasms|diagnosis|genetics|pathology|therapy|",,"https://orcid.org/0000-0002-9490-8583University of Massachusetts Medical School\, UMass Memorial Medical Center\, Worcester\, MA\, USA.,University of Massachusetts Medical School\, UMass Memorial Medical Center\, Worcester\, MA\, USA.,University of Chicago Medical Center\, Chicago\, IL\, USA.,Sun Yat-sen University Cancer Center\, Guangzhou\, China.,University of Massachusetts Medical School\, UMass Memorial Medical Center\, Worcester\, MA\, USA.,University of Massachusetts Medical School\, UMass Memorial Medical Center\, Worcester\, MA\, USA.,Mount Sinai Hospital Medical Center\, Chicago\, IL\, USA.,Memorial Sloan Kettering Cancer Center\, New York\, NY\, USA.,Loyola University Medical Center\, Maywood\, IL\, USA.,University of Massachusetts Medical School\, UMass Memorial Medical Center\, Worcester\, MA\, USA.","Biomarkers, Tumor",,,,"adenocarcinoma,bladder,mutation,next-generation sequencing,targeted therapy,urachal"
31505033,"Nakaguro M,Urano M,Ogawa I,Hirai H,Yamamoto Y,Yamaguchi H,Tanigawa M,Matsubayashi J,Hirano H,Shibahara J,Tada Y,Tsuzuki T,Okada Y,Sato Y,Ikeda K,Sukeda A,Honda Y,Mikami Y,Nagao T",Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm.,"Minor salivary gland tumours showing a predominant papillary-cystic structure are rare\, and constitute a mixture of various types of neoplasm; thus\, the histopathological assessment of these tumours poses a significant diagnostic challenge. We aimed to delineate the histological characteristics of these tumours and further mutational aspects with a particular focus on sialadenoma papilliferum (SP) and intraductal papillary mucinous neoplasm (IPMN).,We retrieved 28 papillary-cystic tumours of the minor salivary glands\, and performed histological re-evaluation and mutation analyses of several key oncogenes. The histological classifications were as follows: SP (n = 10)\, SP-like intraductal papillary tumour (SP-IPT) (n = 2)\, IPMN (n = 9)\, intraductal papilloma\, cystadenoma\, and cystadenocarcinoma (two\, three and two respectively). Whereas SP typically consisted of a combination of exophytic squamous epithelium and endophytic intraductal papillary infoldings\, SP-IPT lacked the exophytic component. SP and SP-IPT frequently harboured BRAF V600E mutations (75.0%)\, which were identified in both squamous and ductal components. IPMN was characterised by a well-demarcated cystic lesion filled exclusively with a papillary proliferation of mucinous cells and a high rate of AKT1 E17K mutations (88.9%). Intraductal papillomas were unilocular cystic lesions with intraluminal papillary growth of bland columnar cells. In contrast\, both cystadenomas and cystadenocarcinomas showed a multicystic appearance with a papillary configuration. Cystadenocarcinomas invaded the surrounding tissue and were composed of markedly atypical tumour cells.,The appropriate interpretation of histological findings and specific genetic alterations (e.g. BRAF V600E and AKT1 E17K in SP and IPMN) would be useful for the correct diagnosis of minor salivary gland papillary-cystic tumours.",Histopathology,vol.76:3:411-422,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Amino Acid Substitution|,|Cystadenocarcinoma|classification|diagnosis|genetics|pathology|,|Cystadenoma|classification|diagnosis|genetics|pathology|,|Female|,|Humans|,|Immunohistochemistry|,|Male|,|Middle Aged|,|Mutation|,|Papilloma\, Intraductal|classification|diagnosis|genetics|pathology|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins c-akt|genetics|,|Salivary Gland Neoplasms|classification|diagnosis|genetics|pathology|,|Salivary Glands\, Minor|pathology|",,"https://orcid.org/0000-0001-6987-3043Department of Pathology and Laboratory Medicine\, Nagoya University Hospital\, Nagoya\, Japan.,Department of Diagnostic Pathology\, School of Medicine\, Fujita Health University\, Toyoake\, Japan.,Centre of Oral Clinical Examination\, Hiroshima University Hospital\, Hiroshima\, Japan.,Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.,Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.,Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.,Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.,https://orcid.org/0000-0001-7545-9332Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.,Department of Pathology\, Tokyo Medical University Hachioji Medical Centre\, Tokyo\, Japan.,Department of Pathology\, Kyorin University\, Tokyo\, Japan.,Department of Head and Neck Oncology and Surgery\, International University of Health and Welfare Mita Hospital\, Tokyo\, Japan.,https://orcid.org/0000-0002-4855-4366Department of Pathology\, Aichi Medical University\, Nagakute\, Japan.,Department of Pathology\, The Nippon Dental University School of Life Dentistry at Niigata\, Niigata\, Japan.,Department of Head and Neck Surgery\, Niigata Cancer Centre Hospital\, Niigata\, Japan.,Head and Neck Oncology Centre\, Showa University\, Tokyo\, Japan.,Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.,Department of Diagnostic Pathology\, Kumamoto University Hospital\, Kumamoto\, Japan.,Department of Diagnostic Pathology\, Kumamoto University Hospital\, Kumamoto\, Japan.,Department of Anatomical Pathology\, Tokyo Medical University\, Tokyo\, Japan.","AKT1 protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins c-akt",,,,"AKT1 E17K mutation,BRAF V600E mutation,intraductal papillary mucinous neoplasm,salivary gland tumour,sialadenoma papilliferum"
31506288,"Le Flahec G,Briolais M,Guibourg B,Lemasson G,Grippari JL,Ledé F,Marcorelles P,Uguen A",Testing for fusions in patients with advanced // wild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy.,"Beyond targeted therapy for patients with BRAF-mutated melanomas and immunotherapy in patients lacking BRAF mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring BRAF fusions. BRAF fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using BRAF fluorescent in situ hybridisation (FISH), we searched for BRAF fusions in 74 samples of 66 patients with advanced BRAF/NRAS/KIT wild-type melanomas. We identified 2/66 (3%) patients with BRAF fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'-BRAF FISH signals. As a result, we conclude that BRAF FISH in patients with advanced BRAF/NRAS/KIT wild-type melanomas is a valuable and easy-to-perform test to diagnose BRAF fusions and to identify patients who could benefit of anti-MEK targeted therapy.",Journal of clinical pathology,vol.73:2:116-119,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Antineoplastic Agents|therapeutic use|,|Biomarkers\, Tumor|genetics|,|Female|,|GTP Phosphohydrolases|genetics|,|Gene Fusion|,|Humans|,|In Situ Hybridization\, Fluorescence|,|Male|,|Melanoma|drug therapy|enzymology|genetics|,|Membrane Proteins|genetics|,|Middle Aged|,|Mitogen-Activated Protein Kinase Kinases|antagonists & inhibitors|metabolism|,|Molecular Targeted Therapy|,|Patient Selection|,|Precision Medicine|,|Predictive Value of Tests|,|Protein Kinase Inhibitors|therapeutic use|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins c-kit|genetics|,|Skin Neoplasms|drug therapy|enzymology|genetics|",,"Department of Pathology\, CHRU Brest\, Brest\, France.,Department of Pathology\, CHRU Brest\, Brest\, France.,Department of Pathology\, CHRU Brest\, Brest\, France.,Department of Pathology\, CHRU Brest\, Brest\, France.,Department of Pathology\, CHRU Brest\, Brest\, France.,Department of Pathology\, CHRU Brest\, Brest\, France.,Department of Pathology\, CHRU Brest\, Brest\, France.,http://orcid.org/0000-0002-0230-2905Department of Pathology\, CHRU Brest\, Brest\, France arnaud.uguen@chu-brest.fr.","Antineoplastic Agents,Biomarkers\, Tumor,Membrane Proteins,Protein Kinase Inhibitors,KIT protein\, human,Proto-Oncogene Proteins c-kit,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Mitogen-Activated Protein Kinase Kinases,GTP Phosphohydrolases,NRAS protein\, human",,,,"\nBRAF\n,fluorescentin situhybridization,gene fusion,melanoma"
32652567,"Bai X,Flaherty KT",Targeted and immunotherapies in BRAF mutant melanoma: where we stand and what to expect.,"The therapeutic landscape for melanoma has evolved drastically in the past decade. Currently, immune checkpoint inhibitors and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway are the two mainstay therapies for BRAFV600 mutant advanced melanoma. Although MAPK dependence has been variably demonstrated in melanomas lacking BRAFV600 mutations, definitive evidence of benefit with MAPK inhibitors has not been demonstrated. Thus, in the BRAFV600 'wild-type' setting, immune checkpoint inhibitors are the standalone option(s). In the BRAFV600 mutant setting, there is no definitive evidence prioritizing one therapeutic modality over another. Herein, we review the updated data of the pivotal phase III randomized controlled trials that established the standard-of-care first-line treatment for advanced melanoma, as it provides insights into long-term benefit, which is a major factor in therapy selection. We discuss the clinical considerations for choosing between these therapies in the front-line setting and beyond, specifically for patients with BRAFV600 mutant melanoma based on currently available evidence. We have previously proposed a time-dependent resistance paradigm in which future therapeutic development strategies can be rooted. We also discuss how these Food and Drug Administration (FDA)-approved therapeutic modalities are being pursued earlier in the course of disease management, namely in adjuvant and neoadjuvant settings. FDA-approved interlesional oncolytic virotherapy in the modern era is also briefly discussed.",The British journal of dermatology,vol.::,2020,Journal Article,,,"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education\, Beijing)\, Department of Renal Cancer and Melanoma\, Peking University Cancer Hospital and Institute\, Beijing\, China.,https://orcid.org/0000-0002-3402-0478Massachusetts General Hospital Cancer Center\, Harvard Medical School\, Boston\, MA\, USA.",,,,,
32653217,"Gerbaux M,Diallo S,Dedeken L,Dangoisse C,Bott A,Heritier S,Salik D,Ferster A",Effective rescue treatment with vemurafenib of an infant with high-risk Langerhans cell histiocytosis.,"The recently identified role of a BRAF somatic mutation in the pathophysiology of Langerhans cell histiocytosis (LCH) offers new therapeutic options. Herein we describe the case of a 10-month-old infant with refractory high-risk LCH successfully treated with vemurafenib.,The patient first presented with cutaneous LCH at the age of 2 months. The disease remained undiagnosed until she was 6 months old\, when it rapidly evolved to a multisystemic high-risk and life-threatening disease\, refractory to 2 lines of chemotherapy. BRAFV600E mutation was found at skin biopsy\, and targeted therapy with vemurafenib was started when she was 10 months old. The treatment induced a fast and sustained response\, but rapid relapse occurred after treatment discontinuation\, leading to resumption of treatment\, once more resulting in a sustained response.,Our case highlights the first-line role of dermatologists in establishing the diagnosis of LCH\, especially in children\, in whom the eruption may be difficult to identify\, leading to delayed diagnosis. Targeted therapy with vemurafenib has recently been described in children in this indication and our results support its efficacy\, highlighting the need for prolonged treatment and raising the question of maintenance therapy\, as well as the necessity for large-scale and long-term studies.",Annales de dermatologie et de venereologie,vol.147:11:782-785,2020,Case Reports,,,"Department of hematology and oncology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, 266\, avenue Brugmann\, 1180 Uccle\, Brussels\, Belgium. Electronic address: margauxgerbaux@gmail.com.,Department of hematology and oncology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, 266\, avenue Brugmann\, 1180 Uccle\, Brussels\, Belgium.,Department of hematology and oncology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, 266\, avenue Brugmann\, 1180 Uccle\, Brussels\, Belgium.,Department of dermatology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, Brussels\, Belgium.,Department of dermatology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, Brussels\, Belgium.,JF. Emile\, laboratory EA4340\, GHU Paris-Saclay\, Versailles university\, Ambroise-Paré hospital\, Paris\, France.,Department of dermatology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, Brussels\, Belgium.,Department of hematology and oncology\, université libre de Bruxelles\, hôpital universitaire des enfants reine Fabiola\, 266\, avenue Brugmann\, 1180 Uccle\, Brussels\, Belgium.",,,,,"Dermatologie pédiatrique,Histiocytic disorders,Histiocytoses,Pediatric dermatology,Vemurafenib,Vémurafenib"
32654047,"Hayase T,Saito S,Shioda Y,Imamura T,Watanabe K,Ohki K,Yoshioka T,Oh Y,Kawahara Y,Niijima H,Imashuku S,Morimoto A",Analysis of the BRAF and MAP2K1 mutations in patients with Langerhans cell histiocytosis in Japan.,"In Langerhans cell histiocytosis (LCH), somatic gene mutations in the mitogen-activated protein kinase pathway have been identified in more than 80% of cases in Western countries, in which mutually exclusive BRAF and MAP2K1 mutations are involved. Among them, BRAF V600E mutation is the major contributor (50-60%). In 59 patients (50 children and nine adults) with LCH (not including pulmonary LCH) in Japan, we first screened for BRAF V600E in all patients followed by target sequencing for other gene mutations in 17 of BRAF V600E-negative patients. As a result, BRAF V600E mutation was detected in 27/59 (46%) patients. We also identified BRAF mutations other than V600E in five and MAP2K1 mutations in nine patients. Thus, gene mutations in BRAF or MAP2K1 were identified in 41/44 (93%) of the fully tested patients. Regarding the correlation of clinical features and genotype in pediatric patients, we found that BRAF V600E mutation status was not correlated with sex, age at diagnosis, disease extent, response to first-line therapy, relapse, or CNS-related sequelae. Interestingly, MAP2K1 exon 2 in-frame deletion was related to the risk organ involvement; however, further studies are required to clarify the impact of these gene mutations on the clinical features of patients with LCH.",International journal of hematology,vol.112:4:560-567,2020,Journal Article,"|Adolescent|,|Child|,|Child\, Preschool|,|Female|,|Genetic Association Studies|,|Histiocytosis\, Langerhans-Cell|genetics|,|Humans|,|Infant|,|Japan|,|MAP Kinase Kinase 1|genetics|,|MAP Kinase Signaling System|genetics|,|Male|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|",,"Department of Pediatrics\, Jichi Medical University\, 3311-1 Yakushiji\, Shimotsuke\, Tochigi\, 329-0498\, Japan.,Department of Pediatrics\, Jichi Medical University\, 3311-1 Yakushiji\, Shimotsuke\, Tochigi\, 329-0498\, Japan.,Department of Children's Cancer Center\, National Center for Child Health and Development\, Tokyo\, Japan.,Department of Pediatrics\, Kyoto Prefectural University of Medicine\, Kyoto\, Japan.,Department of Hematology and Oncology\, Shizuoka Children's Hospital\, Shizuoka\, Japan.,Department of Pediatric Hematology and Oncology Research\, National Research Institute for Child Health and Development\, Tokyo\, Japan.,Department of Pathology\, National Center for Child Health and Development\, Tokyo\, Japan.,Department of Pediatrics\, Jichi Medical University\, 3311-1 Yakushiji\, Shimotsuke\, Tochigi\, 329-0498\, Japan.,Department of Pediatrics\, Jichi Medical University\, 3311-1 Yakushiji\, Shimotsuke\, Tochigi\, 329-0498\, Japan.,Department of Pediatrics\, Jichi Medical University\, 3311-1 Yakushiji\, Shimotsuke\, Tochigi\, 329-0498\, Japan.,Division of Laboratory Medicine\, Uji Tokushukai Medical Center\, Uji\, Japan.,http://orcid.org/0000-0002-9168-5409Department of Pediatrics\, Jichi Medical University\, 3311-1 Yakushiji\, Shimotsuke\, Tochigi\, 329-0498\, Japan. akira@jichi.ac.jp.","BRAF protein\, human,Proto-Oncogene Proteins B-raf,MAP Kinase Kinase 1,MAP2K1 protein\, human","the Ministry of Education\, Culture\, Sports\, Science and Technology\, Japan,the Japan LCH Study Group\, Japan,the Japanese Society of Hematology",",,","18K07828,2016-2 and 2017-2,17133 and 18308","BRAF V600E mutation,Clinical outcome,Langerhans cell histiocytosis,MAP2K1 mutation"
32657049,"Chen X,Xu B,Li Q,Xu X,Li X,You X,Yu Z",Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua.,"We describe the clinical features\, genetic profile\, and their correlation in NSCLC patients.,A total of 256 Chinese patients with NSCLC were enrolled in this study. NGS-based genomic profiling of major lung cancer-related genes was performed on formalin-fixed paraffin-embedded tumor samples.,Of 256 patients with NSCLC\, 219 were adenocarcinoma and most of them were in the early stage. Among patients\, 63.3% patients have more than two gene mutations. By analyzing variant allele frequency (VAF)\, we found that the median VAF has significant differences between squamous cell carcinoma and adenocarcinoma\, as well as early stage and advanced stage. The frequency of mutations in EGFR\, MET\, and RET were significantly higher in nonsmokers than in smokers. Besides\, Pearson correlation analysis found that ALK\, BRAF\, and MET mutations had a strong correlation with age. Notably\, higher frequencies of ALK and BRAF alterations were associated with younger age\, while more frequent MET mutations appear in the patients at age 55 or older.,More unique features of cancer driver genes in Chinese NSCLC were identified by next-generation sequencing. These findings highlighted that it is necessary to carry out targeted detection according to different clinical features for NSCLC.",Molecular genetics & genomic medicine,vol.8:9:e1398,2020,Journal Article,,,"Department of Thoracic Surgery\, Jinhua Municipal Central Hospital\, Jinhua Hospital of Zhejiang University\, Jinhua\, China.,Department of Thoracic Surgery\, Jinhua Municipal Central Hospital\, Jinhua Hospital of Zhejiang University\, Jinhua\, China.,0000-0002-9825-5313Hangzhou D.A. Medical Laboratory\, Hangzhou\, China.,Department of Thoracic Surgery\, Jinhua Municipal Central Hospital\, Jinhua Hospital of Zhejiang University\, Jinhua\, China.,Department of Thoracic Surgery\, Jinhua Municipal Central Hospital\, Jinhua Hospital of Zhejiang University\, Jinhua\, China.,Hangzhou D.A. Medical Laboratory\, Hangzhou\, China.,Hangzhou D.A. Medical Laboratory\, Hangzhou\, China.",,,,,"clinical characteristics,genetic profile,nonsmall cell lung cancer,targeted sequencing"
32776753,"Li Y,Yang S,Hao C,Chen J,Li S,Kang Z,Kang X,Zhang H,Li W",Effect of BRAF/MEK Inhibition on Epithelioid Glioblastoma with BRAFV600E Mutation: a Case Report and Review of the Literature.,"To explore the effect of BRAF inhibitor on epithelioid glioblastoma (Ep-GBM) with BRAFV600E mutation.,A patient of Ep-GBM with BRAFV600E mutation underwent BRAF inhibition therapy. The rationale behind combined BRAF and MEK inhibition in Ep-GBM was reviewed.,Vemurafenib can initially inhibit the progression of Ep-GBM with BRAFV600E mutation. However\, the tumor may become resistant to vemurafenib and then progress.,BRAF inhibition therapy can inhibit the progression of Ep-GBM with BRAFV600E mutation\, but the subsequent resistance development leads to a poor outcome.",Clinical laboratory,vol.66:8:,2020,Case Reports,,,",,,,,,,,",,,,,
32780261,"Manoharan N,Choi J,Chordas C,Zimmerman MA,Scully J,Clymer J,Filbin M,Ullrich NJ,Bandopadhayay P,Chi SN,Yeo KK",Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma.,"Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG often require numerous treatment modalities including surgery\, chemotherapy\, rarely radiation therapy and\, more recently\, molecularly targeted therapy. We describe our institutional experience using the MEK inhibitor\, trametinib\, for recurrent/progressive pLGGs.,We performed a retrospective\, IRB-approved\, chart review of all pediatric patients treated with trametinib for recurrent/progressive pLGGs at Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 2016 and 2018.,Eleven patients were identified\, of which 10 were evaluable for response. Median age at commencement of trametinib treatment was 14.7 years (range 7.3-25.9 years). Tumor molecular status included KIAA1549-BRAF fusion (n = 4)\, NF1 mutation (n = 4)\, FGFR mutation (n = 1) and CDKN2A loss (n = 1). Median number of prior treatment regimens was 5 (range 1-12). Median duration of treatment with trametinib was 19.2 months (range 3.8-29.8 months). Based on modified RANO criteria\, best responses included partial (n = 2)\, minor response (n = 2) and stable disease (n = 6). Two patients remain on therapy (29.8 and 25.9 months\, respectively). The most common toxicities attributable to trametinib were rash\, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced significant intracranial hemorrhage (ICH) while on trametinib. While it is unclear whether ICH was directly attributable to trametinib\, therapy was discontinued.,Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation\, with particular attention to the potential risk for intracranial hemorrhage. Early phase multi-institutional clinical trials are underway.",Journal of neuro-oncology,vol.149:2:253-262,2020,Journal Article,,,"Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Department of Radiology\, Boston Children's Hospital\, Boston\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA.,http://orcid.org/0000-0003-0713-6384Dana-Farber Cancer Institute\, Boston Children's Cancer and Blood Disorder Center\, 450 Brookline Ave\, Boston\, MA\, 02215-5450\, USA. keek_yeo@dfci.harvard.edu.",,,,,"Central nervous system neoplasms,Low-grade glioma,MAPK,MEK inhibitor,Pediatric,Trametinib"
32782486,"Martini G,Dienstmann R,Ros J,Baraibar I,Cuadra-Urteaga JL,Salva F,Ciardiello D,Mulet N,Argiles G,Tabernero J,Elez E",Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer.,"Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.",Therapeutic advances in medical oncology,vol.12::1758835920936089,2020,Review,,,"Università della Campania L. Vanvitelli\, Naples.,VHIO\, Barcelona\, Barcelona\, Spain.,Vall d'Hebron Hospital\, Barcelona\, Catalunya\, Spain.,Vall d'Hebron Hospital\, Barcelona\, Catalunya\, Spain.,Vall d'Hebron Hospital\, Barcelona\, Catalunya\, Spain.,Vall d'Hebron Hospital\, Barcelona\, Catalunya\, Spain.,Università della Campania L. Vanvitelli\, Naples.,Vall d'Hebron Hospital\, Barcelona\, Catalunya\, Spain.,Vall d'Hebron Hospital\, Barcelona\, Spain.,Vall d'Hebron University Hospital\, Barcelona\, Spain.,Vall D'Hebron Institute of Oncology P/Vall D'Hebron 119-121\, Barcelona\, 08035 Spain.",,,,,"EGFR,RAS,biomarkers,colorectal cancer,molecular classification"
32782545,"Brunetti M,Panagopoulos I,Kostolomov I,Davidson B,Heim S,Micci F",Mutation analysis and genomic imbalances of cells found in effusion fluids from patients with ovarian cancer.,"Ovarian carcinomas and carcinosarcomas often cause malignant effusions, an accumulation within serous cavities of fluid containing cancer cells. Few studies have focused on the molecular alterations and genetic mechanisms behind effusion formation. The present study investigated the mutation status of TP53, PIK3CA, KRAS, HRAS, NRAS and BRAF in effusion fluids from 103 patients with ovarian cancer. In addition, array Comparative Genomic Hybridization (aCGH) analysis was performed on 20 effusions from patients with high-grade serous carcinoma (10 cases positive for TP53 mutation and 10 with TP53 wild-type). TP53 mutations, two of which were novel: c.826_830delCCTGT and c.475_476GC>TT, were identified in 44% of the cases. Mutations in KRAS, HRAS, and PIK3CA were identified in two, two and four cases, respectively. None of the effusions analysed showed NRAS or BRAF mutations. The aCGH analysis revealed highly imbalanced genomes similar to those described in primary ovarian carcinomas. No specific profile was indicated to distinguish tumors with TP53 mutations from those without. The molecular profiling of cells found in effusion fluids from patients with ovarian cancer thus showed considerable molecular heterogeneity. TP53 seems to be the most frequently mutated gene in these cells and may serve a leading role in the metastatic process.",Oncology letters,vol.20:3:2273-2279,2020,Journal Article,,,"Section for Cancer Cytogenetics\, Institute for Cancer Genetics and Informatics\, The Norwegian Radium Hospital\, Oslo University Hospital\, 0424 Oslo\, Norway.,Section for Cancer Cytogenetics\, Institute for Cancer Genetics and Informatics\, The Norwegian Radium Hospital\, Oslo University Hospital\, 0424 Oslo\, Norway.,Section for Applied Informatics\, Institute for Cancer Genetics and Informatics\, The Norwegian Radium Hospital\, Oslo University Hospital\, 0424 Oslo\, Norway.,Department of Pathology\, The Norwegian Radium Hospital\, Oslo University Hospital\, 0424 Oslo\, Norway.,Section for Cancer Cytogenetics\, Institute for Cancer Genetics and Informatics\, The Norwegian Radium Hospital\, Oslo University Hospital\, 0424 Oslo\, Norway.,Section for Cancer Cytogenetics\, Institute for Cancer Genetics and Informatics\, The Norwegian Radium Hospital\, Oslo University Hospital\, 0424 Oslo\, Norway.",,,,,"array comparative genomic hybridization,effusions,genomic imbalances,high-grade serous ovarian carcinoma,mutation analysis"
32782671,"Wang S,He Q,Zhang Q,Guan B,Zhou X",Clinicopathologic features and prognosis of epithelioid glioblastoma.,"To improve the understanding of epithelioid glioblastoma (E-GBM) and provide accurate basis for clinical diagnosis\, treatment\, and prognosis through the analysis of clinicopathologic characteristics\, immunohistochemical expression\, molecular characteristics\, and prognosis of E-GBM.,The clinicopathologic characteristics of 33 cases of E-GBM in our hospital from January 2015 to September 2019 were analyzed retrospectively. Kaplan Meier method was used for survival analysis. Multivariate Cox regression analysis was used to screen the independent risk factors affecting the survival time of patients.,Among 33 patients with E-GBM\, 16 were male and 17 were female. The age ranged from 9 to 67 years old\, with the median age of 36 years old and the average age of 38 years old. The tumor size (calculated by the largest diameter): 1-6 cm\, average size: 3.5 cm. The ratio of smoking and non-smoking is 17:16. All the tumors were located in the cerebral hemisphere\, and 26 cases (78.79%) of brain MR showed that the tumors invaded the cortex (white matter).,asymptomatic physical examination was found in 6 cases (18.18%)\, 5 cases (15.15%) had epilepsy history\, 2 cases (6.06%) had malignant vomiting\, 3 cases (9.09%) had hypertension history\, and 17 cases (51.52%) had headache and dizziness. All patients received surgery (total or partial resection). Postoperative radiotherapy was given in 7 cases (21.00%)\, chemotherapy (TMZ temozolomide) in 3 cases (1.00%)\, and combined chemoradiotherapy in 16 cases (48.40%). Immunohistochemical staining: the positive rates of CK\, GFAP\, IDH-1\, IDH-2\, HMB45\, Desmin\, BRAF\, P53\, ATRX\, INI-1\, S-100\, Ki-67 were 20/33\, 30/33\, 1/33\, 1/33\, 0/33\, 0/33\, 33/33\, 5/33\, 30/33\, 33/33\, 6/33\, Ki-67 of all cases were higher than 40%\, among which 11 cases were higher than 60%. The detection of related genes showed that 33 cases (100%) had BRAF V600E mutation. TERT mutation was found in 18 cases (54.5%); IDH1 mutation was found in 1 case (3%); MGMT promoter methylation was found in 15 cases (45.4%); EGFR amplification and 1p/19q co-deletion were not found in any cases.,E-GBM is a highly invasive and rare malignant nervous system tumor\, with poor prognosis and lack of clinical specificity. Immunohistochemically\, the higher expression of CK\, GFAP and Ki67 proliferation index is more conducive to the diagnosis and differential diagnosis of E-GBM. Smoking\, brain MR showing tumor invasion of cortex\, TERT mutation\, radiotherapy\, and chemotherapy are independent risk factors affecting the prognosis (survival time) of patients.",International journal of clinical and experimental pathology,vol.13:7:1529-1539,2020,Journal Article,,,"Department of Medicine\, Yantai Yuhuangding Hospital of Qingdao University Yantai\, Shandong\, China.,Department of Medicine\, Yantai Yuhuangding Hospital of Qingdao University Yantai\, Shandong\, China.,Department of Medicine\, Yantai Yuhuangding Hospital of Qingdao University Yantai\, Shandong\, China.,Department of Medicine\, The Second Hospital of Shandong University Jinan\, Shandong\, China.,School of Basic Medical Sciences\, Binzhou Medical University Yantai\, Shandong\, China.",,,,,"Cox analysis,Epithelioid,clinical pathology,glioblastoma,prognosis"
32895045,"Çankaya N,İzdal M,Azarkan SY","Synthesis, Characterization, Biological Evaluation and Molecular Docking Studies of New Oxoacrylate and Acetamide on heLa Cancer Cell Lines.","In recent years\, discovery and development of new drugs play a critical role in cancer therapy.,In this study\, the effect of MPAEA and p-acetamide on cellular toxicity and on silico in HeLa cancer cells have been investigated.,In this study\, 2-choloro-N-(4-methoxyphenyl)acetamide (p-acetamide) and 2-(4-methoxyphenylamino)-2- oxoethyl acrylate (MPAEA) have been synthesized and characterized by FTIR\, 1H\, and 13C-NMR. Cytotoxicity of pacetamide and MPAEA have been investigated by XTT cell proliferation assay on the HeLa cell line. IC50 values of pacetamide and MPAEA have been identified on the HeLa cell line. Further\, molecular docking study was carried out by Autodock Vina using BCL-2 (PDB ID: 4MAN)\, BCL-W (PDB ID: 2Y6W)\, MCl-1 (PDB ID: 5FDO) AKT (PDB ID: 4GV1) and BRAF (PDB ID: 5VAM) as a possible apoptotic target for anticancer activity.,According to the obtained results\, MPAEA and p-acetamide were successfully synthesized and characterized. The interactions between ligands and anti-apoptotic proteins were evaluated by molecular docking and their free energy of binding were calculated and used as descriptor.,In vitro and in silico the results demonstrated that MPAEA had potent anticancer activity on HeLa cell line.",Current computer-aided drug design,vol.::,2020,Journal Article,,,"Usak University\, Department of Chemistry\, Usak. Turkey.,Usak University\, Department of Molecular Biology and Genetic\, Usak. Turkey.,Kırşehir Ahi Evran University\, Department of Molecular Biology and Genetic\, Kırsehir. Turkey.",,,,,"Anti-apoptotic proteins.\n,Antiproliferative activity,HeLa cell line,Molecular docking,Synthesis and characterization"
32108276,"Cocorocchio E,Martinoli C,Gandini S,Pala L,Conforti F,Stucchi S,Mazzarol G,Ferrucci P",Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors.,"The aim of this study is to verify if baseline hematological markers\, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies\, are independently associated with progression free survival (PFS) and overall survival (OS).,We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation\, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease\, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites.,The median PFS was 9.1 and 3.5 months\, respectively\, for patients with baseline NLR < 5 and NLR ≥ 5\, while median OS was 17.2 and 5.5 months\, respectively\, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28-0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23-0.76; p = 0.004)\, independent of age\, sex\, stage\, LDH > 2xULN\, previous treatments\, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN\, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13-0.62; p = 0.002\,) and OS (HR = 0.23; 95% CI = 0.10-0.55; p = 0.001).,These biomarkers are easily reproducible\, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.",Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico,vol.22:10:1818-1824,2020,Journal Article,,,"http://orcid.org/0000-0003-1184-6426Division of Medical Oncology of Melanoma\, Sarcoma and Rare Tumors\, Istituto Europeo di Oncologia IRCCS\, Via Giuseppe Ripamonti 435\, 20141\, Milan\, Italy. emilia.cocorocchio@ieo.it.,Division of Medical Oncology of Melanoma\, Sarcoma and Rare Tumors\, Istituto Europeo di Oncologia IRCCS\, Via Giuseppe Ripamonti 435\, 20141\, Milan\, Italy.,Department of Experimental Oncology\, Istituto Europeo di Oncologia IRCCS\, Milan\, Italy.,Division of Medical Oncology of Melanoma\, Sarcoma and Rare Tumors\, Istituto Europeo di Oncologia IRCCS\, Via Giuseppe Ripamonti 435\, 20141\, Milan\, Italy.,Division of Medical Oncology of Melanoma\, Sarcoma and Rare Tumors\, Istituto Europeo di Oncologia IRCCS\, Via Giuseppe Ripamonti 435\, 20141\, Milan\, Italy.,Clinical Research Area\, Istituto Europeo di Oncologia IRCCS\, Milan\, Italy.,Division of Pathology\, Istituto Europeo di Oncologia IRCCS\, Milan\, Italy.,Division of Medical Oncology of Melanoma\, Sarcoma and Rare Tumors\, Istituto Europeo di Oncologia IRCCS\, Via Giuseppe Ripamonti 435\, 20141\, Milan\, Italy.",,,,,"Metastatic melanoma,NLR,Targeted therapy"
33304455,"Martinez-Ledesma E,Flores D,Trevino V",Computational methods for detecting cancer hotspots.,"Cancer mutations that are recurrently observed among patients are known as hotspots. Hotspots are highly relevant because they are, presumably, likely functional. Known hotspots in BRAF, PIK3CA, TP53, KRAS, IDH1 support this idea. However, hundreds of hotspots have never been validated experimentally. The detection of hotspots nevertheless is challenging because background mutations obscure their statistical and computational identification. Although several algorithms have been applied to identify hotspots, they have not been reviewed before. Thus, in this mini-review, we summarize more than 40 computational methods applied to detect cancer hotspots in coding and non-coding DNA. We first organize the methods in cluster-based, 3D, position-specific, and miscellaneous to provide a general overview. Then, we describe their embed procedures, implementations, variations, and differences. Finally, we discuss some advantages, provide some ideas for future developments, and mention opportunities such as application to viral integrations, translocations, and epigenetics.",Computational and structural biotechnology journal,vol.18::3567-3576,2020,Review,,,"Tecnologico de Monterrey\, Escuela de Medicina y Ciencias de la Salud\, Bioinformática y Diagnóstico Clínico\, Monterrey\, Nuevo León\, Mexico.,Tecnologico de Monterrey\, Escuela de Medicina y Ciencias de la Salud\, Bioinformática y Diagnóstico Clínico\, Monterrey\, Nuevo León\, Mexico.,Tecnologico de Monterrey\, Escuela de Medicina y Ciencias de la Salud\, Bioinformática y Diagnóstico Clínico\, Monterrey\, Nuevo León\, Mexico.",,,,,"Algorithms,Cancer,Exome,Genomics,Hotspots,Mutations,Recurrent mutations,Sequencing,Whole genome sequencing"
33306619,"Yamada N,Eizuka M,Sugimoto R,Tanaka Y,Yanagawa N,Yamano H,Suzuki H,Matsumoto T,Sugai T",Immunohistochemical Examination is Highly Sensitive and Specific for Detection of the V600E BRAF Mutation in Colorectal Serrated Lesions.,"Mutations in BRAF are important events in colorectal serrated lesions and specific genetic markers for the serrated pathway. However, examination of BRAF mutations is not easy in routine histopathologic analyses. Here, the authors examined 73 colorectal serrated lesions, including 21 hyperplastic polyps, 32 traditional serrated adenomas, and 30 sessile serrated lesions, for comparison of BRAF mutation status with immunopositive expression of the anti-BRAF V600E mutation-specific antibody VE1. Thirty-two tubular adenomas (TAs) were examined as controls. In addition, 5 examples of sessile serrated lesion with dysplasia were included. Mutations in BRAF (exon 15; V600E) and KRAS (exon 2) were analyzed in serrated lesions and TAs using pyrosequencing. Finally, the authors compared BRAF mutations with immunohistochemical expression of VE1 antibodies against the BRAF V600E mutation, which was examined based on quantitative analyses and correlations between semiquantitative (0, 1+, or 2+) and quantitative results in colorectal serrated lesions. The cut-off value of VE1 expression (32%) was set based on receiver operating characteristic curve analysis. In the current study, mutations in BRAF were well correlated with VE1 expression in serrated lesions, although no TAs without BRAF mutations were immunopositive. In contrast, serrated lesions and TAs with mutations in KRAS were not stained for VE1 expression. In serrated lesions, although the sensitivity was 96.2% to 100%, the specificity was 90.0% to 100%. In addition, there was also good correlation between semiquantitative and quantitative results. Analysis of BRAF V600E expression may be pathologically useful, particularly in routine histopathologic diagnosis.",Applied immunohistochemistry & molecular morphology : AIMM,vol.::,2020,Journal Article,,,"Department of Molecular Diagnostic Pathology\, School of Medicine.,Department of Molecular Diagnostic Pathology\, School of Medicine.,Department of Molecular Diagnostic Pathology\, School of Medicine.,Department of Molecular Diagnostic Pathology\, School of Medicine.,Department of Molecular Diagnostic Pathology\, School of Medicine.,Departments of Gastroenterology.,Molecular Biology\, Sapporo Medical University\, School of Medicine\, Cyuuouku\, Sapporo\, Japan.,Department of Internal Medicine\, Division of Gastroenterology\, Iwate Medical University\, Shiwagun'yahabachou.,Department of Molecular Diagnostic Pathology\, School of Medicine.",,,,,
31618797,"Heppt MV,Clanner-Engelshofen BM,Marsela E,Wessely A,Kammerbauer C,Przybilla B,French LE,Berking C,Reinholz M",Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants.,"Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect\, the phototoxic potential of many BRAFi is poorly characterized. In this study\, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi-induced phototoxicity can be alleviated by antioxidants.,The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants\, vitamin C\, vitamin E phosphate\, trolox\, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors.,The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay\, 8 agents were classified as phototoxic\, including vemurafenib\, dabrafenib\, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations.,Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential\, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.","Photodermatology, photoimmunology & photomedicine",vol.36:2:126-134,2020,Journal Article,"|Animals|,|Antioxidants|pharmacology|,|BALB 3T3 Cells|,|Mice|,|Protein Kinase Inhibitors|adverse effects|pharmacology|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|metabolism|,|Reactive Oxygen Species|metabolism|,|Ultraviolet Rays|adverse effects|",,"https://orcid.org/0000-0003-4603-1825Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,https://orcid.org/0000-0002-8716-2568Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.,Department of Dermatology and Allergy\, University Hospital\, LMU Munich\, Munich\, Germany.","Antioxidants,Protein Kinase Inhibitors,Reactive Oxygen Species,Braf protein\, mouse,Proto-Oncogene Proteins B-raf",,,,"BRAF,antioxidant,phototoxicity,protein kinase inhibitor,targeted therapy"
31622618,"Kawasaki K,Fujii M,Sugimoto S,Ishikawa K,Matano M,Ohta Y,Toshimitsu K,Takahashi S,Hosoe N,Sekine S,Kanai T,Sato T",Chromosome Engineering of Human Colon-Derived Organoids to Develop a Model of Traditional Serrated Adenoma.,"Traditional serrated adenomas (TSAs) are rare colorectal polyps with unique histologic features. Fusions in R-spondin genes have been found in TSAs\, but it is not clear whether these are sufficient for TSA development\, due to the lack of a chromosome engineering platform for human tissues. We studied the effects of fusions in R-spondin genes and other genetic alterations found in TSA using CRISPR-Cas9-mediated chromosome and genetic modification of human colonic organoids.,We introduced chromosome rearrangements that involve R-spondin genes into human colonic organoids\, with or without disruption of TP53\, using CRISPR-Cas9 (chromosome-engineered organoids). We then knocked a mutation into BRAF encoding the V600E substitution and overexpressed the GREM1 transgene; the organoids were transplanted into colons of NOG mice and growth of xenograft tumors was measured. Colon tissues were collected and analyzed by immunohistochemistry or in situ hybridization. We also established 2 patient-derived TSA organoid lines and characterized their genetic features and phenotypes. We inserted a bicistronic cassette expressing a dimerizer-inducible suicide gene and fluorescent marker downstream of the LGR5 gene in the chromosome-engineered organoids; addition of the dimerizer eradicates LGR5+ cells. Some tumor-bearing mice were given intraperitoneal injections of the dimerizer to remove LGR5-expressing cells.,Chromosome engineering of organoids required disruption of TP53 or culture in medium containing IGF1 and FGF2. In colons of mice\, organoids that expressed BRAFV600E and fusions in R-spondin genes formed flat serrated lesions. Patient-derived TSA organoids grew independent of exogenous R-spondin\, and 1 line grew independent of Noggin. Organoids that overexpressed GREM1\, in addition to BRAFV600E and fusions in R-spondin genes\, formed polypoid tumors in mice that had histologic features similar to TSAs. Xenograft tumors persisted after loss of LGR5-expressing cells.,We demonstrated efficient chromosomal engineering of human normal colon organoids. We introduced genetic and chromosome alterations into human colon organoids found in human TSAs; tumors grown from these organoids in mice had histopathology features of TSAs. This model might be used to study progression of human colorectal tumors with RSPO fusion gene and GREM1 overexpression.",Gastroenterology,vol.158:3:638-651.e8,2020,"Research Support, Non-U.S. Gov't","|Adenoma|genetics|pathology|,|Animals|,|CRISPR-Cas Systems|,|Colonic Neoplasms|genetics|pathology|,|Eukaryotic Initiation Factor-3|genetics|,|Gene Fusion|,|Genetic Engineering|,|Humans|,|Intercellular Signaling Peptides and Proteins|genetics|,|Male|,|Mice|,|Models\, Biological|,|Neoplasm Transplantation|,|Organoids|pathology|,|Proto-Oncogene Proteins B-raf|genetics|,|Receptor-Like Protein Tyrosine Phosphatases\, Class 2|genetics|,|Receptors\, G-Protein-Coupled|genetics|,|Thrombospondins|genetics|,|Tumor Suppressor Protein p53|genetics|,|Wnt Signaling Pathway|",,"Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan.,Center for Diagnostic and Therapeutic Endoscopy\, Keio University School of Medicine\, Tokyo\, Japan.,Division of Pathology and Clinical Laboratories\, National Cancer Center Hospital\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan.,Department of Gastroenterology\, Keio University School of Medicine\, Tokyo\, Japan; Department of Organoid Medicine\, Keio University School of Medicine\, Tokyo\, Japan. Electronic address: t.sato@keio.jp.","Eukaryotic Initiation Factor-3,GREM1 protein\, human,Intercellular Signaling Peptides and Proteins,LGR5 protein\, human,RSPO3 protein\, human,Receptors\, G-Protein-Coupled,Rspo2 protein\, human,Thrombospondins,Tumor Suppressor Protein p53,BRAF protein\, human,Proto-Oncogene Proteins B-raf,PTPRK protein\, human,Receptor-Like Protein Tyrosine Phosphatases\, Class 2",,,,"BMP Signaling,Colorectal Cancer,Ectopic Crypt,Intestinal Stem Cells"
32698374,"Lonetti A,Indio V,Laginestra MA,Tarantino G,Chiarini F,Astolfi A,Bertuccio SN,Martelli AM,Locatelli F,Pession A,Masetti R",Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of -Rearrangements: A Novel Therapeutic Strategy for Pediatric AML.,"Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.",Cancers,vol.12:7:,2020,Journal Article,,,"0000-0002-3944-3090""Giorgio Prodi"" Cancer Research Center\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.,0000-0002-8854-3821""Giorgio Prodi"" Cancer Research Center\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.,Department of Experimental\, Diagnostic\, and Specialty Medicine\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 9\, 40138 Bologna\, Italy.,0000-0002-6078-6856""Giorgio Prodi"" Cancer Research Center\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.,Institute of Molecular Genetics\, Luigi Luca Cavalli-Sforza-CNR National Research Council of Italy\, 40136 Bologna\, Italy.,0000-0002-2732-0747""Giorgio Prodi"" Cancer Research Center\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.,Pediatric Hematology-Oncology Unit\, Department of Medical and Surgical Sciences DIMEC\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.,0000-0001-5196-7260Department of Biomedical and Neuromotor Sciences\, University of Bologna\, Via Irnerio 48\, 40126 Bologna\, Italy.,Department of Pediatric Hematology-Oncology and Cell and Gene Therapy\, IRCCS Ospedale Pediatrico Bambino Gesù\, Sapienza University of Rome\, Piazza Sant'Onofrio 4\, 00165 Rome\, Italy.,""Giorgio Prodi"" Cancer Research Center\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.,0000-0002-1264-057XPediatric Hematology-Oncology Unit\, Department of Medical and Surgical Sciences DIMEC\, University of Bologna\, S. Orsola-Malpighi Hospital\, Via Massarenti 11\, 40138 Bologna\, Italy.",,"Associazione Italiana per la Ricerca sul Cancro,Fondazione Pezcoller",",","MFAG2016\, Id.19117 to RM,research grant to AL","BRAF,ChIP-seq,DOT1L,Pinometostat,Sorafenib,pediatric acute myeloid leukemia,targeted therapy"
32698386,"Lai WA,Liu CY,Lin SY,Chen CC,Hang JF",Characterization of Driver Mutations in Anaplastic Thyroid Carcinoma Identifies and Mutations as Negative Survival Predictors.,"Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive. We investigated the association of selected driver mutations, including BRAF, RAS, PIK3CA, TERT promoter, TP53, POLE, and mismatch repair deficiency (MMR-D) with the clinicopathological features of ATC to identify prognostic and predictive biomarkers. Thirty-nine retrospective cases from pathology archives were enrolled for clinicopathology analysis and immunohistochemistry, and 27 cases had sufficient specimens for further molecular testing using targeted next-generation sequencing and mass spectrometry. BRAFV600E and RAS mutations were identified in 25.9% and 40.7% of ATC, respectively. BRAFV600E mutation was significantly associated with coexisting papillary thyroid carcinoma (p = 0.009) and RAS mutations with female gender (p = 0.012). In univariant analysis, the non-BRAF/RAS tumors were significantly associated with the presence of a sarcomatoid pattern (p = 0.045). PIK3CA, TERT promoter, and TP53 mutations were identified in 14.8%, 81.5%, and 70.4% of cases, respectively. No MMR-D or POLE mutations were detected. In survival analyses, RAS and PIK3CA mutations were significantly associated with inferior outcomes (p = 0.03 and p = 0.006, respectively). In conclusion, driver mutations in ATC are associated with distinct clinicopathological features. RAS and PIK3CA mutations were negative predictors for patient survival. Emerging therapeutic agents targeting BRAF, RAS, and PI3 kinase may benefit a substantial proportion of ATC patients.",Cancers,vol.12:7:,2020,Journal Article,,,"0000-0001-6382-9180Department of Pathology and Laboratory Medicine\, Taipei Veterans General Hospital\, Taipei 112\, Taiwan.,0000-0002-3996-8452Division of Pathology\, Sijhih Cathay General Hospital\, New Taipei City 221\, Taiwan.,Department of Pathology and Laboratory Medicine\, Taipei Veterans General Hospital\, Taipei 112\, Taiwan.,0000-0001-9599-0884Department of Pathology\, Ditmanson Medical Foundation Chia-Yi Christian Hospital\, Chiayi 600\, Taiwan.,0000-0003-4299-2784Department of Pathology and Laboratory Medicine\, Taipei Veterans General Hospital\, Taipei 112\, Taiwan.",,"Taipei Veterans General Hospital,Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program",",","V108B-011 and V109B-029,108-V-B-003","BRAFV600E,PIK3CA,RAS,TERT promoter,TP53,anaplastic thyroid carcinoma"
32699571,"Wempe MM,Stewart MD,Glass D,Lasiter L,Vega DM,Ramamurthy N,Allen J,Sigal EV",A National Assessment of Diagnostic Test Use for Patients with Advanced NSCLC and Factors Influencing Physician Decision-Making.,"Diagnostic tests\, including US Food and Drug Administration (FDA)-approved tests and laboratory-developed tests\, are frequently used to guide care for patients with cancer\, and\, recently\, have been the subject of several policy discussions and insurance coverage determinations. As the use of diagnostic testing has evolved\, stakeholders have raised questions about the lack of standardized test performance metrics and the risk this poses to patients.,To describe the use of diagnostic testing for patients with advanced non-small-cell lung cancer (NSCLC)\, to analyze the utilization of FDA-approved versus laboratory-developed diagnostic tests\, and to evaluate the impact of existing regulatory and coverage frameworks on diagnostic test ordering and physician treatment decision-making for patients with advanced NSCLC.,We conducted a 2-part study consisting of an online survey and patient chart review from March 1\, 2019\, to March 25\, 2019\, of physicians managing patients with advanced NSCLC. Respondents qualified for this study if they managed at least 5 patients with advanced NSCLC per month and had diagnosed at least 1 patient with advanced NSCLC in the 12 months before the survey. A total of 150 physicians completed the survey; before completing the survey\, they were instructed to review between 4 and 8 charts of patients with stage IV NSCLC from their list of active patients.,A total of 150 practicing oncologists who manage patients with advanced NSCLC responded to the survey and reviewed a total of 815 patient charts. Of these 815 patients\, 812 (99.6%) were tested for at least 1 biomarker\, including 73% of patients who were tested for EGFR\, 70% tested for ALK\, 58% tested for BRAF V600E\, and 38% of patients tested for ROS1\, by FDA-approved diagnostic tests. In all\, 185 (83%) patients who tested positive for EGFR and 60 (83%) patients who tested positive for ALK received an FDA-approved targeted therapy for their biomarker. A total of 98 (65%) physicians responded that the patient's insurance coverage factored into their decision to order diagnostic tests and 69 (45%) physicians responded that cost or the patient's insurance coverage could influence them not to prescribe an indicated targeted therapy.,The survey results indicate that diagnostic testing has become routine in the treatment of patients with advanced NSCLC\, the use of FDA-approved diagnostic tests has increased\, and insurance coverage and cost influence patient access to diagnostic testing as well as to targeted treatment options.",American health & drug benefits,vol.13:3:110-119,2020,Journal Article,,,"Research Associate\, Friends of Cancer Research\, Washington\, DC.,Vice President\, Science Policy\, Friends of Cancer Research\, Washington\, DC.,Managing Director\, Global Market Research\, Deerfield Management\, New York\, NY.,Director\, Health Policy\, Friends of Cancer Research\, Washington\, DC.,Director\, Research Partnerships\, Friends of Cancer Research\, Washington\, DC.,Summer Intern\, Friends of Cancer Research\, Washington\, DC.,President and CEO\, Friends of Cancer Research\, Washington\, DC.,Chairperson and Founder\, Friends of Cancer Research\, Washington\, DC.",,,,,"FDA-approved tests,advanced NSCLC,diagnostic tests,insurance coverage,laboratory-developed tests,lung cancer biomarkers,physician decision-making,targeted therapies"
32699976,"Teshima Y,Kizaki M,Kurihara R,Kano R,Harumiya M",Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation.,"To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting.,The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018\, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled.,The safety analysis set included 112 patients whom almost all patients had stage IV disease (n = 97\, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n = 102\, 91.07%)\, and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n = 105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118-300)\, and median daily dose of trametinib was 2.00 mg/day (1.0-4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%)\, and common ADRs (incidence ≥ 5%) were pyrexia (n = 49\, 43.75%)\, hepatic function abnormal (n = 11\, 9.82%)\, rash and blood creatine phosphokinase increased (n = 9 each\, 8.04%)\, and erythema nodosum (n = 6\, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients\, the objective response rate was 55.45% (95% confidence interval 45.67-64.93%)\, and median progression-free survival was 384.0 days (251.0 days-not reached).,No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.",International journal of clinical oncology,vol.25:10:1870-1878,2020,Multicenter Study,"|Adult|,|Aged|,|Aged\, 80 and over|,|Antineoplastic Combined Chemotherapy Protocols|adverse effects|therapeutic use|,|Asian Continental Ancestry Group|,|Female|,|Fever|chemically induced|,|Humans|,|Imidazoles|administration & dosage|,|Male|,|Melanoma|drug therapy|genetics|mortality|pathology|,|Middle Aged|,|Mutation|,|Oximes|administration & dosage|,|Pregnancy|,|Progression-Free Survival|,|Proto-Oncogene Proteins B-raf|genetics|,|Pyridones|administration & dosage|,|Pyrimidinones|administration & dosage|,|Surveys and Questionnaires|,|Treatment Outcome|,|Young Adult|",,"http://orcid.org/0000-0002-7630-6175Re-Examination\, Patient Safety Japan Re-Examination\, Regulatory Office Japan\, Novartis Pharma K.K.\, Toranomon Hills Mori Tower\, 1-23-1\, Toranomon\, Minato-ku\, Tokyo\, 105-6333\, Japan. yasutomo.teshima@novartis.com.,PVO Japan\, Patient Safety Japan\, Regulatory Office Japan\, Novartis Pharma K.K.\, Toranomon Hills Mori Tower\, 1-23-1\, Toranomon\, Minato-ku\, Tokyo\, 105-6333\, Japan.,Biostatistics\, Clinical Development\, Novartis Pharma K.K.\, Toranomon Hills Mori Tower\, 1-23-1\, Toranomon\, Minato-ku\, Tokyo\, 105-6333\, Japan.,Solid Tumor Medical Franchise Department\, Oncology Medical Affairs Department\, Novartis Pharma K.K.\, Toranomon Hills Mori Tower\, 1-23-1\, Toranomon\, Minato-ku\, Tokyo\, 105-6333\, Japan.,Clinical Development of Solid Tumor Oncology Group\, Clinical Development Department\, Novartis Pharma K.K.\, Toranomon Hills Mori Tower\, 1-23-1\, Toranomon\, Minato-ku\, Tokyo\, 105-6333\, Japan.","Imidazoles,Oximes,Pyridones,Pyrimidinones,trametinib,BRAF protein\, human,Proto-Oncogene Proteins B-raf,dabrafenib",,,,"BRAF mutation,Dabrafenib,Japanese,Melanoma,Real-world,Trametinib"
32700043,"Farrow NE,Turner MC,Salama AKS,Beasley GM",Overall Survival Improved for Contemporary Patients with Melanoma: A 2004-2015 National Cancer Database Analysis.,"Since 2011\, encouraging clinical trial results have led to approval of multiple new therapies for advanced melanoma\, but the impact of these therapies outside of trial populations is largely unknown. This study examines use of novel therapies and survival in contemporary patients with melanoma.,Stage I-IV melanoma patients were identified in the 2004-2015 National Cancer Database and grouped into historic (2004-2010) and contemporary (2011-2015) cohorts. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard modeling adjusting for patient\, tumor\, and facility characteristics.,Of 268\,668 patients\, 136\,828 were classified as historic and 131\,840 as contemporary. Among all stages\, immunotherapy utilization was significantly higher among contemporary patients (5.3% vs. 5.1%\, p = 0.006). Adjusted OS was improved in the contemporary cohort (hazard ratio [HR]: 0.90 p < 0.001). There was no difference in OS among stage I/II patients between groups (HR: 0.99\, p = 0.63)\, while OS was significantly improved for contemporary stage III/IV patients (HR: 0.85\, p < 0.001). Among stage III/IV patients who received immunotherapy\, OS was improved for the contemporary cohort (HR: 0.87\, p = 0.014).,Adjusted overall survival for contemporary melanoma patients is improved. This effect is driven by improvements for those with advanced stage disease\, particularly those that received immunotherapy and BRAF/MEK targeted therapies.",Oncology and therapy,vol.8:2:261-275,2020,Journal Article,,,"Department of Surgery\, Duke University Medical Center\, Durham\, NC\, USA. norma.farrow@duke.edu.,Department of Surgery\, Duke University Medical Center\, Durham\, NC\, USA.,Department of Medicine\, Duke University Medical Center\, Durham\, NC\, USA.,Department of Surgery\, Duke University Medical Center\, Durham\, NC\, USA.",,NCI NIH HHS,United States,T32 CA093245,"Immunotherapy,Melanoma,Metastatic melanoma,Survival outcomes,Targeted therapy"
32700768,"LeBlanc RE,Lefferts JA,Baker ML,Linos KD",Novel LRRFIP2-RAF1 fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications.,"A small subset of cutaneous melanomas harbor oncogenic gene fusions, which could potentially serve as therapeutic targets for patients with advanced disease as novel therapies are developed. Fusions involving RAF1 are exceedingly rare in melanocytic neoplasms, occurring in less than 1% of melanomas, and usually arise in tumors that are wild type for BRAF, NRAS, and NF1. We describe herein a case of acral melanoma with two satellite metastases and sentinel lymph node involvement. The melanoma had a concomitant KIT variant and LRRFIP2-RAF1 fusion. This constellation of molecular findings has not been reported previously in melanoma. We review the existing literature on melanocytic neoplasms with RAF1 fusions and discuss the potential clinical implications of this genetic event.",Journal of cutaneous pathology,vol.47:12:1181-1186,2020,Case Reports,,,"https://orcid.org/0000-0001-8551-0381Department of Pathology and Laboratory Medicine\, Geisel School of Medicine\, Dartmouth-Hitchcock Medical Center\, Lebanon\, New Hampshire\, USA.,Department of Pathology and Laboratory Medicine\, Geisel School of Medicine\, Dartmouth-Hitchcock Medical Center\, Lebanon\, New Hampshire\, USA.,Department of Pathology and Laboratory Medicine\, Geisel School of Medicine\, Dartmouth-Hitchcock Medical Center\, Lebanon\, New Hampshire\, USA.,https://orcid.org/0000-0001-9462-652XDepartment of Pathology and Laboratory Medicine\, Geisel School of Medicine\, Dartmouth-Hitchcock Medical Center\, Lebanon\, New Hampshire\, USA.",,"Norris Cotton Cancer Center,Dartmouth-Hitchcock Medical Center,Audrey and Theodor Geisel School of Medicine at Dartmouth,MD Anderson Cancer Center",",,,",,"RAF1,acral melanoma,melanoma,molecular pathology"
32707813,"Mukherji R,Marshall JL,Seeber A",Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives.,"The selection of treatment according to genomic alterations is a standard approach in metastatic colorectal cancer but is only starting to have an impact in the earlier stages of the disease. The status if genes like KRAS, BRAF, and MMR has substantial survival implications, and concerted research efforts have revolutionized treatment towards precision oncology. In contrast, a genomic-based approach has not changed the adjuvant setting after curative tumor-resection in the daily routine so far. This review focuses on the current knowledge regarding prognostic and predictive genomic biomarkers in patients with locally advanced nonmetastasized colorectal cancer. Furthermore, we provide an outlook on future challenges for a personalized adjuvant treatment approach in patients with colorectal cancer.",Cancers,vol.12:8:,2020,Review,,,"0000-0001-7384-0498Ruesch Center for The Cure of Gastrointestinal Cancers\, Lombardi Comprehensive Cancer Center\, Georgetown University Medical Center\, Washington\, DC 20057\, USA.,Ruesch Center for The Cure of Gastrointestinal Cancers\, Lombardi Comprehensive Cancer Center\, Georgetown University Medical Center\, Washington\, DC 20057\, USA.,0000-0001-8529-7824Department of Hematology and Oncology\, Comprehensive Cancer Center Innsbruck\, Medical University of Innsbruck\, Innsbruck A-6020\, Austria.",,,,,"adjuvant,chemotherapy,colorectal cancer,genomic,microsatellite instability,prognosis"
32708268,"Testori AAE,Chiellino S,van Akkooi ACJ","Adjuvant Therapy for Melanoma: Past, Current, and Future Developments.","This review describes the progress that the concept of adjuvant therapies has undergone in the last 50 years and focuses on the most recent development where an adjuvant approach has been scientifically evaluated in melanoma clinical trials. Over the past decade the development of immunotherapies and targeted therapies has drastically changed the treatment of stage IV melanoma patients. These successes led to trials studying the same therapies in the adjuvant setting, in high risk resected stage III and IV melanoma patients. Adjuvant immune checkpoint blockade with anti-CTLA-4 antibody ipilimumab was the first drug to show an improvement in recurrence-free and overall survival but this was accompanied by high severe toxicity rates. Therefore, these results were bypassed by adjuvant treatment with anti-PD-1 agents nivolumab and pembrolizumab and BRAF-directed target therapy, which showed even better recurrence-free survival rates with more favorable toxicity rates. The whole concept of adjuvant therapy may be integrated with the new neoadjuvant approaches that are under investigation through several clinical trials. However, there is still no data available on whether the effective adjuvant therapy that patients finally have at their disposal could be offered to them while waiting for recurrence, sparing at least 50% of them a potentially long-term toxic side effect but with the same rate of overall survival (OS). Adjuvant therapy for melanoma has radically changed over the past few years-anti-PD-1 or BRAF-directed therapy is the new standard of care.",Cancers,vol.12:7:,2020,Review,,,"0000-0003-3685-0210Department of Dermatology\, Fondazione IRCCS Policlinico San Matteo\, 27100 Pavia\, Italy.,Department of Medical Oncology\, Fondazione IRCCS Policlinico San Matteo\, 27100 Pavia\, Italy.,0000-0002-3262-6935Department of Surgical Oncology\, Netherlands Cancer Institute-Antoni van Leeuwenhoek\, 1066cx Amsterdam\, The Netherlands.",,,,,"adjuvant therapy,anti PD-1,immunotherapy,melanoma,target therapy"
32708968,"Garutti M,Buriolla S,Bertoli E,Vitale MG,Rossi E,Schinzari G,Minisini AM,Puglisi F","""To Anticipate"": Neoadjuvant Therapy in Melanoma with a Focus on Predictive Biomarkers.","Despite surgical resection and adjuvant therapies, stage III melanomas still have a substantial risk of relapse. Neoadjuvant therapy is an emerging strategy that might offer superior efficacy compared to adjuvant therapy. Moreover, neoadjuvant therapy has some virtual advantages: it might allow for less demolitive surgery, permit the in vivo evaluation of drug efficacy, help tailor adjuvant treatments, and play a crucial role in innovative translational research. Herein, we review the available literature to explore the scientific background behind the neoadjuvant approach. We also discuss published clinical trials with a focus on predictive biomarkers and ongoing studies. Finally, we outline a possible framework for future neoadjuvant clinical trial development based on the International Neoadjuvant Melanoma Consortium guidelines.",Cancers,vol.12:7:,2020,Review,,,"Dipartimento di Oncologia Medica\, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS\, 33081 Aviano\, Italy.,Dipartimento di Oncologia Medica\, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS\, 33081 Aviano\, Italy.,Dipartimento di Oncologia Medica\, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS\, 33081 Aviano\, Italy.,Department of Medicine (DAME)\, University of Udine\, 33100 Udine\, Italy.,0000-0002-6442-1707Medical Oncology\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, 00168 Rome\, Italy.,Medical Oncology\, Fondazione Policlinico Universitario A. Gemelli IRCCS\, 00168 Rome\, Italy.,Department of Medicine (DAME)\, University of Udine\, 33100 Udine\, Italy.,0000-0003-0573-4938Dipartimento di Oncologia Medica\, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS\, 33081 Aviano\, Italy.",,,,,"BRAF,MEK,adjuvant,immunotherapy,melanoma,neoadjuvant"
32684022,"Dong SY,Chen J,Xia EJ,Lin RX,Du HY,Wang OC,Zhang XH,Hao RT",Clinical Analysis of BRAF Mutation and Its Correlation With Sonographic Image Characteristics in Papillary Thyroid Carcinoma in Chinese Coastal Areas.,"This study analyzed the characteristics of BRAFV600E mutation in papillary thyroid carcinoma (PTC) in Chinese coastal areas. We intended to identify noninvasive methods to determine BRAFV600E status in thyroid nodules prior to surgery. BRAFV600E mutation and the sonographic characteristics of thyroid nodules were investigated in 670 PTC patients in our hospital. We aimed to determine the relationship between BRAFV600E mutation and the clinicopathological and sonographic imaging characteristics of PTC. The mutation rate of the BRAFV600E was 78.2%. BRAFV600E mutation was significantly associated with central node (univariate analyses, P = .005; multivariate analyses, P < .001, odds ratio [OR] = 10.255) and lateral node metastases (univariate analyses, P = .001; multivariate analyses, P < .001, OR = 22). It was less frequent in PTC coexisting with Hashimoto's thyroiditis (univariate analyses, P = .016; multivariate analyses, P < .001, OR = .034). Nodules without blood flow had a significantly higher mutation rate of BRAFV600E in PTC patients (univariate analyses, P = .026). BRAFV600E mutation was significantly associated with high suspicion in the Thyroid Imaging Reporting and Data System 5 (univariate analyses, P = .004; multivariate analyses, P = .014, OR = 6.456). Our results strongly suggest that BRAFV600E mutation plays a potential role in lymph node metastasis (central node metastasis, OR = 10.225; lateral node metastasis, OR = 22). Some sonographic imaging features might be helpful in estimating the status of BRAFV600E preoperatively.",The American surgeon,vol.86:5:450-457,2020,Journal Article,"|Adult|,|China|,|Correlation of Data|,|Female|,|Humans|,|Male|,|Middle Aged|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Thyroid Cancer\, Papillary|diagnostic imaging|genetics|,|Thyroid Neoplasms|diagnostic imaging|genetics|,|Thyroid Nodule|genetics|,|Ultrasonography|",,"89657 Department of Thyroid and Breast Surgery\, The First Affiliated Hospital of Wenzhou Medical University\, Zhejiang\, China.,89657 Operating Room\, The First Affiliated Hospital of Wenzhou Medical University\, China.,89657 Department of Thyroid and Breast Surgery\, The First Affiliated Hospital of Wenzhou Medical University\, Zhejiang\, China.,89657 Department of Pathology\, The First Affiliated Hospital of Wenzhou Medical University\, China.,89657 Department of Medical Ultrasound\, The First Affiliated Hospital of Wenzhou Medical University\, China.,89657 Department of Thyroid and Breast Surgery\, The First Affiliated Hospital of Wenzhou Medical University\, Zhejiang\, China.,89657 Department of Thyroid and Breast Surgery\, The First Affiliated Hospital of Wenzhou Medical University\, Zhejiang\, China.,89657 Department of Thyroid and Breast Surgery\, The First Affiliated Hospital of Wenzhou Medical University\, Zhejiang\, China.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF mutation,papillary thyroid carcinoma,sonographic image"
32689779,"Kim HM,Chong GO,Kim MJ,Park JY,Lee YH",Retroperitoneal Erdheim-Chester disease without skeletal bone involvement mimicking uterine sarcoma with multiple organ involvement.,"Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis and is characterized by the diffuse histiocytic infiltration of multiple organs. Retroperitoneal ECD, especially with uterine involvement, is extremely rare. We report about a 73-year-old woman who presented with vaginal spotting for a month and experienced abdominal pain along with pus-like urine. Computed tomography revealed an irregular mass-like lesion in the uterus, possibly a uterine sarcoma, invading the ureter, rectosigmoid, and bladder. A tissue biopsy of the retroperitoneal mass revealed typical morphological and immunohistochemical features of ECD. However, clinical features, especially long bone involvement, did not coincide with ECD, and BRAF V600E gene mutation was not detected. We made a diagnosis of atypical retroperitoneal ECD mimicking uterine sarcoma with multiple organ involvement.",Obstetrics & gynecology science,vol.63:4:534-537,2020,Journal Article,,,"Department of Obstetrics and Gynecology\, School of Medicine\, Kyungpook National University\, Daegu\, Korea.,Department of Obstetrics and Gynecology\, School of Medicine\, Kyungpook National University\, Daegu\, Korea.,Department of Obstetrics and Gynecology\, School of Medicine\, Kyungpook National University\, Daegu\, Korea.,Department of Pathology\, School of Medicine\, Kyungpook National University\, Daegu\, Korea.,Department of Obstetrics and Gynecology\, School of Medicine\, Kyungpook National University\, Daegu\, Korea.",,,,,"Erdheim-Chester disease,Ureter,Uterus"
32692912,"Bhaumik S,Boyer J,Banerjee C,Clark S,Sebastiao N,Vela E,Towne P",Fluorescent multiplexing of 3D spheroids: Analysis of biomarkers using automated immunohistochemistry staining platform and multispectral imaging.,"In preclinical cancer studies, three-dimensional (3D) cell spheroids and aggregates are preferred over monolayer cell cultures due to their architectural and functional similarity to solid tumors. We performed a proof-of-concept study to generate physiologically relevant and predictive preclinical models using non-small cell lung adenocarcinoma, and colon and colorectal adenocarcinoma cell line-derived 3D spheroids and aggregates. Distinct panels were designed to determine the expression profiles of frequently studied biomarkers of the two cancer subtypes. The lung adenocarcinoma panel included ALK, EGFR, TTF-1, and CK7 biomarkers, and the colon and colorectal adenocarcinoma panel included BRAF V600E, MSH2, MSH6, and CK20. Recent advances in immunofluorescence (IF) multiplexing and imaging technology enable simultaneous detection and quantification of multiple biomarkers on a single slide. In this study, we performed IF staining of multiple biomarkers per section on formalin-fixed paraffin-embedded 3D spheroids and aggregates. We optimized protocol parameters for automated IF and demonstrated staining concordance with automated chromogenic immunohistochemistry performed with validated protocols. Next, post-acquisition spectral unmixing of the captured fluorescent signals were utilized to delineate four differently stained biomarkers within a single multiplex IF image, followed by automated quantification of the expressed markers. This workflow has the potential to be adapted to preclinical high-throughput screening and drug efficacy studies utilizing 3D spheroids from cancer cell lines and patient-derived organoids. The process allows for cost, time, and resource savings through concurrent staining of several biomarkers on a single slide, the ability to study the interactions of multiple expressed proteins within a single region of interest, and enable quantitative assessment of biomarkers in cancer cells.",Journal of cellular biochemistry,vol.::,2020,Journal Article,,,"Roche Tissue Diagnostics\, Tucson\, Arizona.,Roche Tissue Diagnostics\, Tucson\, Arizona.,http://orcid.org/0000-0001-7668-5112Roche Tissue Diagnostics\, Tucson\, Arizona.,Roche Tissue Diagnostics\, Tucson\, Arizona.,Roche Tissue Diagnostics\, Tucson\, Arizona.,Roche Tissue Diagnostics\, Tucson\, Arizona.,Roche Tissue Diagnostics\, Tucson\, Arizona.",,Roche,,,"biomarkers,chromogenic staining,fluorescent multiplexing,formalin-fixed paraffin-embedded,immunofluorescence,immunohistochemistry,multispectral imaging"
32693944,"Xie Z,Gu Y,Xie X,Lin X,Ouyang M,Qin Y,Zhang J,Lizaso A,Chen S,Zhou C",Lung Adenocarcinoma Harboring Concomitant EGFR Mutations and BRAF V600E Responds to a Combination of Osimertinib and Vemurafenib to Overcome Osimertinib Resistance.,,Clinical lung cancer,vol.::,2020,Case Reports,,,"Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Department of Pathology\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China.,Burning Rock Biotech\, Guangzhou\, China.,Burning Rock Biotech\, Guangzhou\, China.,Department of Pulmonary and Critical Care Medicine\, Guangzhou Institute of Respiratory Disease\, The First Affiliated Hospital of Guangzhou Medical University\, Guangzhou\, China. Electronic address: doctorzcz@163.com.",,,,,"Case report,Double driver,EGFR-TKI,NSCLC,Osimertinib resistance"
32695793,"Vanni I,Tanda ET,Spagnolo F,Andreotti V,Bruno W,Ghiorzo P",The Current State of Molecular Testing in the BRAF-Mutated Melanoma Landscape.,"The incidence of melanoma, among the most lethal cancers, is widespread and increasing. Metastatic melanoma has a poor prognosis, representing about 90% of skin cancer mortality. The increased knowledge of tumor biology and the greater understanding of the immune system role in the anti-tumor response has allowed us to develop a more rational approach to systemic therapies. The discovery of activating BRAF mutations in half of all melanomas has led to the development of molecularly targeted therapy with BRAF and MEK inhibitors, which dramatically improved outcomes of patients with stage IV BRAF-mutant melanoma. More recently, the results of clinical phase III studies conducted in the adjuvant setting led to the combined administration of BRAF and MEK inhibitors also in patients with resected high-risk melanoma (stage III). Therefore, BRAF mutation testing has become a priority to determine the oncologist's choice and course of therapy. In this review, we will report the molecular biology-based strategies used for BRAF mutation detection with the main advantages and disadvantages of the most commonly used diagnostic strategies. The timing of such molecular assessment in patients with cutaneous melanoma will be discussed, and we will also examine considerations and approaches for accurate and effective BRAF testing.",Frontiers in molecular biosciences,vol.7::113,2020,Review,,,"Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genoa\, Italy.,Medical Oncology IRCCS Ospedale Policlinico San Martino\, Genoa\, Italy.,Medical Oncology IRCCS Ospedale Policlinico San Martino\, Genoa\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genoa\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genoa\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genoa\, Italy.",,,,,"BRAF mutation,NGS,liquid biopsy,melanoma,molecular techniques,targeted therapy"
32843426,"Sen S,Tanaka R,Khatua S,Zaky W,Janku F,Penas-Prado M,Weathers SP,Behrang A,Roszik J,Subbiah V","Dual inhibition of BRAF and mTOR in -mutant pediatric, adolescent, and young adult brain tumors.","Although BRAF inhibition has demonstrated activity in BRAF V600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF V600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.",Cold Spring Harbor molecular case studies,vol.6:4:,2020,"Research Support, N.I.H., Extramural",,,"Sarah Cannon Research Institute at HealthONE\, Denver\, Colorado 80218\, USA.,Pediatrics\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Pediatrics\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Pediatrics\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Investigational Cancer Therapeutics\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Neuro-oncology\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Neuro-oncology\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Diagnostic Radiology\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,Department of Melanoma Medical Oncology and Genomic Medicine\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.,0000-0002-6064-6837Pediatrics\, University of Texas MD Anderson Cancer Center\, Houston\, Texas 77030\, USA.",,"NCI NIH HHS,NCATS NIH HHS,NCI NIH HHS","United States,United States,United States","U01 CA180964,UL1 TR000371,P30 CA016672",neoplasm of the central nervous system
32843432,"Busch E,Kreutzfeldt S,Agaimy A,Mechtersheimer G,Horak P,Brors B,Hutter B,Fröhlich M,Uhrig S,Mayer P,Schröck E,Stenzinger A,Glimm H,Jäger D,Springfeld C,Fröhling S,Zschäbitz S",Successful BRAF/MEK inhibition in a patient with -mutated extrapancreatic acinar cell carcinoma.,"Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAF V600E-mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAF V600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.",Cold Spring Harbor molecular case studies,vol.6:4:,2020,"Research Support, Non-U.S. Gov't",,,"Department of Medical Oncology\, University Hospital Heidelberg\, National Center for Tumor Diseases (NCT) Heidelberg\, Heidelberg\, 69120\, Germany.,Department of Translational Medical Oncology\, NCT Heidelberg and German Cancer Research Center (DKFZ)\, Heidelberg\, 69120\, Germany.,Institute of Pathology\, University Hospital Erlangen\, Erlangen\, 91054\, Germany.,Institute of Pathology\, University Hospital Heidelberg\, Heidelberg\, 69120\, Germany.,0000-0003-4536-9306Department of Translational Medical Oncology\, NCT Heidelberg and German Cancer Research Center (DKFZ)\, Heidelberg\, 69120\, Germany.,Division of Applied Bioinformatics\, DKFZ and NCT Heidelberg\, Heidelberg\, 69120\, Germany.,Division of Applied Bioinformatics\, DKFZ and NCT Heidelberg\, Heidelberg\, 69120\, Germany.,Division of Applied Bioinformatics\, DKFZ and NCT Heidelberg\, Heidelberg\, 69120\, Germany.,Division of Applied Bioinformatics\, DKFZ and NCT Heidelberg\, Heidelberg\, 69120\, Germany.,Department of Diagnostic and Interventional Radiology\, University Hospital Heidelberg\, Heidelberg\, 69120\, Germany.,NCT Partner Site Dresden\, University Cancer Center (UCC) Dresden\, Dresden\, 01307\, Germany.,Institute of Pathology\, University Hospital Heidelberg\, Heidelberg\, 69120\, Germany.,NCT Partner Site Dresden\, University Cancer Center (UCC) Dresden\, Dresden\, 01307\, Germany.,Department of Medical Oncology\, University Hospital Heidelberg\, National Center for Tumor Diseases (NCT) Heidelberg\, Heidelberg\, 69120\, Germany.,Department of Medical Oncology\, University Hospital Heidelberg\, National Center for Tumor Diseases (NCT) Heidelberg\, Heidelberg\, 69120\, Germany.,Department of Translational Medical Oncology\, NCT Heidelberg and German Cancer Research Center (DKFZ)\, Heidelberg\, 69120\, Germany.,Department of Medical Oncology\, University Hospital Heidelberg\, National Center for Tumor Diseases (NCT) Heidelberg\, Heidelberg\, 69120\, Germany.",,,,,neoplasm of the pancreas
32843902,"Zhan J,Zhang LH,Yu Q,Li CL,Chen Y,Wang WP,Ding H",Prediction of cervical lymph node metastasis with contrast-enhanced ultrasound and association between presence of BRAF and extrathyroidal extension in papillary thyroid carcinoma.,"This study aimed to evaluate the correlation between cervical lymph node metastasis (CLNM) and each of the ultrasound features\, immunohistochemical factors\, and B-type Raf (BRAFV600E) mutation.,A retrospective analysis was performed on 405 patients with single papillary thyroid carcinoma (PTC) nodules\, all of whom underwent preoperative sonographic examinations\, including gray-scale ultrasound\, color Doppler ultrasound\, and contrast-enhanced ultrasound (CEUS). All PTC patients were evaluated using 14 clinical and sonographic features\, eight immunohistochemical factors\, and BRAFV600E. Multivariate analyses were performed to identify the risk factors for CLNM\, and an equation for CLNM was established. The diagnostic value of each modality was compared with a receiver operating characteristic (ROC) curve.,Among the 405 PTC nodules removed surgically\, CLNM was confirmed in 138 patients\, whereas extrathyroidal extension was confirmed in 185 patients. Multivariate analyses indicated significant differences between CLNM and non-CLNM groups in three conventional ultrasound features (p < 0.05)\, whereas other sonographic features\, eight immunohistochemical factors\, and BRAFV600E did not indicate significant differences. A ROC curve of 0.757 in the equation exhibited a significant difference compared with the solo factors (p < 0.05 for all). Hyper or isoechoic enhancement at peak time on CEUS was associated with CLNM\, whereas the presence of the BRAFV600E mutation was associated with extrathyroidal extensions although BRAF appeared to be uncorrelated with CLNM in the present study.,Intensity at peak time\, homogeneity\, and size are the three most significant features in predicting CLNM in PTC patients\, and the presence of the BRAFV600E mutation was associated with extrathyroidal extensions when PTCs showed a hyper or isoechoic enhancement at peak time in CEUS.",Therapeutic advances in medical oncology,vol.12::1758835920942367,2020,Journal Article,,,"https://orcid.org/0000-0002-2179-4095Department of Ultrasound\, Huadong Hospital\, Fudan University\, Shanghai P.R. China.,Department of Ultrasound\, Zhongshan Hospital\, Fudan University\, Shanghai\, P.R. China.,Department of Ultrasound\, Zhongshan Hospital\, Fudan University\, Shanghai\, P.R. China.,Department of Ultrasound\, Zhongshan Hospital\, Fudan University\, Shanghai\, P.R. China.,Department of Ultrasound\, Huadong Hospital\, Fudan University\, Shanghai P.R. China.,Department of Ultrasound\, Zhongshan Hospital\, Fudan University\, Shanghai\, P.R. China.,Department of Ultrasound\, Zhongshan Hospital\, Fudan University\, Fenglin Road No.180\, Shanghai\, 200032\, P.R. China.",,,,,"BRAF gene,contrast-enhanced ultrasound,extrathyroidal extension,lymph node metastasis,papillary thyroid carcinoma"
32847629,"Zou Y,Sun Y,Zeng X,Liu Y,Cen Q,Gu H,Lin X,Cai R,Chen H",Novel genetic alteration in congenital melanocytic nevus: MAP2K1 germline mutation with BRAF somatic mutation.,"Congenital melanocytic nevus (CMN) represent a benign proliferative skin disease in the epidermis and dermis. CMN are historically known to be associated with activating NRAS or BRAF mutations. Melanoma frequently harbors the BRAF p.Val600Glu mutation, which is also commonly found in benign nevi. A recent study reported mutation of MAP2K1, a downstream effector of the RAS-RAF-MEK pathway, in melanoma with an overall frequency of 8%. Later, in 2019, Jansen P detected one activating MAP2K1 mutation in acral nevi. However, it is unknown whether MAP2K1 mutations are common in CMN, and how MAP2K1 contributes to the pathogenesis of CMN remains to be determined.In this study, we report one patient clinically and histologically diagnosed with CMN, with the MAP2K1 germline mutation and a BRAF p.Val600Glu somatic hit in the lesion. To the best of our knowledge, this is the first report of the coexistence of mutated BRAF and MAP2K1 in CMN, which may suggest that MAP2K1 mutations contribute to the occurrence and development of nevus expanding our knowledge of the genetics of CMN.",Hereditas,vol.157:1:35,2020,Journal Article,,,"Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China.,Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China.,Children's Hospital\, Zhejiang University School of Medicine\, National Clinical Research Center for Child Health\, National Children's Regional Medical Center\, Hangzhou\, China.,Institutes of Biomedical Sciences\, Fudan University\, Shanghai\, PR China.,Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China.,Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China.,Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China. linxiaoxi@126.com.,http://orcid.org/0000-0002-6025-0170Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China. DrRenCai@gmail.com.,Department of Plastic and Reconstructive Surgery\, Shanghai Peoples Hospital Affiliated to Shanghai Jiaotong University\, Shanghai\, China. chenhui9801640@163.com.",,"Clinical Research Plan of SHDC,Clinical Research Program of 9th People's Hospital\, Shanghai Jiao Tong University School of Medicine,Clinical Research Project of Multi-Disciplinary Team\, Shanghai Ninth People's Hospital\, Shanghai Jiao Tong University School of Medicine",",,","16CR1007A,JYLJ001,201701001",
32850329,"Bruera G,D'Andrilli A,Simmaco M,Guadagni S,Rendina EA,Ricevuto E",Relevance of Pharmacogenomics and Multidisciplinary Management in a Young-Elderly Patient With Mutant Colorectal Cancer Treated With First-Line Aflibercept-Containing Chemotherapy.,"Introduction: Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies. Case presentation: A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by KRAS c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1-4, 15-18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of UGT1A1 *28 variable number of tandem repeats (VNTR) 7R/7R homozygote, ABCB1 c.C3435T, c.C1236T, MTHFR c.C667T homozygote, DPYD c.A166G, TSER 28bp VNTR 2R/3R heterozygote. Conclusions: In clinical practice, a complex management evaluating clinical parameters and RAS/BRAF genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.",Frontiers in oncology,vol.10::1155,2020,Case Reports,,,"Oncology Territorial Care\, S. Salvatore Hospital\, Oncology Network ASL1 Abruzzo\, University of L'Aquila\, L'Aquila\, Italy.,Thoracic Surgery\, S. Andrea Hospital\, Faculty of Medicine and Psychology\, University La Sapienza\, Rome\, Italy.,Advanced Molecular Diagnostics\, S. Andrea Hospital\, Rome\, Italy.,Department of Biotechnological and Applied Clinical Sciences\, University of L'Aquila\, L'Aquila\, Italy.,Thoracic Surgery\, S. Andrea Hospital\, Faculty of Medicine and Psychology\, University La Sapienza\, Rome\, Italy.,Oncology Territorial Care\, S. Salvatore Hospital\, Oncology Network ASL1 Abruzzo\, University of L'Aquila\, L'Aquila\, Italy.",,,,,"aflibercept/chemotherapy,case report,multidisciplinary management,pharmacogenomic analyses,young-elderly unfit MCRC"
32850378,"Xue X,Asuquo I,Hong L,Gao J,Dong Z,Pang L,Jiang T,Meng M,Fan J,Wen J,Deng H,Zang X,Ma X,Guo R,Qin C,Meng Y,Ma H,Han J,Wang H,Xue Z,Zhao D,Lin D,Pan L",Catalog of Lung Cancer Gene Mutations Among Chinese Patients.,"Background: Detailed catalog of lung cancer-associated gene mutations provides valuable information for lung cancer diagnosis and treatment. In China, there has never been a wide-ranging study cataloging lung cancer-associated gene mutations. This study aims to reveal a comprehensive catalog of lung cancer gene mutations in china, focusing on EGFR, ALK, KRAS, HER2, PIK3CA, MET, BRAF, HRAS, and CTNNB1 as major targets. Additionally, we also aim to correlate smoking history, gender, and age distribution and pathological types with various types of gene mutations. Patients and Methods: A retrospective data acquisition was conducted spanning 6 years (2013-2018) among all patients who underwent lung cancer surgeries not bronchial or percutaneous lung biopsy at three major tertiary hospitals. Finally, we identified 1,729 patients who matched our inclusion criteria. Results: 1081 patients (62.49%) harbored EGFR mutation. ALK (n = 42, 2.43%), KRAS (n = 201, 11.62%), CTNNB1 (n = 28, 1.62%), BRAF (n = 31, 1.79%), PIK3CA (n = 51, 2.95%), MET (n = 14, 0.81%), HER2 (n = 47, 2.72%), HRAS (n = 3, 0.17%), and other genes(n = 232, 13.4%). Females expressed 55.38% vs. males 44.62% mutations. Among subjects with known smoking histories, 32.82% smokers, 67.15% non-smokers were observed. Generally, 51.80% patients were above 60 years vs. 48.20% in younger patients. Pathological types found includes LUADs 71.11%, SQCCs 1.68%, ASC 0.75%, LCC 0.58%, SCC 0.35%, ACC 0.17%, and SC 0.06%, unclear 25.19%. Conclusion: We offer a detailed catalog of the distribution of lung cancer mutations. Showing how gender, smoking history, age, and pathological types are significantly related to the prevalence of lung cancer in China.",Frontiers in oncology,vol.10::1251,2020,Journal Article,,,"Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Radiology\, Jinzhou Medical University\, Jinzhou\, China.,Internal Medicine Department\, Xuhui Changqiao Community Health Care Centre\, Shanghai\, China.,Department of Pathology\, Chinese PLA General Hospital\, Beijing\, China.,Department of Pathology\, Chinese PLA General Hospital\, Beijing\, China.,Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Radiology\, Affiliated Hospital of Qingdao University\, Qingdao\, China.,Department of Gastroenterology\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Respiratory and Critical Care\, Second Affiliated Hospital of Anhui Medical University\, Anhui\, China.,Department of Chest Surgery\, Chinese PLA General Hospital\, Beijing\, China.,Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Laboratory\, Chinese PLA General Hospital\, Beijing\, China.,Department of Respiratory and Critical Care\, Affiliated Hospital of Weifang Medical University\, Shandong\, China.,Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Chest Surgery\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Radiology\, Jinzhou Medical University\, Jinzhou\, China.,Department of Radiology\, Third Affiliated Hospital of Chongqing Medical University\, Chongqing\, China.,Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.,Department of Chest Surgery\, Chinese PLA General Hospital\, Beijing\, China.,Department of Respiratory and Critical Care\, Second Affiliated Hospital of Anhui Medical University\, Anhui\, China.,Department of Pathology\, Affiliated Hospital of Qingdao University\, Qingdao\, China.,Department of Respiratory and Critical Care\, Beijing Shijitan Hospital\, Capital Medical University\, Beijing\, China.",,,,,"China,aging,gene mutation,lung cancer,pathology,tobacco smoking"
32850962,"Vanni I,Tanda ET,Dalmasso B,Pastorino L,Andreotti V,Bruno W,Boutros A,Spagnolo F,Ghiorzo P",Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications.,"Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.",Frontiers in molecular biosciences,vol.7::172,2020,Review,,,"Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Medical Oncology\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Medical Oncology\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Medical Oncology\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.,Genetics of Rare Cancers\, IRCCS Ospedale Policlinico San Martino\, Genova\, Italy.",,,,,"WES,WGS,driver mutations,genetic,heterogeneity,melanoma,non-BRAF mutation,targeted therapy"
32853962,"Torrez M,Braunberger RC,Yilmaz E,Agarwal S",Primary squamous cell carcinoma of thyroid with a novel BRAF mutation and High PDL-1 expression: A case report with treatment implications and review of literature.,"Primary squamous cell carcinoma of thyroid (SCC-T) is an extremely rare, aggressive neoplasm with median survival of 9 months. Pure squamous morphology with absence of other cell types is required for diagnosis of SCC-T. Clinically, SCC-T behaves like anaplastic thyroid carcinoma (ATC) showing rapid growth, and extra thyroidal extension. We report a 91-year-old woman presenting with an enlarging thyroid mass and accompanying dysphagia and hoarseness. Fine needle aspiration revealed hypercellular specimen with large, pleomorphic, malignant cells. Intraoperative assessment revealed an inoperable tumor involving both thyroid lobes and extensively infiltrating surrounding soft tissues. A subtotal thyroidectomy was performed. Histology revealed squamous cell carcinoma replacing native thyroid tissue and infiltrating adjacent skeletal muscle. Lymphovascular and perineural invasion were present. Immunohistochemistry showed tumor cells positive for CK5-p40, Pax-8, TTF-1 and negative for thyroglobulin. P53 expression by IHC was high and Ki-67 proliferation index was > 90 %. (Next generation sequencing revealed a novel BRAF mutation (BRAF c.1799 T > A; 1801_1812del) along with TP53 and TERT mutations. PDL-1 immunohistochemistry showed positive expression in tumor cells (>80%), making patient also amenable to anti-PDL-1 immunotherapy. Patient was treated with BRAF inhibitor therapy with initial relief but eventually was put on hospice care due to increasing intolerance to therapy. This case represents a rare thyroid malignancy with a unique molecular signature consisting of a novel BRAF mutation [previously not described in SCC-T or ATC], associated with TERT-TP53 mutations. Further, importance of PDL-1 testing as a prognostic marker and as a guide to immunotherapy in refractory tumors is discussed.","Pathology, research and practice",vol.216:10:153146,2020,Journal Article,,,"Department of Pathology\, University of New Mexico School of Medicine\, Albuquerque\, New Mexico\, United States.,Department of Pathology\, University of New Mexico School of Medicine\, Albuquerque\, New Mexico\, United States.,Department of Oncology/ Hematology\, University of New Mexico Comprehensive Cancer Center\, Albuquerque\, New Mexico\, United States.,Department of Pathology\, University of New Mexico School of Medicine\, Albuquerque\, New Mexico\, United States. Electronic address: shagarwal@salud.unm.edu.",,,,,"Anaplastic,BRAF,PD-L1,Squamous,TERT"
32858528,"Li X,Cai Y",Risk stratification of cutaneous melanoma reveals carcinogen metabolism enrichment and immune inhibition in high-risk patients.,"Cutaneous melanoma (CM) is the most lethal form of skin cancer. Risk assessment should facilitate stratified surveillance and guide treatment selection. Here, based on the mRNA-seq data from 419 CM patients in the Cancer Genome Atlas (TCGA), we developed a prognostic 21-gene signature to distinguish the outcomes of high- and low-risk patients, which was further validated in two external cohorts. The signature achieved a higher C-index as compared with other known biomarkers and clinical characteristics in both the TCGA and validation cohorts. Notably, in high-risk patients the expression levels of three driver genes, BRAF, NRAS, and NF1 in the MAPK pathway, were lower but exhibited a stronger positive correlation as compared with low-risk patients. Moreover, the genes involved in nicotinamide adenine dinucleotide metabolism were negatively correlated with the expression of BRAF in the high-risk group. Function analysis revealed that the upregulated genes in the high-risk group were enriched in the cytochrome P450-mediated metabolism of chemical carcinogens. Furthermore, the low-risk group had high levels of gamma delta T cells infiltration, while regulatory T cells were accumulated in the high-risk group. The present study offers a promising new prognostic signature for CM, and provides insight into the mechanisms of melanoma progression.",Aging,vol.12:16:16457-16475,2020,"Research Support, Non-U.S. Gov't",,,"Research Center for Biomedical Information Technology\, Shenzhen Institutes of Advanced Technology\, Chinese Academy of Sciences\, Shenzhen 518055\, P.R. China.,Research Center for Biomedical Information Technology\, Shenzhen Institutes of Advanced Technology\, Chinese Academy of Sciences\, Shenzhen 518055\, P.R. China.",,,,,"biomarker,cutaneous melanoma,driver gene,immune cell type,metabolism"
32858845,"Woycinck Kowalski T,Brussa Reis L,Finger Andreis T,Ashton-Prolla P,Rosset C",Systems Biology Approaches Reveal Potential Phenotype-Modifier Genes in Neurofibromatosis Type 1.,"Neurofibromatosis type (NF1) is a syndrome characterized by varied symptoms, ranging from mild to more aggressive phenotypes. The variation is not explained only by genetic and epigenetic changes in the NF1 gene and the concept of phenotype-modifier genes in extensively discussed in an attempt to explain this variability. Many datasets and tools are already available to explore the relationship between genetic variation and disease, including systems biology and expression data. To suggest potential NF1 modifier genes, we selected proteins related to NF1 phenotype and NF1 gene ontologies. Protein-protein interaction (PPI) networks were assembled, and network statistics were obtained by using forward and reverse genetics strategies. We also evaluated the heterogeneous networks comprising the phenotype ontologies selected, gene expression data, and the PPI network. Finally, the hypothesized phenotype-modifier genes were verified by a random-walk mathematical model. The network statistics analyses combined with the forward and reverse genetics strategies, and the assembly of heterogeneous networks, resulted in ten potential phenotype-modifier genes: AKT1, BRAF, EGFR, LIMK1, PAK1, PTEN, RAF1, SDC2, SMARCA4, and VCP. Mathematical models using the random-walk approach suggested SDC2 and VCP as the main candidate genes for phenotype-modifiers.",Cancers,vol.12:9:,2020,Journal Article,,,"Laboratório de Medicina Genômica\, Centro de Pesquisa Experimental\, Hospital de Clínicas de Porto Alegre\, Porto Alegre 90035-007\, Rio Grande do Sul\, Brazil.,0000-0002-9833-9058Laboratório de Medicina Genômica\, Centro de Pesquisa Experimental\, Hospital de Clínicas de Porto Alegre\, Porto Alegre 90035-007\, Rio Grande do Sul\, Brazil.,Laboratório de Medicina Genômica\, Centro de Pesquisa Experimental\, Hospital de Clínicas de Porto Alegre\, Porto Alegre 90035-007\, Rio Grande do Sul\, Brazil.,Laboratório de Medicina Genômica\, Centro de Pesquisa Experimental\, Hospital de Clínicas de Porto Alegre\, Porto Alegre 90035-007\, Rio Grande do Sul\, Brazil.,0000-0002-1728-4770Laboratório de Medicina Genômica\, Centro de Pesquisa Experimental\, Hospital de Clínicas de Porto Alegre\, Porto Alegre 90035-007\, Rio Grande do Sul\, Brazil.",,,,,"neurofibromatosis type 1,phenotype-modifier genes,systems biology"
32859224,"Yanagawa N,Sato A,Nishiya M,Suzuki M,Sugimoto R,Osakabe M,Uesugi N,Saito H,Sugai T","Pulmonary epithelial-myoepithelial carcinoma without AKT1, HRAS or PIK3CA mutations: a case report.","Pulmonary epithelial-myoepithelial carcinoma is a rare subtype of lung cancer. Because of its rarity\, the molecular information on this carcinoma is insufficient.,We report a case of pulmonary epithelial-myoepithelial carcinoma without AKT1\, HRAS or PIK3CA mutations in a 76-year-old woman. Computed tomography revealed a tumor located in the left lower lung. Thoracoscopic left lower lobectomy was performed. Histopathologically\, the tumor consisted of duct-like structures and polygonal and spindle cell features. The duct-like structures were composed of two distinct cell layers. The inner layer consisted of cuboidal cells that were positive for pan-cytokeratin and negative for p63\, whereas the outer layer consisted of polygonal and spindle cells that were positive for p63 and weakly positive for pan-cytokeratin. We evaluated mutations in AKT1\, BRAF\, CTNNB1\, HRAS\, KRAS and PIK3CA but did not detect any mutations.,Pulmonary epithelial-myoepithelial carcinoma is a rare subtype of lung cancer\, with only 56 previous cases reported in the English literature. The genetic alterations in pulmonary epithelial-myoepithelial carcinoma are still unknown. We examined the 6 genes mutation analysis\, however no mutation was detected.",Diagnostic pathology,vol.15:1:105,2020,Journal Article,,,"http://orcid.org/0000-0002-0818-7151Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan. nyanagaw@iwate-med.ac.jp.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Thoracic Surgery\, Iwate Medical University\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.,Department of Molecular Diagnostic Pathology\, Iwate Medical University\, 2-1-1 Idaidori\, Yahaba-cho\, Shiwa-gun\, Iwate\, 0283695\, Japan.",,,,,"AKT1,Epithelial–myoepithelial carcinoma,HRAS,PIK3CA,Pulmonary"
32861617,"Necchi A,Madison R,Pal SK,Ross JS,Agarwal N,Sonpavde G,Joshi M,Yin M,Miller VA,Grivas P,Chung JH,Ali SM",Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma.,"Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC)\, by site of origin\, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms.,To describe the genomic landscape of UC based on the anatomic site of the primary tumor.,In total\, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs\, tumor mutational burden (TMB)\, and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT).,Hybrid-capture-based CGP.,Descriptive analyses and differences between anatomic subgroups were reported.,In total\, 39% of patients with UC harbored one or more tier 1-2 GAs\, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%)\, the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%\, p=0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p<0.001). Non-FGFR3 kinase fusions were observed in 1% of patients\, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p=0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites\, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%\, p<0.001).,Differences in the genomic landscapes of UTUC and BUC were modest; however\, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC\, stratified by the site of origin\, is warranted. In addition\, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.,Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients\, particularly those with upper tract urothelial carcinoma\, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart\, which is often treated based on the data extrapolated from bladder cancer.",European urology focus,vol.::,2020,Journal Article,,,"Fondazione IRCCS-Istituto Nazionale dei Tumori\, Milan\, Italy. Electronic address: andrea.necchi@istitutotumori.mi.it.,Foundation Medicine\, Inc.\, Cambridge\, MA\, USA.,City of Hope Comprehensive Cancer Center\, Duarte\, CA\, USA.,Foundation Medicine\, Inc.\, Cambridge\, MA\, USA; Upstate Medical University\, Syracuse\, NY\, USA.,Huntsman Cancer Institute and University of Utah\, Salt Lake City\, UT\, USA.,Dana Farber Cancer Institute\, Boston\, MA\, USA.,Penn State Cancer Institute\, Hershey\, PA\, USA.,The Ohio State University Comprehensive Cancer Center\, Columbus\, OH\, USA.,Foundation Medicine\, Inc.\, Cambridge\, MA\, USA.,University of Washington\, Seattle Cancer Care Alliance\, Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA.,Foundation Medicine\, Inc.\, Cambridge\, MA\, USA.,Foundation Medicine\, Inc.\, Cambridge\, MA\, USA.",,,,,"Bladder cancer,Comprehensive genomic profiling,Genomic alterations,Upper tract urothelial carcinoma,Urothelial cancer"
32836055,"Jašek K,Váňová B,Grendár M,Štanclová A,Szépe P,Hornáková A,Holubeková V,Plank L,Lasabová Z",BRAF mutations in KIT/PDGFRA positive gastrointestinal stromal tumours (GISTs): Is their frequency underestimated?,"BRAF V600E mutations in GISTs are considered to be one of the mutational events in KIT/PDGFRA negative or positive GISTs, respectively. BRAF mutated GISTs usually do not respond to imatinib treatment, even more GISTs with imatinib sensitive KIT mutation. However, they are almost phenotypically and morphologically identical with KIT/PDGFRA positive GISTs. In general, due to the small number of BRAF mutations in GIST and because of the rarity of concomitant BRAF/KIT or BRAF/PDGFRA mutations, their frequency may be depreciated. The aim of this study was BRAF mutation detection in KIT/PDGFRA positive GISTs and their verification by other molecular methods. We applied the sensitive droplet digital PCR on 35 randomly selected KIT/PDGFRA positive GISTs to detect V600E mutations. We have established two criteria for the evaluation of samples: false positive rate (FPR) based on the negative controls; Limit of Detection (LoD) based on the serial dilution of positive control from RKO cell line harboring heterozygous V600E mutation in constant wild-type DNA background. Results from ddPCR were verified by other molecular methods: allele-specific PCR, dideoxysequencing, competitive allele-specific TaqMan PCR (castPCR). FPR was determined as 5 (∼4.4) positive droplets, and LoD was assessed to 3.4293 copies/μL what is the method sensitivity of 0.0162 %. We identified eight KIT/PDGFRA positive patients with concomitant V600E mutation. The five of them were in coexistence with KIT mutation and three with PDGFRA mutation. We also included the liver metastasis, but data from primary tumour were not available. We achieved the very high sensitivity of the ddPCR method for detecting BRAF mutation in GISTs to have importance from the point of view of therapy.","Pathology, research and practice",vol.216:11:153171,2020,Journal Article,,,"Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Biomedical Center Martin JFM CU\, 036 01 Martin\, Slovakia. Electronic address: jasek@jfmed.uniba.sk.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Biomedical Center Martin JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Biomedical Center Martin JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Department of Pathological Anatomy JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Department of Pathological Anatomy JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Biomedical Center Martin JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Biomedical Center Martin JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Biomedical Center Martin JFM CU\, 036 01 Martin\, Slovakia; Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Department of Pathological Anatomy JFM CU\, 036 01 Martin\, Slovakia.,Comenius University in Bratislava\, Jessenius Faculty of Medicine in Martin (JFM CU)\, Department of Molecular Biology and Genomics JFM CU\, 036 01 Martin\, Slovakia.",,,,,"BRAF inhibitor,BRAF mutation,BRAF/KIT/PDGFRA genes,Concomitant mutations,Droplet digital PCR,Gastrointestinal stromal tumours"
32839179,"Zanazzi G,Liechty BL,Pendrick D,Krasnozhen-Ratush O,Snuderl M,Allen JC,Garvin JH,Mansukhani MM,Roth KA,Hsiao SJ","Diffuse midline glioma with novel, potentially targetable, fusion.","We report a case of a slow-growing, diffuse, infiltrating glioma in the right brainstem of a 9-yr-old boy. The tumor was negative by immunohistochemical staining for histone H3 K27M, BRAF V600E, and IDH1 R132H mutations. Fluorescence in situ hybridization did not reveal a BRAF duplication. Genomic profiling of the tumor, by DNA methylation array and cancer whole-exome and transcriptome sequencing, was performed. This analysis showed copy-number alterations, including gains of several chromosomes. In addition, a novel fusion involving the first 17 exons of FGFR2 fused to exon 2 of VPS35 was identified. This novel fusion is predicted to result in activation of fibroblast growth factor receptor (FGFR) signaling and is potentially targetable using FGFR inhibitors. This tumor expands the spectrum of pediatric diffuse gliomas.",Cold Spring Harbor molecular case studies,vol.6:5:,2020,"Research Support, Non-U.S. Gov't",,,"Department of Pathology and Cell Biology\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.,Department of Pathology and Cell Biology\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.,Department of Pathology and Cell Biology\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.,Department of Pathology\, NYU Langone Medical Center\, New York\, New York\, 10016\, USA.,Department of Pathology\, NYU Langone Medical Center\, New York\, New York\, 10016\, USA.,0000-0001-9957-6664Department of Pediatrics\, NYU Langone Medical Center\, New York\, New York 10016\, USA.,Department of Pediatrics\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.,Department of Pathology and Cell Biology\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.,Department of Pathology and Cell Biology\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.,Department of Pathology and Cell Biology\, Columbia University Irving Medical Center\, New York\, New York 10032\, USA.",,,,,neoplasm of the central nervous system
32590884,"Zhao M,Yin M,Kuick CH,Chen H,Aw SJ,Merchant K,Ng EHQ,Gunaratne S,Loh AHP,Gu W,Tang H,Chang KTE","Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6-NTRK3 fusion, and the rare KLHL7-BRAF fusion.","Congenital mesoblastic nephroma (CMN) is histologically classified into classic\, cellular and mixed subtypes. The aims of this study were to characterise the clinical\, pathological and molecular features of a series of CMNs\, and to determine the utility of pan-Trk and epidermal growth factor receptor (EGFR) immunohistochemistry as surrogate markers for NTRK gene fusions and EGFR internal tandem duplications (ITDs).,Twenty-two archival CMN cases (12 classic\, five cellular\, and five mixed) were tested for the ETV6-NTRK3 fusion and EGFR ITD transcripts by the use of reverse transcriptase polymerase chain reaction (PCR)\, and next-generation sequencing-based anchored multiplex PCR. All 12 classic CMNs had EGFR ITD. Of the five cellular CMNs\, four had the ETV6-NTRK3 fusion and one had the KLHL7-BRAF fusion. Of the five mixed CMNs\, four had EGFR ITD\, and one had the ETV6-NTRK3 fusion. Pan-Trk immunoreactivity was 100% sensitive and 94.1% specific for the presence of NTRK rearrangement. However\, EGFR staining was only 62.5% sensitive and 33.3% specific for EGFR ITD.,EGFR ITD is a consistent genetic event in classic CMN. A majority of cellular CMNs have the ETV6-NTRK3 fusion. Rare cellular CMNs may harbour non-canonical mutations such as the KLHL7-BRAF fusion\, which was found in one case. Mixed CMNs may have either EGFR ITD or the ETV6-NTRK3 fusion. Pan-Trk immunohistochemistry is a sensitive\, albeit not perfectly specific\, marker for NTRK rearrangement. EGFR immunohistochemistry is not helpful as a marker of EGFR ITD.",Histopathology,vol.77:4:611-621,2020,Journal Article,,,"https://orcid.org/0000-0002-7864-3853Department of Pathology\, The Children's Hospital\, Zhejiang University School of Medicine\, National Clinical Research Center for Child Health\, Hangzhou\, Zhejiang Province\, China.,Department of Pathology\, Shanghai Children's Medical Centre\, Shanghai\, China.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore.,Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore.,Lady Ridgeway Hospital for Children\, Colombo\, i Lanka.,Department of Paediatric Surgery\, KK Women's and Children's Hospital.,Department of Pathology\, The Children's Hospital\, Zhejiang University School of Medicine\, National Clinical Research Center for Child Health\, Hangzhou\, Zhejiang Province\, China.,Department of Pathology\, The Children's Hospital\, Zhejiang University School of Medicine\, National Clinical Research Center for Child Health\, Hangzhou\, Zhejiang Province\, China.,https://orcid.org/0000-0001-5244-4285Department of Pathology and Laboratory Medicine\, KK Women's and Children's Hospital\, Singapore.",,"VIVA-KKH Paediatric Brain and Solid Tumour Program based at KK Women's and Children's Hospital,Fundamental Public Benefit Research Plan of Zhejiang Province",",","02/FY2018/EX/23-A64,LGC20H040001","EGFR immunohistochemistry,EGFR internal tandem duplication,KLHL7-BRAF gene fusion,congenital mesoblastic nephroma,pan-Trk immunohistochemistry"
32591646,"Pegoraro F,Papo M,Maniscalco V,Charlotte F,Haroche J,Vaglio A",Erdheim-Chester disease: a rapidly evolving disease model.,"Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with a putative neoplastic and inflammatory nature. The disease is driven by mutations in proto-oncogenes such as BRAF and MEK, while immune-mediated mechanisms contribute to disease development and progression. The clinical presentation of ECD is highly heterogeneous, ranging from smouldering unifocal forms to multiorgan life-threatening disease. Almost any organ can be involved, but the most common lesions include long-bone involvement, retroperitoneal fibrosis, interstitial lung disease, pericardial and myocardial infiltration, CNS, retro-orbital, and large-vessel involvement. These manifestations may mimic those of neoplastic and systemic immune-mediated diseases. Overlap with these conditions represents an emerging challenge for the clinician. A variety of treatments are efficacious for ECD, targeting both the MAPK-pathway and the immune-mediated pathomechanisms. The traditional approach is based on immunomodulatory agents (interferon-α), but recent alternatives-including anti-cytokine therapies (IL1- and TNFα-blockers) and immunosuppressants (mTOR-inhibitors)-showed promising results. However, since the detection of MAPK pathway activation in most patients and the dramatic efficacy of BRAF and MEK inhibitors, these targeted treatments represent the first-line approach in patients with severe disease forms. High rates of radiologic responses do not often mean clinical remission, especially for CNS involvement, which often results in chronic disability. This review will outline the main clinical features of ECD, with emphasis on the emerging challenges in pathogenesis and management, and on the role of recent targeted approaches.",Leukemia,vol.34:11:2840-2857,2020,Review,"|Biomarkers|,|Biopsy|,|Diagnostic Imaging|,|Disease Management|,|Disease Susceptibility|,|Erdheim-Chester Disease|diagnosis|epidemiology|etiology|therapy|,|Genetic Predisposition to Disease|,|Histiocytosis|complications|,|Humans|,|Immunohistochemistry|,|Molecular Diagnostic Techniques|,|Mutation|,|Neoplasms|complications|,|Organ Specificity|",,"http://orcid.org/0000-0002-4954-5744Department of Health Sciences\, University of Firenze\, Firenze\, Italy.,Sorbonne University\, Assistance Publique-Hôpitaux\, Internal Medicine 2\, Histiocytosis National Reference Centre\, Pitié-Salpêtrière Hospital\, Paris\, France.,http://orcid.org/0000-0003-3287-846XDepartment of Health Sciences\, University of Firenze\, Firenze\, Italy.,http://orcid.org/0000-0003-2803-6606Service d'Anatomie Pathologique\, Sorbonne Université\, Assistance Publique-Hôpitaux de Paris\, Hôpital Pitié-Salpêtrière\, Paris\, France.,Sorbonne Université\, Assistance Publique-Hôpitaux de Paris\, Service de Médecine Interne 2 maladies auto-immunes et systémiques\, Centre National de Références des Histiocytoses\, Hôpital Pitié-Salpêtrière\, Paris\, France.,http://orcid.org/0000-0002-3814-9172Department of Biomedical\, Experimental and Clinical Sciences ""Mario Serio""\, University of Firenze\, and Nephrology and Dialysis Unit\, Meyer Children's Hospital\, Firenze\, Italy. augusto.vaglio@unifi.it.",Biomarkers,,,,
32598268,"Neha R,Beulah E,Anusha B,Vasista S,Stephy C,Subeesh V",Vemurafenib Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Disproportionality Analysis in FAERS Database.,"Signal strength for any drug event combination can be determined using disproportionality analysis. Vemurafenib is a BRAF inhibitor approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of metastatic melanoma. This study aims to identify the signal strength of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with vemurafenib using disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS).,Data were obtained from the public release of data in FAERS. Case/non-case method was adopted for the analysis of association between vemurafenib use and DRESS. The data mining algorithm used for the analysis was Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE>1\, PRR≥2 were considered as positive signal strength.,A total of 7\,171 reports for DRESS have been reported in the FDA database. Amongst which 125 reports were associated with vemurafenib. A cumulative ROR of 17.72 (95% CI 14.83; 21.18) and PRR of 17.46 (95% CI 14.65; 20.81) were observed. Combination treatment of vemurafenib with cobimetinib had higher number of reports (100) with ROR of 103.42 (84.13- 127.14) and PRR of 94.52 (78.26- 114.15). Four deaths were reported and the non-death serious reports included hospitalization\, life-threatening\, disability\, and other serious events with 61\, 11\, 2 and 39 reports respectively.,Positive signal strength was observed for vemurafenib associated DRESS. The signal strength was higher for vemurafenib in combination with cobimetinib than vemurafenib alone. Health care professionals should be cautious about encountering serious adverse events and should be reported to the regulatory authorities.",Current clinical pharmacology,vol.::,2020,Journal Article,,,"Department of Pharmacy Practice\, Faculty of Pharmacy\, M S Ramaiah University of Applied Sciences\, Bengaluru. India.,Department of Pharmacy Practice\, Faculty of Pharmacy\, M S Ramaiah University of Applied Sciences\, Bengaluru. India.,Department of Pharmacy Practice\, Faculty of Pharmacy\, M S Ramaiah University of Applied Sciences\, Bengaluru. India.,Department of Pharmacy Practice\, Faculty of Pharmacy\, M S Ramaiah University of Applied Sciences\, Bengaluru. India.,Department of Pharmacy Practice\, Faculty of Pharmacy\, M S Ramaiah University of Applied Sciences\, Bengaluru. India.,Department of Pharmacy Practice\, Faculty of Pharmacy\, M S Ramaiah University of Applied Sciences\, Bengaluru. India.",,,,,"Disproportionality,Drug Reaction with Eosinophilia and Systemic Symptoms,FAERS,Vemurafenib"
32600657,"Ge R,Chang Y,Gan Y,Zhu H,Liu C",Histiocytic sarcoma arising from thyroid gland with BRAF V600E mutation.,,Pathology,vol.52:5:603-605,2020,"Research Support, Non-U.S. Gov't",,,"Department of Diagnosis\, Ningbo Diagnostic Pathology Center\, Ningbo\, China.,Department of Pathology\, Shibei Hospital\, Shanghai\, China. Electronic address: 18518827@qq.com.,Department of Diagnosis\, Ningbo Diagnostic Pathology Center\, Ningbo\, China.,Department of Radiology\, Ningbo Medical Center Lihuili Hospital\, Ningbo\, China.,Department of Diagnosis\, Ningbo Diagnostic Pathology Center\, Ningbo\, China.",,,,,
32601947,"Kelly ZR,Gorantla VC,Davar D",The Role of Neoadjuvant Therapy in Melanoma.,"Neoadjuvant therapy in melanoma is an area of active investigation with numerous completed and ongoing trials studying a variety of therapeutic interventions utilizing diverse designs. Here\, we review completed and ongoing neoadjuvant trials in melanoma\, discuss endpoint assessment\, and highlight biomarker development in this context.,High-risk resectable melanoma with clinically detectable lymph node (LN) with or without in-transit and/or satellite metastases represent ~ 20% of melanoma patients and have a high risk of relapse despite definitive surgery. Adjuvant therapy with anti-PD-1 immunotherapy or BRAF/MEK-targeted therapy has improved relapse-free survival (RFS) and overall survival (OS) in large phase III trials and is approved for this indication. However\, despite surgery and adjuvant therapy\, many patients relapse and/or experience treatment-related toxicity\, underscoring the need to identify and understand mechanisms of response and resistance. In melanoma\, neoadjuvant therapy is an active area of research with numerous completed and ongoing trials utilizing FDA-approved and novel agents with intriguing results. Neoadjuvant therapy for regionally metastatic disease is an established standard in multiple cancers\, where it has been shown to improve operability\, facilitate biomarker development\, and even is a registrational endpoint for drug development in breast cancer. Recently\, a spate of neoadjuvant studies in melanoma has looked at a swathe of agents with promising clinical and biomarker results. Coordinated efforts are underway to translate these findings to earlier stage disease while prioritizing the evaluation of new strategies in unresectable disease.",Current oncology reports,vol.22:8:80,2020,"Research Support, Non-U.S. Gov't",,,"University of Pittsburgh and Department of Medicine\, UPMC Cancer Pavilion\, 5150 Centre Avenue\, Room 463\, Pittsburgh\, PA\, 15232\, USA.,UPMC Hillman Cancer Center\, 5115 Centre Ave. Floor\, Pittsburgh\, PA\, 15232\, USA.,University of Pittsburgh and Department of Medicine\, Hillman Cancer Center Research Pavilion\, 5115 Centre Avenue\, Suite 1.32d\, Pittsburgh\, PA\, 15232\, USA. davard@upmc.edu.",,,,,"Adjuvant,Anti-PD1,BRAF,Biomarker,Immunotherapy,Interferon,Ipilimumab,MEK,Melanoma,Neoadjuvant,Nivolumab,Pathologic complete response,Pembrolizumab,Recurrence,Survival,TVEC"
32605254,"Tomasova K,Cumova A,Seborova K,Horak J,Koucka K,Vodickova L,Vaclavikova R,Vodicka P","DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome.","There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, highpenetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.",Cancers,vol.12:7:,2020,Review,,,"Department of Molecular Biology of Cancer\, Institute of Experimental Medicine of the Czech Academy of Sciences\, Videnska 1083\, 14220 Prague\, Czech Republic.,Department of Molecular Biology of Cancer\, Institute of Experimental Medicine of the Czech Academy of Sciences\, Videnska 1083\, 14220 Prague\, Czech Republic.,Toxicogenomics Unit\, National Institute of Public Health\, obarova 48\, 10042 Prague\, Czech Republic.,Department of Molecular Biology of Cancer\, Institute of Experimental Medicine of the Czech Academy of Sciences\, Videnska 1083\, 14220 Prague\, Czech Republic.,Toxicogenomics Unit\, National Institute of Public Health\, obarova 48\, 10042 Prague\, Czech Republic.,Department of Molecular Biology of Cancer\, Institute of Experimental Medicine of the Czech Academy of Sciences\, Videnska 1083\, 14220 Prague\, Czech Republic.,Toxicogenomics Unit\, National Institute of Public Health\, obarova 48\, 10042 Prague\, Czech Republic.,Department of Molecular Biology of Cancer\, Institute of Experimental Medicine of the Czech Academy of Sciences\, Videnska 1083\, 14220 Prague\, Czech Republic.",,"Grantová Agentura České Republiky,Agentura Pro Zdravotnický Výzkum České Republiky,Ministerstvo Školství\, Mládeže a Tělovýchovy,Ministerstvo Školství\, Mládeže a Tělovýchovy,Univerzita Karlova v Praze,Univerzita Karlova v Praze",",,,,,","19-10543S,NV-18/03/00199,LTC19020,(NPU I) Nr. LO1503,PROGRES Q 28,UNCE/MED/006","DNA repair,carcinogenesis,ovarian cancer,prognosis,therapy response"
32606919,"Chen Y,Yang Y,Gu J",Clinical Implications of the Associations Between Intestinal Microbiome and Colorectal Cancer Progression.,"Intestinal microbiome influences host immunity and several diseases, including cancer, in their areas of colonization. Microbial dysbiosis and over-colonization of specific microbes within the colorectal mucosa can impact the progress of carcinogenesis. Investigations initially focused on the mechanisms by which the intestinal microbiome initiates or promotes the development of colorectal cancer, including DNA damage, induction of chromosomal instability, and regulation of host immune responses. Some studies on the clinicopathological features have reported that specific strains present at high abundance are associated with advanced stage and positive lymph nodes in colorectal cancer. In this context, we reviewed the relationship between the intestinal microbiome and the clinical features (patient age, disease staging, prognosis, etc.) of patients with colorectal cancer, and evaluated the potential pathogenesis caused by the intestinal microbiome in disease progress. This article assessed whether changes in distinct species or strains occur during the period of cancer advancement. Overall, age grouping does not bring about significant differences in the constitution of microbiome. The disease stages show their distinct distribution in some species and strains. Oncogenic species are generally enriched in patients with poor prognosis, including low infiltration of CD3+ T cells, poor differentiation, widespread invasion, high microsatellite instability, CpG island methylator phenotype, BRAF mutation, short overall survival, and disease-free survival. The implications of those changes we discussed may assist in comprehensive understanding of the tumorigenesis of colorectal cancer from a microbiological perspective, finding potential biomarkers for colorectal cancer.",Cancer management and research,vol.12::4117-4128,2020,Review,,,"Department of Gastrointestinal Surgery III\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing 100142\, People's Republic of China.,0000-0002-4225-547XDepartment of Gastrointestinal Surgery III\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing 100142\, People's Republic of China.,0000-0001-6277-9062Department of Gastrointestinal Surgery III\, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)\, Peking University Cancer Hospital & Institute\, Beijing 100142\, People's Republic of China.",,,,,"colorectal cancer,disease stage,intestinal microbiome,patient age,prognosis"
32609446,"Nguyen JK,Schlichte MJ,Jogi R,Alikhan M,Patel AB",A case of new-onset vitiligo in a patient on tofacitinib and brief review of paradoxical presentations with other novel targeted therapies.,"With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects.",Dermatology online journal,vol.26:3:,2020,Review,"|Adult|,|Arthritis\, Rheumatoid|complications|drug therapy|,|Female|,|Hidradenitis Suppurativa|chemically induced|,|Humans|,|Janus Kinase Inhibitors|adverse effects|therapeutic use|,|Keratoacanthoma|chemically induced|,|Melanoma|chemically induced|,|Piperidines|adverse effects|therapeutic use|,|Programmed Cell Death 1 Receptor|antagonists & inhibitors|,|Protein Kinase Inhibitors|adverse effects|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|,|Psoriasis|chemically induced|drug therapy|,|Pyrimidines|adverse effects|therapeutic use|,|Pyrroles|adverse effects|therapeutic use|,|Tumor Necrosis Factor-alpha|antagonists & inhibitors|,|Vitiligo|chemically induced|",,",,,,Department of Dermatology\, Division of Internal Medicine\, University of Texas MD Anderson Cancer Center\, Houston\, TX Department of Dermatology\, University of Texas Health Science Center at Houston\, Houston\, TX. APatel11@mdanderson.org.","Janus Kinase Inhibitors,Piperidines,Programmed Cell Death 1 Receptor,Protein Kinase Inhibitors,Pyrimidines,Pyrroles,Tumor Necrosis Factor-alpha,tofacitinib,Proto-Oncogene Proteins B-raf",,,,
32610387,"Xie M,Guan WB,Wang RF,Qiao M,Jiang RQ,Yu WW,Wang LF",[Expression and clinical significance of BRAF V600E in children with Langerhans cell histiocytosis].,,Zhonghua bing li xue za zhi = Chinese journal of pathology,vol.49:7:733-735,2020,Journal Article,"|Child|,|DNA Mutational Analysis|,|Histiocytosis\, Langerhans-Cell|,|Humans|,|Mutation|,|Proto-Oncogene Proteins B-raf|metabolism|",,"Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China(is working on Department of Pathology\, Hainan Women and Children's Medical Center (Hainan Maternal and Child Health Hospital)\, Haikou 570206\, China).,Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China.,Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China.,Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China.,Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China.,Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China.,Department of Pathology\, Xinhua Hospital\, Shanghai Jiaotong University School of Medicine\, Shanghai 200092\, China.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,
32612457,"Najmuddin SUFS,Amin ZM,Tan SW,Yeap SK,Kalyanasundram J,Ani MAC,Veerakumarasivam A,Chan SC,Chia SL,Yusoff K,Alitheen NB","Cytotoxicity study of the interleukin-12-expressing recombinant Newcastle disease virus strain, rAF-IL12, towards CT26 colon cancer cells in vitro and in vivo.","Oncolytic viruses have emerged as an alternative therapeutic modality for cancer as they can replicate specifically in tumour cells and induce toxic effects leading to apoptosis. Despite the great potentials and promising results shown in multiple studies\, it appears that their efficacy is still moderate and deemed as not sufficient in clinical studies. In addressing this issue\, genetic/molecular engineering approach has paved its way to improve the therapeutic efficacy as observed in the case of herpes simplex virus (HSV) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). This study aimed to explore the cytotoxicity effects of recombinant NDV strain AF2240-i expressing interleukin-12 (rAF-IL12) against CT26 colon cancer cells.,The cytotoxicity effect of rAF-IL12 against CT26 colon cancer cell line was determined by MTT assay. Based on the IC50 value from the anti-proliferative assay\, further downward assays such as Annexin V FITC and cell cycle progression were carried out and measured by flow cytometry. Then\, the in vivo study was conducted where the rAF-IL12 viral injections were given at the intra-tumoral site of the CT26 tumour-burden mice. At the end of the experiment\, serum biochemical\, T cell immunophenotyping\, serum cytokine\, histopathology of tumour and organ section\, TUNEL assay\, and Nanostring gene expression analysis were performed.,The rAF-IL12 induced apoptosis of CT26 colon cancer cells in vitro as revealed in the Annexin V FITC analysis and also arrested the cancer cells progression at G1 phase of the cell cycle analysis. On the other hand\, the rAF-IL12 significantly (p < 0.05) inhibited the growth of CT26 tumour in Balb/c mice and had regulated the immune system by increasing the level of CD4 + \, CD8 + \, IL-2\, IL-12\, and IFN-γ. Furthermore\, the expression level of apoptosis-related genes (bax and p53) was up-regulated as a result of the rAF-IL12 treatment. Additionally\, the rAF-IL12 had also down-regulated the expression level of KRAS\, BRAF\, MAPK1\, Notch1\, CCL2\, and VEGF oncogenes. Besides\, rAF-IL12 intra-tumoral delivery was considered safe and not hazardous to the host as evidenced in pathophysiology of the normal tissues and organs of the mice as well as from the serum biochemistry profile of liver and kidney.,These results indicated that rAF-IL12 had better anti-tumoral and cytotoxicity effects compared to its parental wild-type\, AF2240-i in combatting the CT26 colon cancer model.",Cancer cell international,vol.20::278,2020,Journal Article,,,"Institute of Bioscience\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,Institute of Bioscience\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,Institute of Bioscience\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,Xiamen University Malaysia\, Jalan Sunsuria\, Bandar Sunsuria\, Sepang\, Selangor Darul Ehsan Malaysia.,Faculty of Biotechnology and Biomolecular Sciences\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,Faculty of Biotechnology and Biomolecular Sciences\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,Sunway University\, 5\, Jalan Universiti\, Bandar Sunway\, Subang Jaya\, 47500 Selangor Darul Ehsan Malaysia.,School of Foundation Studies\, Perdana University\, Block B and D1\, MAEPS Building\, MARDI Complex\, Jalan MAEPS Perdana\, 43400 Serdang\, Selangor Darul Ehsan Malaysia.,Institute of Bioscience\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,Faculty of Biotechnology and Biomolecular Sciences\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.,0000-0003-1966-8580Institute of Bioscience\, Universiti Putra Malaysia\, Serdang\, Selangor Darul Ehsan 43400 Malaysia.",,,,,"Apoptosis,Colon cancer,Immune systems,Recombinant NDV"
32612709,"Giunta EF,De Falco V,Napolitano S,Argenziano G,Brancaccio G,Moscarella E,Ciardiello D,Ciardiello F,Troiani T",Optimal treatment strategy for metastatic melanoma patients harboring mutations.,"BRAF-V600 mutations occur in approximately 50% of patients with metastatic melanoma. Immune-checkpoint inhibitors and targeted therapies are both active as first-line treatments in these patients regardless of their mechanisms of action and toxicities. However, an upfront therapeutic strategy is still controversial. In fact, waiting for results of ongoing clinical trials and for new biomarkers, clinicians should base their decision on the clinical characteristics of the patient and on the biological aspects of the tumor. This review provides an overview on BRAF-V600 mutations in melanoma and will discuss their prognostic and clinical significance. Moreover, it will suggest a therapeutic algorithm that can drive therapeutic choice in a first-line setting for BRAF-V600 mutant melanoma patients.",Therapeutic advances in medical oncology,vol.12::1758835920925219,2020,Review,,,"https://orcid.org/0000-0002-5383-4469Medical Oncology\, Department of Precision Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Medical Oncology\, Department of Precision Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Medical Oncology\, Department of Precision Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Dermatology Unit\, Department of Mental and Physical Health and Preventive Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Dermatology Unit\, Department of Mental and Physical Health and Preventive Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Dermatology Unit\, Department of Mental and Physical Health and Preventive Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Medical Oncology\, Department of Precision Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Medical Oncology\, Department of Precision Medicine\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Naples\, Italy.,Dipartimento di Medicina di Precisione\, Università degli Studi della Campania ""Luigi Vanvitelli""\, Via S Pansini 5\, Naples 80131\, Italy.",,,,,"BRAF-V600 mutations,immunotherapy,metastatic melanoma,prognostic biomarker,targeted therapy"
32615728,"Suh S,Goh TS,Kim YH,Oh SO,Pak K,Seok JW,Kim IJ",Development and Validation of a Risk Scoring System Derived from Meta-Analyses of Papillary Thyroid Cancer.,"The aim of this study was to develop a scoring system to stratify the risk of papillary thyroid cancer (PTC) and to select the proper management.,We performed a systematic search of MEDLINE and Embase. Data regarding patients' prognoses were obtained from the included studies. Odds ratios (ORs) with statistical significance were extracted from the publications. To generate a risk scoring system (RSS)\, ORs were summed (RSS1)\, and summed after natural-logarithmic transformation (RSS2). RSS1 and RSS2 were compared to the eighth edition of the American Joint Committee on Cancer (AJCC) staging system and the 2015 American Thyroid Association (ATA) guidelines for thyroid nodules and differentiated thyroid carcinoma.,Five meta-analyses were eligible for inclusion in the study. Eight variables (sex\, tumour size\, extrathyroidal extension\, BRAF mutation\, TERT mutation\, histologic subtype\, lymph node metastasis\, and distant metastasis) were included. RSS1 was the best of the analysed models.,We developed and validated a new RSS derived from previous meta-analyses for patients with PTC. This RSS seems to be superior to previously published systems.","Endocrinology and metabolism (Seoul, Korea)",vol.35:2:435-442,2020,Journal Article,,,"Department of Internal Medicine\, Dong-A University College of Medicine\, Busan\, Korea.,Department of Orthopaedic Surgery and Biomedical Research Institute\, Pusan National University Hospital\, Busan\, Korea.,Department of Anatomy\, Pusan National University School of Medicine\, Yangsan\, Korea.,Department of Anatomy\, Pusan National University School of Medicine\, Yangsan\, Korea.,Department of Nuclear Medicine and Biomedical Research Institute\, Pusan National University Hospital\, Busan\, Korea.,Department of Nuclear Medicine\, Chung-Ang University College of Medicine\, Seoul\, Korea.,Department of Nuclear Medicine and Biomedical Research Institute\, Pusan National University Hospital\, Busan\, Korea.",,,,," Prognosis, Recurrence,Thyroid cancer\, papillary"
31543246,"Coura BP,de Resende TAC,de Menezes VCB,Bernardes VF,de Sousa SF,Diniz MG,Gomez RS,Gomes CC",Assessing pathogenic mutations in dental follicles as an attempt to identify early events in odontogenic tumours tumourigenesis.,"Driver oncogenic mutations have been reported in several benign neoplasms. While ameloblastomas show BRAF p.V600E mutations\, adenomatoid odontogenic tumours harbour either KRAS p.G12R or p.G12 V. The lack of understanding of the core molecular changes involved in tumour initiation and progression represents a critical barrier to developing new strategies for cancer detection and prevention. Considering the fact that ameloblastoma and adenomatoid odontogenic tumours can originate from dental follicles\, we hypothesized that the BRAF and KRAS mutations might be early events in odontogenic tumours tumourigenesis. We aimed to assess BRAF and KRAS mutations in dental follicles associated with asymptomatic impacted teeth.,Forty-eight dental follicles containing odontogenic epithelial remnants were included in the study. As ameloblastomas most often occur in the posterior mandible and adenomatoid odontogenic tumours have a predilection for the anterior jaws\, we assessed by allele-specific qPCR the presence of BRAF p.V600E in 32 dental follicles associated with impacted 3rd mandibular molar teeth and KRAS p.G12 V and KRAS p.G12R mutations in 16 dental follicle specimens obtained from around impacted anterior teeth. Sanger sequencing was used as an additional method.,None of the dental follicle cases tested positive for the mutations.,In conclusion\, we tried to detect the early genetic events associated with odontogenic tumours development in dental follicles\, but we were unable to showcase that BRAF p.V600E and KRAS p.G12R or p.G12 V mutations are the early genetic events associated with odontogenic tumours development.",Archives of oral biology,vol.113::104523,2020,Journal Article,"|Adenoma|genetics|,|Carcinogenesis|,|Dental Sac|pathology|,|Humans|,|Mutation|,|Odontogenic Tumors|genetics|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|",,"Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil.,Department of Oral Surgery and Pathology\, School of Dentistry\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil. Electronic address: rsgomez@ufmg.br.,Department of Pathology\, Biological Sciences Institute\, Universidade Federal de Minas Gerais (UFMG)\, Belo Horizonte\, Brazil. Electronic address: carolinacgomes@ufmg.br.","KRAS protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)",,,,"Benign tumour,Genetics,Mutation,Normal tissue,Odontogenesis,Odontogenic tumour"
31545109,"Jin J,Shi Y,Zhang S,Yang S"," mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis.","Background: There is conflicting evidence regarding the association between PIK3CA mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between PIK3CA mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of PIK3CA mutations in CRC.Materials and Methods: A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between PIK3CA mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of PIK3CA mutations on outcome parameters.Results: Forty-four studies enrolling 17621 patients were eligible for inclusion. PIK3CA mutations were associated with proximal tumor location, mucinous differentiation, KRAS mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that PIK3CA exon 9 mutations were positively associated with proximal tumor location and KRAS mutations, and negatively associated with BRAF mutations and MSI; exon 20 mutations were associated with proximal tumor location, KRAS mutations, BRAF mutations and MSI.Conclusions: Our findings suggest that overall or exon-specific PIK3CA mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC. As PIK3CA mutations were found to be closely associated with KRAS mutations, their relationship warrants further investigation. Since PIK3CA exon 9 and 20 mutations showed different tendencies with regard to BRAF mutation and MSI status, they may have distinct molecular impacts on CRC.","Acta oncologica (Stockholm, Sweden)",vol.59:1:66-74,2020,Systematic Review,"|Class I Phosphatidylinositol 3-Kinases|genetics|,|Colorectal Neoplasms|genetics|metabolism|pathology|,|Humans|,|Microsatellite Instability|,|Mutation|,|Neoplasm Grading|,|Prognosis|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Signal Transduction|",,"Department of Medical Oncology\, Fudan University Shanghai Cancer Center\, Shanghai\, China.,Department of Medical Oncology\, the First Hospital Affiliated to Soochow University\, Suzhou\, China.,Department of Gynecological Oncology\, Fudan University Shanghai Cancer Center\, Shanghai\, China.,Department of Vascular Surgery\, Renji Hospital\, School of Medicine\, Shanghai Jiaotong University\, Shanghai\, China.","KRAS protein\, human,Class I Phosphatidylinositol 3-Kinases,PIK3CA protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)",,,,
31557757,"Busico A,Maisonneuve P,Prinzi N,Pusceddu S,Centonze G,Garzone G,Pellegrinelli A,Giacomelli L,Mangogna A,Paolino C,Belfiore A,Kankava K,Perrone F,Tamborini E,Pruneri G,Fazio N,Milione M","Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin.","In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs)\, Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3\, neuroendocrine carcinoma (NEC) <55%\, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets\, including PD-L1.,In GEP-NEN patients\, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS).,Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53\, 32.9%; KRAS\, 5.5%; BRAF\, 4.1%) were detected in 46.6% NENs\, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3\, 1.8 years in NEC <55%\, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type\, 0.7 years with ≥1 mutation (p <0.0001)\, 0.8 years in PD-L1-positive patients\, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis\, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3\, HR 14.1\, 95% CI 2.2-89.8\, p = 0.005; NEC ≥55% vs. NET G3\, HR 25.8\, 95% CI 3.9-169\, p = 0.0007).,These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.",Neuroendocrinology,vol.110:7-8:616-629,2020,Journal Article,,,"1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,Division of Epidemiology and Biostatistics\, IEO\, European Institute of Oncology IRCCS\, Milan\, Italy.,Medical Oncology Department\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,Medical Oncology Department\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,Department of Pathology\, ASST Franciacorta\, Mellino Mellini Hospital\, Chiari\, Brescia\, Italy.,Department of Surgical Sciences and Integrated Diagnostics\, School of Medicine\, University of Genoa\, Genoa\, Italy.,Pathology Unit\, Clinical Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Ospedale di Cattinara\, Trieste\, Italy.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,Teaching\, Scientific and Diagnostic Pathology Laboratory\, Tbilisi State Medical University\, Tbilisi\, Georgia.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy.,School of Medicine\, University of Milan\, Milan\, Italy.,Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors\, IEO\, European Institute of Oncology IRCCS\, Milan\, Italy.,1st Pathology Division\, Department of Pathology and Laboratory Medicine\, Fondazione IRCCS - Istituto Nazionale dei Tumori\, Milan\, Italy\, Massimo.milione@istitutotumori.mi.it.",,,,,"Ki-67,Neuroendocrine tumor G3,PD-L1,Targeted next-generation sequencing"
31562035,"Morice A,Neiva C,Fabre M,Spina P,Jouenne F,Galliani E,Vazquez MP,Picard A",Conservative management is effective in unicystic ameloblastoma occurring from the neonatal period: A case report and a literature review.,"Unicystic ameloblastoma (UA), a benign odontogenic tumor of the jaw, represents less than a third of all ameloblastomas and seems less aggressive than other types of ameloblastoma. We present here the first case of UA that developed prenatally and was successfully managed in the early neonatal period with marsupialization and curettage performed carefully to avoid injury to the tooth germ. BRAF and SMO mutations were not detected. After 2 years of follow-up, complete reossification and normal eruption of deciduous teeth were noted, and there was no recurrence of UA. We recommend conservative treatment of UA in the pediatric population to avoid loss of and/or injury to the tooth germ, provided close follow-up is carried out all through the individual's growth for early detection of potential recurrences, growth impairments, or tooth eruption disorders. The intratumoral somatic mutational status of BRAF, SMO, RAS family, and FGFR2 may help determine personalized targeted treatment, particularly in case of recurrence.","Oral surgery, oral medicine, oral pathology and oral radiology",vol.129:5:e234-e242,2020,Review,"|Ameloblastoma|,|Child|,|Conservative Treatment|,|Humans|,|Infant\, Newborn|,|Mutation|,|Neoplasm Recurrence\, Local|,|Odontogenic Tumors|",,"Department of Maxillofacial and Plastic Surgery\, Rare Diseases Reference Center Coordinator for Clefts and Facial Malformations\, Hôpital Universitaire Necker-Enfants Malades\, Paris\, France; Université Paris Descartes-Sorbonne Paris Cité\, Paris\, France. Electronic address: annemoriceaertgeerts@gmail.com.,Department of Maxillofacial and Plastic Surgery\, Rare Diseases Reference Center Coordinator for Clefts and Facial Malformations\, Hôpital Universitaire Necker-Enfants Malades\, Paris\, France.,Department of Pathology\, Hôpital Universitaire Necker-Enfants Malades\, Assistance Publique-Hôpitaux de Paris\, and Université Paris Descartes\, Paris\, France.,Cantonal Institute of Pathology\, Locarno\, Switzerland; Department of Health Sciences\, University of Eastern Piedmont\, Novara\, Italy.,Genomic of Solid Tumors Department\, Hôpital Saint-Louis\, Assistance Publique-Hôpitaux de Paris; Université Paris-Diderot\, Sorbonne Paris Cité\, Paris\, France.,Department of Maxillofacial and Plastic Surgery\, Rare Diseases Reference Center Coordinator for Clefts and Facial Malformations\, Hôpital Universitaire Necker-Enfants Malades\, Paris\, France.,Department of Maxillofacial and Plastic Surgery\, Rare Diseases Reference Center Coordinator for Clefts and Facial Malformations\, Hôpital Universitaire Necker-Enfants Malades\, Paris\, France; Université Paris Descartes-Sorbonne Paris Cité\, Paris\, France.,Department of Maxillofacial and Plastic Surgery\, Rare Diseases Reference Center Coordinator for Clefts and Facial Malformations\, Hôpital Universitaire Necker-Enfants Malades\, Paris\, France; Université Paris Descartes-Sorbonne Paris Cité\, Paris\, France.",,,,,
31566049,"Zhang Q,Young GQ,Yang Z",Pure Discrete Punctate Nuclear Staining Pattern for MLH1 Protein Does Not Represent Intact Nuclear Expression.,"Immunohistochemical staining for DNA mismatch repair (MMR) proteins is commonly used to screen for Lynch syndrome. Several laboratories have noticed a discrete punctate nuclear staining pattern for MLH1 that caused confusion in interpretation. This study was designed to investigate whether this particular staining pattern represents intact nuclear expression of MLH1. MMR proteins immunostaining and follow-up testing in 161 consecutive colorectal adenocarcinoma cases (86 biopsies, 75 resections) were retrospectively reviewed. Both discrete punctate nuclear staining and diffuse nuclear staining patterns for MLH1 were observed in internal control cells in 76 biopsies and 27 resections. Only diffuse nuclear staining was seen in the remaining 10 biopsies and 48 resections (P < .0001). Pure discrete punctate nuclear staining pattern for MLH1 was observed in 11 tumors (9 biopsies, 2 resections), and completely negative staining was seen in 13 tumors (2 biopsies, 11 resections; P = .003). Those 24 tumors (21 patients) invariably showed loss of PMS2. Three patients whose biopsies showed pure punctate staining for MLH1 underwent repeat testing on resections: 1 retained the punctate staining and 2 showed complete loss of MLH1. Nine patients who showed loss of PMS2 and pure punctate MLH1 staining underwent molecular testing: 4 had BRAF V600E mutations and 1 had MLH1 gene mutation. Our data showed that discrete punctate nuclear staining for MLH1 is more commonly seen in biopsy specimens. Pure discrete punctate staining pattern is paired with loss of PMS2 expression and may be associated with BRAF or MLH1 gene mutation, thus it should not be interpreted as intact nuclear expression.",International journal of surgical pathology,vol.28:2:146-152,2020,Journal Article,"|Adenocarcinoma|diagnosis|metabolism|pathology|,|Adult|,|Aged|,|Aged\, 80 and over|,|Biopsy|,|Cell Nucleus|metabolism|pathology|,|Colorectal Neoplasms|diagnosis|metabolism|pathology|,|Colorectal Neoplasms\, Hereditary Nonpolyposis|diagnosis|metabolism|pathology|,|DNA Mismatch Repair|,|Female|,|Humans|,|Male|,|Middle Aged|,|MutL Protein Homolog 1|metabolism|,|Retrospective Studies|",,"Penn State Health Milton S. Hershey Medical Center\, Hershey\, PA\, USA.,New York University\, New York\, NY\, USA.,https://orcid.org/0000-0001-8121-5721Penn State Health Milton S. Hershey Medical Center\, Hershey\, PA\, USA.",MutL Protein Homolog 1,,,,"DNA mismatch repair,Lynch syndrome,colorectal neoplasms,hereditary nonpolyposis,immunohistochemistry"
31571052,"Graf W,Cashin PH,Ghanipour L,Enblad M,Botling J,Terman A,Birgisson H",Prognostic Impact of BRAF and KRAS Mutation in Patients with Colorectal and Appendiceal Peritoneal Metastases Scheduled for CRS and HIPEC.,"KRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer\, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore\, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC.,In a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017\, 111 subjects with peritoneal metastases from primaries of the appendix\, colon\, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation.,Mutation in KRAS was present in 51/111 (46%)\, and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type\, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis\, completeness of cytoreduction score (CCS\, p = 0.000001)\, presence of signet cell differentiation (p = 0.000001)\, and BRAF mutation (p = 0.0021) were linked with poor prognosis.,BRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC\, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.",Annals of surgical oncology,vol.27:1:293-300,2020,Journal Article,"|Adenocarcinoma|genetics|mortality|pathology|therapy|,|Aged|,|Antineoplastic Combined Chemotherapy Protocols|therapeutic use|,|Appendiceal Neoplasms|genetics|mortality|pathology|therapy|,|Biomarkers\, Tumor|genetics|,|Colorectal Neoplasms|genetics|mortality|pathology|therapy|,|Combined Modality Therapy|,|Cytoreduction Surgical Procedures|,|Female|,|Humans|,|Hyperthermia\, Induced|,|Male|,|Middle Aged|,|Mutation|,|Peritoneal Neoplasms|secondary|,|Prognosis|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Survival Rate|",,"Department of Surgical Sciences\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden. Wilhelm.graf@surgsci.uu.se.,Department of Surgical Sciences\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden.,Department of Surgical Sciences\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden.,Department of Surgical Sciences\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden.,Department of Immunology\, Genetics and Pathology\, Clinical and Experimental Pathology\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden.,Department of Immunology\, Genetics and Pathology\, Clinical and Experimental Pathology\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden.,Department of Surgical Sciences\, Akademiska sjukhuset\, Uppsala University\, Uppsala\, Sweden.","Biomarkers\, Tumor,KRAS protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)",The Swedish Cancer Society,,150767,
32358694,"Hua X,Newcomb PA,Chubak J,Malen RC,Ziebell R,Kamineni A,Zhu LC,Upton MP,Wurscher MA,Thomas SS,Newman H,Hardikar S,Burnett-Hartman AN",Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia.,"BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies\, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia.,Study subjects included Kaiser Permanente Washington members aged 20-75 years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation\, CpG island methylator phenotype (CIMP)\, and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia\, comparing index serrated polyps with different molecular markers.,We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant\, CIMP-high\, and MLH1-methylated serrated polyps were 51%\, 4%\, and 2%\, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66\, 95% CI 1.06-20.51).,Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps\, MLH1 methylation may be an important marker to identify high-risk CRC precursors.",Cancer causes & control : CCC,vol.31:7:631-640,2020,Journal Article,"|Adenoma|genetics|pathology|,|Adult|,|Aged|,|Case-Control Studies|,|Colonoscopy|,|Colorectal Neoplasms|epidemiology|genetics|pathology|,|Cross-Sectional Studies|,|DNA Methylation|,|Female|,|Humans|,|Intestinal Polyps|epidemiology|genetics|pathology|,|Longitudinal Studies|,|Male|,|Middle Aged|,|Mutation|,|Phenotype|,|Proto-Oncogene Proteins B-raf|genetics|,|SEER Program|,|Washington|epidemiology|,|Young Adult|",,"School of Public Health\, University of Washington\, Seattle\, WA\, USA.,School of Public Health\, University of Washington\, Seattle\, WA\, USA.,School of Public Health\, University of Washington\, Seattle\, WA\, USA.,Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA.,Kaiser Permanente Washington Health Research Institute\, Seattle\, WA\, USA.,Kaiser Permanente Washington Health Research Institute\, Seattle\, WA\, USA.,Kaiser Permanente Washington Health Research Institute\, Seattle\, WA\, USA.,Department of Pathology\, University of Washington\, Seattle\, WA\, USA.,Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA.,Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA.,Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA.,Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA.,Fred Hutchinson Cancer Research Center\, Seattle\, WA\, USA. Andrea.N.Burnett-Hartman@kp.org.","BRAF protein\, human,Proto-Oncogene Proteins B-raf","NIH HHS,NIH HHS,NIH HHS,NIH HHS,NCI NIH HHS,NIH HHS","United States,United States,United States,United States,United States,United States","R01 CA097325,K07 CA222060,P01 CA074184,R01 CA168338,K07 CA222060,K05 CA152715","BRAF mutation,Biomarkers,Colorectal cancer,CpG island methylator phenotype,MLH1 methylation,Sessile serrated adenoma/polyp"
32360274,"Xu B,Ghossein R",Poorly differentiated thyroid carcinoma.,"Poorly differentiated thyroid carcinoma (PDTC) is an aggressive form of follicular cell derived thyroid carcinoma with a prognosis intermediate between the indolent well differentiated thyroid carcinomas and the rapidly growing often fatal anaplastic carcinoma. While all investigators agree on the presence of this entity, there is disagreement in regard to its definition. In 2006, a set of criteria based solely on mitotic index ≥5/10 high power fields and/or tumor necrosis was proposed by a group of researchers from Memorial Sloan Kettering Cancer Center (MSKCC criteria) in New York. A year later, alternative diagnostic criteria of PDTC, so called the Turin proposal, were advocated by an international consensus group. The Turin proposal requires three criteria: 1) solid/trabecular/insular growth pattern; 2) absence of nuclear features of papillary carcinoma; and 3) at least one of the following three features: mitotic index ≥3/10 high power fields (HPFs), necrosis, or convoluted nuclei. In this review, we summarize the histology, diagnostic criteria (Turin proposal and MSKCC criteria) with their pros and cons, the prognostic factors, and molecular profile of PDTC, aiming to provide a practical and compreshensive review of this challenging entity.",Seminars in diagnostic pathology,vol.37:5:243-247,2020,Review,,,"Department of Pathology\, Memorial Sloan Kettering Cancer Center\, 1275 York Avenue\, New York\, NY 10065\, U.S.,Department of Pathology\, Memorial Sloan Kettering Cancer Center\, 1275 York Avenue\, New York\, NY 10065\, U.S. Electronic address: ghosseir@mskcc.org.",,,,,"BRAF,Insular carcinoma,Poorly differentiated thyroid carcinoma,RAS,Turin proposal"
32360841,"Osman W,Hassoun A,Jelinek HF,Almahmeed W,Afandi B,Tay GK,Alsafar H",Genetics of type 2 diabetes and coronary artery disease and their associations with twelve cardiometabolic traits in the United Arab Emirates population.,"The United Arab Emirates (UAE) population has a high rate of type 2 diabetes mellitus (T2DM) and other metabolic risk factors for coronary artery disease (CAD). Previous studies have indicated strong genetic associations between T2DM and CAD. The objective of this study was to replicate previously reported significant genetic associations for T2DM and CAD which were in a genome-wide significance level in a cohort from the Arab population of the UAE\, and to investigate the associations of these loci with twelve cardiometabolic traits that may influence the development of T2DM and CAD.,A total of nine hundreds and fourteen Emiratis were recruited to this study to investigate associations of 101 loci for T2DM (422 patients and 455 controls)\, and 53 loci for CAD (160 patients and 245 controls)\, using logistic regression models which incorporating possible confounding factors. Results are presented using odds ratios with their corresponding 95% confidence intervals and p-values. Linear regression models\, which included possible covariates were applied to determine any associations between the T2DM and CAD reported loci with the twelve cardiometabolic traits and results were presented as effect sizes (beta)\, standard errors\, and p-values. Furthermore\, the overall risks for all the loci found to be associated with T2DM and CAD were determined using the cumulative effects of the risk alleles. For those found to be associated with the twelve cardiometabolic traits\, risks were determined using calculations of their polygenic risk scores.,The mean age of the T2DM group was 61.5 ± 11.3 and of the CAD group was 66.2 ± 9.3 years. The prevalence of most of the cardiovascular disease risk factors in this cohort were high: mean body mass index (BMI) = 29.4\, T2DM (51.9%)\, hypertension (60.9%)\, dyslipidemia (68.8%)\, and smoking (47.9%). All individuals who were tested for CAD (n = 405) also had a diagnosis of T2DM. The highest association variant for T2DM was in SNP rs1977833 in HHEX (p = 0.0016\, OR = 0.56 for allele A)\, which is a multi-ethnic locus for T2DM. The strongest association with CAD was detected with SNP rs264 in LPL\, which encodes lipoprotein lipase (p = 0.009\, OR = 1.96 for allele A). For the cardiometabolic traits analyses\, most notable associations were those of FTO with BMI and waist circumference; ABO with height; KCNK16 with diastolic blood pressure; PROX1-AS1\, GCKR\, and MIR129-LEP with fasting blood glucose; random blood glucose with ZEB2 and THADA; HbA1c levels with TLE1 and FAM99B loci; HDL-cholesterol levels with BRAF; and triglyceride levels with ZEB2. Furthermore\, accumulation of risk alleles and polygenic scores of the associated loci was clearly associated with increased risks for all tested diseases and traits in this cohort.,The present study highlighted many known genetic loci\, which are linked to T2DM and CAD and their associations with major cardiometabolic traits in Arab descendants. We confirmed that some loci are associated with T2DM\, CAD\, and metabolic traits independently of the ethnic background\, with a novel association also detected between height and ABO.",Gene,vol.750::144722,2020,Journal Article,"|Aged|,|Alpha-Ketoglutarate-Dependent Dioxygenase FTO|genetics|metabolism|,|Body Mass Index|,|Cohort Studies|,|Coronary Artery Disease|genetics|,|Diabetes Mellitus\, Type 2|genetics|,|Female|,|Genetic Predisposition to Disease|,|Genetic Variation|,|Genome-Wide Association Study|,|Humans|,|Male|,|Middle Aged|,|Myocardium|metabolism|,|Obesity|genetics|,|Odds Ratio|,|Risk Factors|,|United Arab Emirates|epidemiology|,|Waist Circumference|",,"College of Arts and Sciences\, Khalifa University\, Abu Dhabi\, United Arab Emirates; Khalifa University Center for Biotechnology\, Abu Dhabi\, United Arab Emirates.,Dubai Diabetes Centre\, Dubai Health Authority\, Dubai\, United Arab Emirates.,Clinical Medicine\, Macquarie University\, Sydney\, Australia; School of Community Health\, Charles Sturt University\, Albury\, Australia.,Heart and Vascular Institute\, Cleveland Clinic\, Abu Dhabi\, United Arab Emirates; Institute of Cardiac Science\, Sheikh Khalifa Medical City\, Abu Dhabi\, United Arab Emirates.,Endocrine Diabetes Center\, Tawam Hospital\, SEHA\, Al-Ain\, United Arab Emirates.,School of Health and Medical Sciences\, Edith Cowan University\, Australia; School of Psychiatry and Clinical Neurosciences\, University of Western Australia\, Australia.,Khalifa University Center for Biotechnology\, Abu Dhabi\, United Arab Emirates; Department of Biomedical Engineering\, Khalifa University\, United Arab Emirates; College of Medicine and Health Sciences\, Khalifa University\, United Arab Emirates. Electronic address: habiba.alsafar@ku.ac.ae.","Alpha-Ketoglutarate-Dependent Dioxygenase FTO,FTO protein\, human",,,,"Cardiometabolic traits,Coronary artery disease,Epidemiology,Genetics,Type 2 diabetes mellitus"
32361034,"Scheffler M,Holzem A,Kron A,Nogova L,Ihle MA,von Levetzow C,Fassunke J,Wömpner C,Bitter E,Koleczko S,Abdulla DSY,Michels S,Fischer R,Riedel R,Weber JP,Westphal T,Gerigk U,Kern J,Kaminsky B,Randerath W,Kambartel KO,Merkelbach-Bruse S,Büttner R,Wolf J",Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations.,"MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches\, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach.,Between 2012 and 2018\, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients\, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy.,We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking\, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients\, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable\, including EGFR mutations\, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment.,Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.","Lung cancer (Amsterdam, Netherlands)",vol.144::40-48,2020,Journal Article,,,"University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University of Cologne\, Cologne Institute of Pathology\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University of Cologne\, Cologne Institute of Pathology\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany.,GFO Clinics Bonn\, Marien-Hospital Bonn\, Bonn\, Germany.,KWM Missio Clinic\, Würzburg\, Germany.,Bethanien Hospital Solingen\, Clinic for Pulmonology and Allergology\, Solingen\, Germany.,Bethanien Hospital Solingen\, Clinic for Pulmonology and Allergology\, Solingen\, Germany.,Bethanien Hospital Moers\, Lung Center\, Moers\, Germany.,University of Cologne\, Cologne Institute of Pathology\, Cologne\, Germany.,University of Cologne\, Cologne Institute of Pathology\, Cologne\, Germany.,University Hospital of Cologne\, Lung Cancer Group Cologne\, Department I of Internal Medicine\, Cologne\, Germany. Electronic address: juergen.wolf@uk-koeln.de.",,,,,"MAP2K1,Non-small cell lung cancer,mutations,therapeutic options"
32361787,"Zhao Y,Pan Y,Cheng C,Zheng D,Zhang Y,Gao Z,Fu F,Li H,Zheng S,Zhuge L,Mao H,Kuang M,Tao X,Peng Y,Hu H,Xiang J,Li Y,Sun Y,Chen H",EGFR-mutant lung adenocarcinoma harboring co-mutational tumor suppressor genes predicts poor prognosis.,"EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However\, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinoma patients with co-mutation of EGFR and tumor suppressor genes.,From November 2009 to May 2016\, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples\, while direct sequencing of major driver genes\, including EGFR\, KRAS\, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes\, including TP53\, KEAP1\, MGA\, NF1\, RB1\, SMARCA4 and STK11\, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed.,The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%)\, respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%)\, while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations\, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010)\, while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007)\, worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018).,Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.",Journal of cancer research and clinical oncology,vol.146:7:1781-1789,2020,Journal Article,"|Adenocarcinoma of Lung|genetics|mortality|,|Biomarkers\, Tumor|,|ErbB Receptors|genetics|,|Follow-Up Studies|,|Genes\, Tumor Suppressor|,|Humans|,|Kaplan-Meier Estimate|,|Mutation|,|Prognosis|,|Proportional Hazards Models|,|Tumor Suppressor Protein p53|genetics|,|Whole Exome Sequencing|",,"Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,Department of Oncology\, Shanghai Medical College\, Fudan University\, Shanghai\, 200032\, China.,Department of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China.,http://orcid.org/0000-0002-1305-971XDepartment of Thoracic Surgery\, Fudan University Shanghai Cancer Center\, 270 Dong-An Road\, Shanghai\, 200032\, China. hqchen1@yahoo.com.","Biomarkers\, Tumor,Tumor Suppressor Protein p53,EGFR protein\, human,ErbB Receptors","Natural Science Foundation of China,Natural Science Foundation of China,Shanghai Shen Kang Hospital Development Center (CN),Shanghai Municipal Health Commission Key Discipline Project,Shanghai Municipal Health Commission Key Discipline Project",",,,,","81930073,81572253,SHDC12017102,2017ZZ02025,2017ZZ01019","Co-mutation,EGFR,Lung adenocarcinoma,Tumor suppressor genes,Unique subtype"
32365867,"Marin E,Teixido C,Carmona-Rocha E,Reyes R,Arcocha A,Viñolas N,Rodríguez-Mues M,Cabrera C,Sánchez M,Vollmer I,Castillo S,Muñoz S,Sullivan IG,Rodriguez A,Garcia M,Alos S,Jares P,Martinez A,Prat A,Molina-Vila MÁ,Reguart N",Usefulness of Two Independent DNA and RNA Tissue-Based Multiplex Assays for the Routine Care of Advanced NSCLC Patients.,"Personalized medicine is nowadays a paradigm in lung cancer management, offering important benefits to patients. This study aimed to test the feasibility and utility of embedding two multiplexed genomic platforms as the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients. Two parallel multiplexed approaches were performed based on DNA sequencing and direct digital detection of RNA with nCounter® technology to evaluate gene mutations and fusions. The results were used to guide genotype-directed therapies and patient outcomes were collected. A total of 224 advanced non-squamous NSCLC patients were prospectively included in the study. Overall, 85% of samples were successfully characterized at DNA and RNA levels and oncogenic drivers were found in 68% of patients, with KRAS, EGFR, METΔex14, BRAF, and ALK being the most frequent (31%, 19%, 5%, 4%, and 4%, respectively). Among all patients with complete genotyping results and follow-up data (n = 156), the median overall survival (OS) was 1.90 years (confidence interval (CI) 95% 1.69-2.10) for individuals harbouring an actionable driver treated with a matched therapy, compared with 0.59 years (CI 95% 0.39-0.79) in those not eligible for any targeted therapy and 0.61 years (CI 95% 0.12-1.10) in patients with no drivers identified (p < 0.001). Integrating DNA and RNA multiplexing technologies into the routine molecular testing of advanced NSCLC patients is feasible and useful and highlights the necessity of widespread integrating comprehensive molecular diagnosis into lung cancer care.",Cancers,vol.12:5:,2020,Journal Article,,,"Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,0000-0002-7226-6567Translational Genomics and Targeted Therapeutics in Solid Tumors\, Institut d'Investigacions Biomèdiques August Pi I Sunyer\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Instituto Oncologico Dr. Rosell\, Teknon Hospital\, 08028 Barcelona\, Spain.,Unitat Funcional de Tumors Toràcics\, Hospital Clínic\, 08036 Barcelona\, Spain.,Unitat Funcional de Tumors Toràcics\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Medical Oncology\, Hospital General de Granollers\, 08402 Barcelona\, Spain.,Division of Medical Oncology\, Hospital General de Granollers\, 08402 Barcelona\, Spain.,0000-0002-0434-3436Division of Medical Oncology\, Hospital de la Santa Creu i Sant Pau\, 08041 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Pathology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Pathology\, Hospital Clínic\, 08036 Barcelona\, Spain.,Division of Pathology\, Hospital Clínic\, 08036 Barcelona\, Spain.,0000-0003-0790-9017Division of Pathology\, Hospital Clínic\, 08036 Barcelona\, Spain.,0000-0003-2377-540XDivision of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.,0000-0001-8866-9881Laboratory of Oncology\, Pangaea Oncology\, Quirón Dexeus University Hospital\, 08028 Barcelona\, Spain.,Division of Medical Oncology\, Hospital Clínic\, 08036 Barcelona\, Spain.",,"Pfizer,Novartis,Acción Estratégica en Salud; Instituto de Salud Carlos III",",,","WI230526,CINC280AES01T,FIS16/00890\, PI N.Reguart.","advanced non-small cell lung cancer,molecular diagnostics,mutations,oncogenic drivers,targeted therapies"
32366411,"Miyauchi S,Shien K,Takeda T,Araki K,Nakata K,Miura A,Takahashi Y,Kurihara E,Ogoshi Y,Namba K,Suzawa K,Yamamoto H,Okazaki M,Soh J,Tomida S,Yamane M,Sakaguchi M,Toyooka S",Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic Mutation.,"The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120\, a newly discovered pan-RAF inhibitor\, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation.,We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments.,LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation.,LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.",Anticancer research,vol.40:5:2667-2673,2020,Journal Article,"|Animals|,|Antineoplastic Agents|pharmacology|,|Cell Line\, Tumor|,|Cell Proliferation|drug effects|,|Female|,|Humans|,|Inhibitory Concentration 50|,|Lung Neoplasms|genetics|,|Mice\, Inbred BALB C|,|Mice\, Nude|,|Mutation|genetics|,|Oncogenes|,|Phenylurea Compounds|pharmacology|,|Protein Kinase Inhibitors|pharmacology|,|Proto-Oncogene Proteins B-raf|genetics|,|Pyrimidines|pharmacology|,|Signal Transduction|drug effects|,|Xenograft Model Antitumor Assays|",,"Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan k.shien@okayama-u.ac.jp.,Department of Clinical Pharmacy\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Center for Comprehensive Genomic Medicine\, Okayama University Hospital\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of Cell Biology\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.,Department of General Thoracic\, Breast\, and Endocrinological Surgery\, Okayama University Graduate School of Medicine\, Dentistry and Pharmaceutical Sciences\, Okayama University\, Okayama\, Japan.","Antineoplastic Agents,LY3009120,Phenylurea Compounds,Protein Kinase Inhibitors,Pyrimidines,Proto-Oncogene Proteins B-raf",,,,"BRAF mutation,LY3009120,Pan-RAF inhibitor,non-small cell lung cancer"
32367668,"Augustin J,Calderaro J,Pujals A",BRAF-associated bile duct adenomatosis: a new entity?,,Histopathology,vol.77:1:160-161,2020,Letter,,,"0000-0001-8194-0624Pathology Department\, Assistance Publique Hôpitaux de Paris\, Groupe Hospitalier Henri Mondor\, Créteil\, France.,Pathology Department\, Assistance Publique Hôpitaux de Paris\, Groupe Hospitalier Henri Mondor\, Créteil\, France.,Pathology Department\, Assistance Publique Hôpitaux de Paris\, Groupe Hospitalier Henri Mondor\, Créteil\, France.",,,,,
32368160,"Jastania RA,Saeed M,Al-Khalidi H,AlQuthami K,Nageeti TH,Al-Allaf FA,Valerie K,Taher MM",Adamantinomatous Craniopharyngioma in an Adult: A Case Report with NGS Analysis.,"Several recent studies have documented CTNNB1 and BRAF mutations which are mutually exclusive for adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) tumors. This discovery is helpful in the development of novel targeted therapies in successful clinical trials with BRAF mutations in PCP cases. However\, no such targeted therapy is available yet for ACP. Here\, we report novel mutations\, which are not previously reported\, in a case of an adult ACP using NGS analysis.,Patient DNA was sequenced using Ion PI v3 chip on Ion Proton. A total of 16 variants were identified in this tumor by NGS analysis\, out of which four were missense mutations\, seven were synonymous mutations\, and five were intronic variants. In CTNNB1 gene a known missense mutation in c.101G>T; in TP53 a known missense mutation in c.215C>G; and two known missense variants in PIK3CA\, viz.\, in c.1173A>G; in exon 7\, and in c.3128T>C; in exon 21\, were found\, respectively. Seven synonymous mutations were detected in this tumor\, viz.\, in IDH1 (rs11554137)\, in FGFR3 (rs7688609)\, in PDGFRA (rs1873778)\, in APC (COSM3760869)\, in EGFR (rs1050171)\, in MET (rs35775721)\, and in RET (rs1800861)\, respectively. Three known\, intronic variants were found in genes\, such as PIK3CA\, KDR\, and JAK3\, respectively. Also\, a 3'-UTR and a splice site acceptor site variant in CSF1R and FLT3 genes were found in this tumor. We have shown allele coverage\, allele ratio\, and p-value\, for all these mutations. The p-values and Phred quality score were significantly high for these variants.,As reported in previous studies\, in ACP tumors we found a CTNNB1 mutation by NGS analysis. The PIK3CA variants we detected were not known previously in ACP tumors. Finding the PIK3CA mutations in the ACP tumors may help develop targeted therapy for a subset of craniopharyngiomas with PIK3CA activating mutations. Clinical trials are in progress with specific PIK3CA inhibitors in advanced stages of many cancers.",International medical case reports journal,vol.13::123-137,2020,Case Reports,,,"Department of Pathology\, Faculty of Medicine\, Umm-Al-Qura University\, Makkah\, Saudi Arabia.,Department of Radiology\, Faculty of Medicine\, Umm-Al-Qura University\, Makkah\, Saudi Arabia.,0000-0002-7094-5646Department of Pathology\, King Saud University\, Riyadh\, Saudi Arabia.,0000-0002-2055-8728Division of Histopathology\, Department of Laboratory Medicine and Blood Bank\, Al-Noor Specialty Hospital\, Makkah\, Saudi Arabia.,Department of Radiation Oncology\, King Abdullah Medical City\, Makkah\, Saudi Arabia.,Science and Technology Unit\, Umm-Al-Qura University\, Makkah\, Saudi Arabia.,0000-0002-7907-7873Department of Radiation Oncology and Massey Cancer Center\, Virginia Commonwealth University\, Richmond\, VA\, USA.,0000-0003-3044-3809Science and Technology Unit\, Umm-Al-Qura University\, Makkah\, Saudi Arabia.",,,,,"CTNNB1,NGS,adamantinomatous,brain tumor,craniopharyngioma,next generation DNA sequencing"
32368388,Alqathama A,BRAF in malignant melanoma progression and metastasis: potentials and challenges.,"Recent advances in gene sequencing have shown that activated BRAF mutations are present in more than 50% of malignant melanomas and contribute to constitutive signals in the MAPK pathway. Besides the importance of its mutations in cell proliferation, BRAF is associated with lymph node, brain and liver metastasis, along with the loss of PTEN expression and ATG5. Knowledge of this genetic alteration has led to the development of personalized and targeted therapy strategies which block different pathways driving melanoma pathogenesis. Several targeted therapy agents such as vemurafenib, dabrafenib and encorafenib have been approved by the FDA as BRAF inhibitors, as well as other immunotherapies such as anti-CTLA-4 (ipilimumab). However, one of the main challenges is acquired resistance via reactivation of MAPK via CRAF/COT overexpression. Resistance to current BRAF inhibitors is a clinical challenge and one of the strategies to overcome this phenomenon is combination treatment, with the most recently approved combination being BRAF/MEK inhibitors (dabrafenib and trametinib) and BRAF or MEK inhibitors with immunocheckpoint blockers. This review delineates the current role of BRAF in melanoma progression and metastasis. It discusses targeted therapies and resistance mechanisms to BRAF inhibitors, and illustrates strategies to overcome this mechanism with recently approved agents.",American journal of cancer research,vol.10:4:1103-1114,2020,Review,,,"Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University Makkah, Saudi Arabia.",,,,,"BRAF,combination treatment,melanoma,metastasis,resistance,targeted therapy"
32368535,"Kalantzis I,Nonni A,Pavlakis K,Delicha EM,Miltiadou K,Kosmas C,Ziras N,Gkoumas K,Gakiopoulou H",Clinicopathological differences and correlations between right and left colon cancer.,"The differences in histopathology and molecular biology between right colon cancer (RCC) and left colon cancer (LCC) were first reported in the literature by Bufill in 1990. Since then\, a large number of studies have confirmed their differences in epidemiology\, clinical presentation\, comorbidities and biological behaviours\, which may be related to the difference in prognosis and overall survival (OS) between the two groups.,To investigate statistically significant differences between Greek patients with LCC and RCC.,The present observational study included 144 patients diagnosed with colon cancer of any stage who received chemotherapy in a Greek tertiary oncology hospital during a 2.5-year period. Clinical information\, comorbidities\, histopathologic characteristics and molecular biomarkers were collected from the patients' medical records retrospectively\, while administered chemotherapy regimens\, targeted agents\, progression-free survival (PFS) periods with first- and second-line chemotherapy and OS were recorded retroactively and prospectively. Data analysis was performed with the SPSS statistical package.,Eighty-six males and 58 females participated in the study. One hundred (69.4%) patients had a primary lesion in the left colon\, and 44 (30.6%) patients had a primary lesion in the right colon. Patients with RCC were more likely to display anaemia than patients with LCC [odds ratio (OR) = 3.09]\, while LCC patients were more likely to develop rectal bleeding (OR = 3.37) and a feeling of incomplete evacuation (OR = 2.78) than RCC patients. Considering comorbidities\, RCC patients were more likely to suffer from diabetes (OR = 3.31) and coronary artery disease (P = 0.056) than LCC patients. The mucinous differentiation rate was higher in the right-sided group than in the left-sided group (OR = 4.49)\, as was the number of infiltrated lymph nodes (P = 0.039)\, while the percentage of high-grade differentiation was higher in the group of patients with left-sided colon cancer than in RCC patients (OR = 2.78). RAS wild-type patients who received anti-epidermal growth factor receptor (EGFR): Treatment experienced greater benefit (PFS: 16.5 mo) than those who received anti-vascular endothelial growth factor treatment (PFS: 13.7 mo) (P = 0.05)\, while among RAS wild-type patients who received anti-EGFR treatment\, LCC patients experienced greater benefit (PFS: 15.8 mo) than the RCC subgroup (PFS: 5.5 mo) in the first-line chemotherapy setting (P = 0.034). BRAF-mutant patients had shorter PFS (9.3 mo) than BRAF wild-type patients (14.5 mo) (P = 0.033). RCC patients showed a shorter tumour recurrence period (7.7 mo) than those with LCC (14.5 mo) (P < 0.001)\, as well as shorter (OS) (58.4 mo for RCC patients; 82.4 mo for LCC patients) (P = 0.018).,RCC patients present more comorbidities\, worse histological and molecular characteristics and a consequently higher probability of tumour recurrence\, poor response to targeted therapy and shorter OS than LCC patients.",World journal of clinical cases,vol.8:8:1424-1443,2020,Journal Article,,,"Department of Gastroenterology\, Korgialenio-Mpenakeio Hellenic Red Cross Hospital\, Athens 11526\, Greece.,First Department of Pathology\, National and Kapodistrian University of Athens\, Medical School\, Athens 11527\, Greece.,First Department of Pathology\, National and Kapodistrian University of Athens\, Medical School\, Athens 11527\, Greece.,Independent Biostatistical Consultant\, ASTAT\, Statistics in Clinical Research\, Glyfada 16675\, Greece.,Hepatogastroenterology Unit\, Second Department of Internal Medicine\, Attikon University General Hospital\, Athens 12462\, Greece.,Department of Oncology\, Metaxa Anticancer Hospital\, Piraeus 18537\, Greece.,Department of Oncology\, Metaxa Anticancer Hospital\, Piraeus 18537\, Greece.,Department of Gastroenterology\, Korgialenio-Mpenakeio Hellenic Red Cross Hospital\, Athens 11526\, Greece.,First Department of Pathology\, National and Kapodistrian University of Athens\, Medical School\, Athens 11527\, Greece.",,,,,"Colorectal neoplasm,Epidermal growth factor,Histology,Metabolic syndrome,Molecular biology,Vascular endothelial growth factor"
32371339,"de Jel DVC,Hol JA,Ooms AHAG,de Krijger RR,Jongmans MCJ,Littooij AS,Drost J,van Grotel M,van den Heuvel-Eibrink MM",Paediatric metanephric tumours: a clinicopathological and molecular characterisation.,"To characterize metanephric tumours in children, we performed a literature review investigating paediatric metanephric adenomas (MA), metanephric stromal tumours (MST) and metanephric adenofibromas (MAF). Including two patients from our own institution (MA, MAF), 110 individual cases (41 MA, 20 MAF, 49 MST) were identified. Additionally, fifteen composite tumours were identified, with areas of MA/MAF and Wilms tumour (WT) or papillary carcinoma. No distinct clinical or radiological features could be defined. In pure metanephric tumours, histologically proven distant metastases were reported once (MA), relapse was reported once (MST) and one tumour-related death occurred (MST). Somatic BRAF-V600E mutations were tested in 15 cases, and identified in 3/6 MA, 3/3 MAF, and 6/6 MST. In our institution the MA harboured a somatic KRAS-G12R mutation. Overall, paediatric metanephric tumours are difficult to discriminate from other renal tumours at presentation, behave relatively benign, and the occurrence of composite tumours warrants analysis of underlying (genetic) pathways.",Critical reviews in oncology/hematology,vol.150::102970,2020,Review,"|Adenoma|genetics|pathology|,|Biomarkers\, Tumor|genetics|,|Carcinoma\, Papillary|genetics|pathology|,|Child|,|DNA Mutational Analysis|,|Humans|,|Immunohistochemistry|,|Immunophenotyping|,|Kidney Neoplasms|genetics|pathology|,|Neoplasm Recurrence\, Local|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Wilms Tumor|genetics|pathology|",,"Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands. Electronic address: j.hol@prinsesmaximacentrum.nl.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands; Department of Pathology\, Pathan\, Rotterdam\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands; Department of Pathology\, University Medical Center Utrecht (UMCU)\, Utrecht\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands; Department of Clinical Genetics\, University Medical Center Utrecht (UMCU)\, Utrecht\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands; Department of Radiology\, University Medical Center Utrecht (UMCU)\, Utrecht\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands; Oncode Institute\, Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands.,Princess Máxima Center for Pediatric Oncology\, Utrecht\, The Netherlands.","Biomarkers\, Tumor,KRAS protein\, human,Proto-Oncogene Proteins p21(ras)",,,,"adenofibroma,adenoma,metanephric,paediatric,renal,stromal tumour"
32373219,"Tang J,Sui CJ,Wang DF,Lu XY,Luo GJ,Zhao Q,Lian QY,Jeong S,Lin XM,Zhu YJ,Zheng B,Wu R,Wang Q,Liu XL,Liu JF,Xia Q,Wu G,Gu J,Wang HY,Chen L",Targeted sequencing reveals the mutational landscape responsible for sorafenib therapy in advanced hepatocellular carcinoma.,"Rationale: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Results: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in OCT4 (OCT4 mut) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in TP53 showed the opposite outcome both in vitro and in vivo. OCT4 wt-induced stem cell factor (encoded by KITLG gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of KITLG promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion: Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.",Theranostics,vol.10:12:5384-5397,2020,"Research Support, Non-U.S. Gov't",,,"Cancer Center\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan 430022\, China.,Department of special treatment and liver transplantation\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Changhai Road 225\, Shanghai 200438\, China.,MOE Key Laboratory for Bioinformatics\, BNRIST Bioinformatics Division\, Department of Automation\, Tsinghua University\, Beijing 100084\, China.,Department of Pathology\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Changhai Road 225\, Shanghai\, Shanghai 200438\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,Department of Clinical Pharmacology\, Xiangya Hospital\, Central South University\, Changsha\, Hunan\, China. 2Institute of Clinical Pharmacology\, Central South University\, Changsha\, Hunan 410013\, China.,MOE Key Laboratory for Bioinformatics\, BNRIST Bioinformatics Division\, Department of Automation\, Tsinghua University\, Beijing 100084\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,Department of Biliary Surgery I\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Changhai Road 225\, Shanghai 200438\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province\, Mengchao Hepatobiliary Hospital of Fujian Medical University\, Fuzhou 350025\, China.,The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province\, Mengchao Hepatobiliary Hospital of Fujian Medical University\, Fuzhou 350025\, China.,Department of Liver Surgery\, Renji Hospital\, School of Medicine\, Shanghai Jiao Tong University\, Shanghai\, 200127\, China.,Cancer Center\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan 430022\, China.,MOE Key Laboratory for Bioinformatics\, BNRIST Bioinformatics Division\, Department of Automation\, Tsinghua University\, Beijing 100084\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.,The International Cooperation Laboratory on Signal Transduction\, Eastern Hepatobiliary Surgery Hospital\, Second Military Medical University\, Shanghai 200438\, China.",,,,," OCT4,Hepatocellular Carcinoma.,Mutational Landscape,Sorafenib Resistance,TP53"
32373528,"Wang S,Chen R,Tang Y,Yu Y,Fang Y,Huang H,Wu D,Fang H,Bai Y,Sun C,Yu A,Fan Q,Gu D,Yi X,Li N",Comprehensive Genomic Profiling of Rare Tumors: Routes to Targeted Therapies.,"Comprehensive Genomic Profiling may be informative for novel treatment strategies and to improve outcomes for patients with rare tumors. This study aims to discover opportunities for use of targeted therapies already approved for routine use in patients with rare tumors. Solid tumors with an incidence lower than 2.5/100,000 per year was defined as rare tumors in China after comprehensive analysis based on epidemiological data and current availability of standardized treatment. Genomic data of rare tumors from the public database cBioPortal were compared with that of the Chinese population for targetable genomic alterations (TGAs). TGAs were defined as mutations of ALK, ATM, BRAF, BRCA1, BRCA2, CDKN2A, EGFR, ERBB2, FGFR1,2,3, KIT, MET, NF1, NTRK1,2,3, PIK3CA, PTEN, RET, and ROS1 with level 1 to 4 of evidence according to the OncoKB knowledge database. Genomic data of 4,901 patients covering 63 subtypes of rare tumor from cBioPortal were used as the western cohort. The Chinese cohort was comprised of next generation sequencing (NGS) data of 1,312 patients from across China covering 67 subtypes. Forty-one subtypes were common between the two cohorts. The accumulative prevalence of TGAs was 20.40% (1000/4901) in cBioPortal cohort, and 53.43% (701/1312) in Chinese cohort (p < 0.001). Among those 41 overlapping subtypes, it was still significantly higher in Chinese cohort compared with cBioPortal cohort (54.1%% vs. 26.1%, p < 0.001). Generally, targetable mutations in BRAF, BRCA2, CDKN2A, EGFR, ERBB2, KIT, MET, NF1, ROS1 were ≥3 times more frequent in Chinese cohort compared with that of the cBioPortal cohort. Cancer of unknown primary tumor type, gastrointestinal stromal tumor, gallbladder cancer, intrahepatic cholangiocarcinoma, and sarcomatoid carcinoma of the lung were the top 5 tumor types with the highest number of TGAs per tumor. The incidence of TGAs in rare tumors was substantial worldwide and was even higher in our Chinese rare tumor population. Comprehensive genomic profiling may offer novel treatment paradigms to address the limited options for patients with rare tumors.",Frontiers in oncology,vol.10::536,2020,Journal Article,,,"Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Department of Medical Center\, Geneplus-Beijing Institute\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.,Department of Medical Center\, Geneplus-Beijing Institute\, Beijing\, China.,Department of Medical Center\, Geneplus-Beijing Institute\, Beijing\, China.,Clinical Cancer Center\, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences and Peking Union Medical College\, Beijing\, China.",,,,,"China,NGS,actionable mutation,genomic profile,rare tumors,targetable genomic alterations"
30801710,"Verver D,van der Veldt A,van Akkooi A,Verhoef C,Grünhagen DJ,Louwman WJ",Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population-based study.,"Melanoma of unknown primary (MUP) may have a different biology to melanoma of known primary, but clinical trials of novel therapies (e.g., immune checkpoint or BRAF/MEK inhibitors) have not reported the outcomes in this population. We therefore evaluated the overall survival (OS) among patients with MUP in the era of novel therapy. Data for stage III or IV MUP were extracted from a nationwide database for the period 2003-2016, with classification based on the eighth edition of the American Joint Committee on Cancer criteria. The population was divided into pre- (2003-2010) and post- (2011-2016) novel therapy eras. Also, OS in the post-novel era was compared between patients with stage IV MUP by whether they received novel therapy. In total, 2028 of 65,110 patients (3.1%) were diagnosed with MUP. Metastatic sites were known in 1919 of 2028 patients, and most had stage IV disease (53.8%). For patients with stage III MUP, the 5-year OS rates were 48.5% and 50.2% in the pre- and post-novel eras, respectively (p = 0.948). For those with stage IV MUP, the median OS durations were unchanged in the pre-novel era and post-novel era when novel therapy was not used (both 4 months); however, OS improved to 11 months when novel therapy was used in the post-novel era (p < 0.001). In conclusion, more than half of the patients with MUP are diagnosed with stage IV and the introduction of novel therapy appears to have significantly improved the OS of these patients.",International journal of cancer,vol.146:1:26-34,2020,Journal Article,"|Aged|,|Drug Delivery Systems|,|Female|,|Humans|,|Immunotherapy|,|Male|,|Melanoma|epidemiology|secondary|therapy|,|Middle Aged|,|Neoplasms\, Unknown Primary|pathology|therapy|,|Netherlands|epidemiology|,|Survival Analysis|",,"0000-0003-0034-3575Department of Surgical Oncology\, Erasmus MC Cancer Institute\, EA Rotterdam\, The Netherlands.,Department of Medical Oncology and Radiology & Nuclear Medicine\, Erasmus MC Cancer Institute\, EA Rotterdam\, The Netherlands.,Department of Surgical Oncology\, Netherlands Cancer Institute-Antoni van Leeuwenhoek\, CX Amsterdam\, The Netherlands.,Department of Surgical Oncology\, Erasmus MC Cancer Institute\, EA Rotterdam\, The Netherlands.,Department of Surgical Oncology\, Erasmus MC Cancer Institute\, EA Rotterdam\, The Netherlands.,Department of Research\, Netherlands Comprehensive Cancer Organization (IKNL)\, DB Utrecht\, The Netherlands.",,,,,"immunotherapy,melanoma,targeted therapy,unknown primary"
31668133,"Masoodi T,Siraj AK,Siraj S,Azam S,Qadri Z,Albalawy WN,Parvathareddy SK,Al-Sobhi SS,Al-Dayel F,Alkuraya FS,Al-Kuraya KS",Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer.,"Background: Distant metastasis is a rare occurrence in thyroid cancer, and it can be associated with poor prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain underexplored in metastatic papillary thyroid cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. Methods: We performed whole-exome sequencing on 14 matched distant metastases, primary PTC tumors, and normal tissues. Point mutations, copy number alterations, cancer cell fractions, and mutational signatures were defined using the state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Results: Genomic differences were observed between primary and distant metastatic deposits, with a median of 62% (range 21-92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including BRAF, NRAS, and HRAS were shared and preferentially clonal in both sites. However, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including SIN3A, RBBP1, and CHD4 were found to be restricted in the metastatic lesions. Moreover, a mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Conclusions: Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.",Thyroid : official journal of the American Thyroid Association,vol.30:1:42-56,2020,"Research Support, Non-U.S. Gov't",,,"Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Department of Surgery\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Department of Pathology\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Department of Genetics\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.,Human Cancer Genomic Research\, King Faisal Specialist Hospital and Research Centre\, Riyadh\, Saudi Arabia.",,,,,"DNA methylation,distant metastasis,exome sequencing,papillary thyroid cancer"
31672771,"Capdevila J,Arqués O,Hernández Mora JR,Matito J,Caratù G,Mancuso FM,Landolfi S,Barriuso J,Jimenez-Fonseca P,Lopez Lopez C,Garcia-Carbonero R,Hernando J,Matos I,Paolo N,Hernández-Losa J,Esteller M,Martínez-Cardús A,Tabernero J,Vivancos A,Palmer HG",Epigenetic Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas.,"The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs.,We performed a multi-omic analysis of co-NEC to identify genetic or epigenetic alterations that could be exploited as effective drug targets. We compared co-NEC samples with colorectal carcinomas (CRC) to identify neuroendocrine-specific traits. Patients with co-NEC and patient-derived xenografts were treated with a BRAFV600E-blocking drug to demonstrate sensitivity.,co-NEC and CRC are similar in their mutational repertoire\, although co-NECs are particularly enriched in BRAFV600E mutations. We report for the first time that V600EBRAF-mutant co-NECs may benefit from BRAF inhibition in monotherapy and how EGFR status is essential to predict innate sensitivity and acquired resistance by a differential methylation of its gene regulatory regions.,The identification of V600E BRAF mutations in high-grade co-NECs has allowed the description of radiological responses to combination therapy of BRAF and MEK inhibitors in basket clinical trials. However\, the molecular rationale for this treatment combination was based on the presence of the BRAF mutation and the efficacy observed in other cancer types such as melanoma. Future drug development in this setting should test BRAF inhibitors upfront and the addition of anti-EGFR antibodies instead of MEK inhibitors for an efficient blockade of acquired resistance.",Clinical cancer research : an official journal of the American Association for Cancer Research,vol.26:4:902-909,2020,"Research Support, Non-U.S. Gov't","|Animals|,|Carbamates|pharmacology|,|Carcinoma\, Neuroendocrine|drug therapy|genetics|pathology|,|Cetuximab|pharmacology|,|Colonic Neoplasms|drug therapy|genetics|pathology|,|Drug Resistance\, Neoplasm|,|Epigenesis\, Genetic|,|ErbB Receptors|antagonists & inhibitors|genetics|,|Humans|,|Mice|,|Mice\, Inbred NOD|,|Mice\, SCID|,|Mutation|,|Protein Kinase Inhibitors|pharmacology|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|,|Sulfonamides|pharmacology|,|Treatment Outcome|,|Xenograft Model Antitumor Assays|",,"Department of Medical Oncology\, Vall d'Hebron University Hospital (HUVH)\, Vall d'Hebron Institute of Oncology (VHIO)\, Universitat Autònoma de Barcelona (UAB)\, CIBERONC\, Barcelona\, Spain.,Stem Cells and Cancer Laboratory\, Vall d'Hebron Institute of Oncology (VHIO)\, CIBERONC\, Barcelona\, Spain.,0000-0001-6218-4544Cancer Epigenetics Group\, Cancer Epigenetics and Biology Program (PEBC)\, Bellvitge Biomedical Research Institute (IDIBELL)\, Barcelona\, Catalonia\, Spain.,Cancer Genomics Group\, Vall d'Hebron Institute of Oncology (VHIO)\, Barcelona\, Spain.,Cancer Genomics Group\, Vall d'Hebron Institute of Oncology (VHIO)\, Barcelona\, Spain.,0000-0001-5499-6630Cancer Genomics Group\, Vall d'Hebron Institute of Oncology (VHIO)\, Barcelona\, Spain.,0000-0002-1059-635XDepartment of Pathology\, Vall d'Hebron University Hospital (HUVH)\, Universitat Autònoma de Barcelona\, CIBERONC\, Barcelona\, Spain.,0000-0002-5641-9105Department of Medical Oncology\, European Neuroendocrine Tumor Society (ENETS) Centre of Excellence\, The Christie NHS Foundation Trust\, Division of Cancer Sciences\, University of Manchester\, Manchester\, United Kingdom.,0000-0003-4592-3813Department of Medical Oncology\, Central de Asturias University Hospital\, Oviedo\, Spain.,0000-0002-8901-741XDepartment of Medical Oncology\, Marques de Valdecilla University Hospital\, Santander\, Spain.,0000-0002-3342-397XDepartment of Medical Oncology\, Doce de Octubre University Hospital\, Instituto de Investigacion Hospital 12 de Octubre (i+12)\, Centro Nacional de Investigacion Oncologica (CNIO)\, CIBERONC\, Universidad Complutense de Madrid (UCM)\, Madrid\, Spain.,Department of Medical Oncology\, Vall d'Hebron University Hospital (HUVH)\, Vall d'Hebron Institute of Oncology (VHIO)\, Universitat Autònoma de Barcelona (UAB)\, CIBERONC\, Barcelona\, Spain.,Early Clinical Drug Development Group\, Medical Oncology Department\, Vall d'Hebron University Hospital (HUVH)\, Vall d'Hebron Institute of Oncology (VHIO)\, Universitat Autònoma de Barcelona (UAB)\, Barcelona\, Spain.,Molecular Oncology Group\, Vall d'Hebron Institute of Oncology (VHIO)\, Barcelona\, Spain.,Molecular Oncology Group\, Vall d'Hebron Institute of Oncology (VHIO)\, Barcelona\, Spain.,Cancer Epigenetics Group\, Cancer Epigenetics and Biology Program (PEBC)\, Bellvitge Biomedical Research Institute (IDIBELL)\, Barcelona\, Catalonia\, Spain.,Cancer Epigenetics Group\, Cancer Epigenetics and Biology Program (PEBC)\, Bellvitge Biomedical Research Institute (IDIBELL)\, Barcelona\, Catalonia\, Spain.,0000-0002-2495-8139Department of Medical Oncology\, Vall d'Hebron University Hospital (HUVH)\, Vall d'Hebron Institute of Oncology (VHIO)\, Universitat Autònoma de Barcelona (UAB)\, CIBERONC\, Barcelona\, Spain.,Cancer Genomics Group\, Vall d'Hebron Institute of Oncology (VHIO)\, Barcelona\, Spain. hgpalmer@vhio.net avivancos@vhio.net.,Stem Cells and Cancer Laboratory\, Vall d'Hebron Institute of Oncology (VHIO)\, CIBERONC\, Barcelona\, Spain. hgpalmer@vhio.net avivancos@vhio.net.","Carbamates,Protein Kinase Inhibitors,Sulfonamides,encorafenib,EGFR protein\, human,ErbB Receptors,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Cetuximab",,,,
31672856,"Lin SY,Chang SC,Lam S,Irene Ramos R,Tran K,Ohe S,Salomon MP,Bhagat AAS,Teck Lim C,Fischer TD,Foshag LJ,Boley CL,O'Day SJ,Hoon DSB",Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy.,"Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel.,Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical outcomes were assessed.,CTCs were detected in 88% of blood samples from patients with melanoma. CTC-derived biomarkers and clinical variables analyzed using classification and regression tree analysis revealed that a combination of lactate dehydrogenase\, CTC-mRNA biomarkers\, and tumor BRAF-mutation status was indicative of clinical outcomes for patients with stage IV melanoma (n = 52). The panel stratified low-risk and high-risk patients\, whereby the latter had poor disease-free (P = 0.03) and overall survival (P = 0.02). Incorporation of a DNA biomarker with mRNA profiling increased overall CTC-detection capability by 57% compared to mRNA profiling only. RNA sequencing of isolated CTCs identified significant catenin beta 1 (CTNNB1) overexpression (P <0.01) compared to nondisease donor blood. CTC-CTNNB1 was associated with progressive disease/stable disease compared to complete-responder patient status (P = 0.02). Serial CTC profiling identified subclinical disease in patients who developed progressive disease during treatment/follow-up.,CTC-derived mRNA/DNA biomarkers have utility for monitoring CII\, targeted\, and combinatorial therapies in metastatic melanoma patients.",Clinical chemistry,vol.66:1:169-177,2020,"Research Support, Non-U.S. Gov't","|Aged|,|Antibodies\, Monoclonal\, Humanized|therapeutic use|,|Biomarkers\, Tumor|blood|genetics|,|Disease-Free Survival|,|Female|,|Humans|,|Immunotherapy|,|Kaplan-Meier Estimate|,|Male|,|Melanoma|mortality|pathology|therapy|,|Middle Aged|,|Neoplasm Staging|,|Neoplastic Cells\, Circulating|metabolism|,|Proportional Hazards Models|,|Prospective Studies|,|Proto-Oncogene Proteins B-raf|genetics|,|RNA\, Messenger|metabolism|,|Risk Factors|,|Up-Regulation|,|beta Catenin|genetics|metabolism|",,"Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.,Medical Data Research Center\, Providence Saint Joseph Health\, Portland\, OR.,Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.,Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.,Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.,Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.,Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.,Department of Biomedical Engineering and Department of Mechanical Engineering\, National University of Singapore\, Singapore.,Department of Biomedical Engineering and Department of Mechanical Engineering\, National University of Singapore\, Singapore.,Department of Surgical Oncology\, John Wayne Cancer Institute\, PHS\, Santa Monica\, CA.,Department of Surgical Oncology\, John Wayne Cancer Institute\, PHS\, Santa Monica\, CA.,Department of Immuno-Oncology and Clinical Research\, John Wayne Cancer Institute\, PHS\, Santa Monica\, CA.,Department of Immuno-Oncology and Clinical Research\, John Wayne Cancer Institute\, PHS\, Santa Monica\, CA.,Department of Translational Molecular Medicine\, John Wayne Cancer Institute\, Saint John's Health Center\, PHS\, Santa Monica\, CA.","Antibodies\, Monoclonal\, Humanized,Biomarkers\, Tumor,CTNNB1 protein\, human,RNA\, Messenger,beta Catenin,pembrolizumab,BRAF protein\, human,Proto-Oncogene Proteins B-raf",NCI NIH HHS,United States,R01 CA167967,
31677173,"Zamolo G,Grahovac M,Žauhar G,Vučinić D,Kovač L,Brajenić N,Grahovac B","Matrix metalloproteinases MMP-1, MMP-2, and MMP-13 are overexpressed in primary nodular melanoma.","The spread and invasion of malignant melanoma cells involve degradation and reorganization of the extracellular matrix by the activation of several matrix metalloproteinases (MMPs). This study analyzed the expression of MMP-1\, MMP-2\, and MMP-13 proteins in primary nodular melanoma (NM) and dysplastic nevi (DN) as a significant risk factor for melanoma development. The secondary goal was to analyze the correlation of MMPs protein expression in NM with tumor invasion\, BRAF V600 mutation status\, and overall survival.,Immunohistochemistry for MMP-1\, MMP-2\, and MMP-13 was performed on nodular melanoma (n = 52) and dysplastic nevi (n = 28) on tissue microarray (TMA). BRAF V600 mutation analysis on NM samples was performed by the Sanger sequencing method.,A high level of MMPs expression in NM samples (>30%) compared with DN (<8%) was statistically significant (P < 0.001). BRAF V600 mutations were detected in 15 of 39 (38.5%) NM samples. This study revealed an interesting finding that MMP-1 and MMP-13 protein expression in the BRAF V600 mutated melanomas were significantly lower than in the BRAF V600 wild type (P < 0.05).,Cox analysis revealed that Clark categories\, Breslow thickness\, and MMP-1 high protein expression are predictive factors for shorter overall survival (P < 0.05).",Journal of cutaneous pathology,vol.47:2:139-145,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Female|,|Gene Expression Regulation\, Enzymologic|,|Gene Expression Regulation\, Neoplastic|,|Humans|,|Male|,|Matrix Metalloproteinase 1|biosynthesis|,|Matrix Metalloproteinase 13|biosynthesis|,|Matrix Metalloproteinase 2|biosynthesis|,|Melanoma|enzymology|pathology|,|Middle Aged|,|Neoplasm Proteins|biosynthesis|,|Skin Neoplasms|enzymology|pathology|",,"https://orcid.org/0000-0002-7702-1876Department of Pathology\, Faculty of Medicine\, University of Rijeka\, Rijeka\, Croatia.,Polyclinic of Dermatology\, Gutenbergstr. 8\, 87600\, Kaufbeuren\, Germany.,Department of Physics\, University of Rijeka\, Rijeka\, Croatia.,https://orcid.org/0000-0002-5804-0799Department of Radiotherapy and Oncology\, Clinical Hospital Centre Rijeka\, Rijeka\, Croatia.,Department of Pathology\, Faculty of Medicine\, University of Rijeka\, Rijeka\, Croatia.,The University of Rijeka\, Faculty of Medicine\, Rijeka\, Croatia.,The University of Rijeka\, Faculty of Medicine\, Rijeka\, Croatia.","Neoplasm Proteins,MMP13 protein\, human,Matrix Metalloproteinase 13,MMP2 protein\, human,Matrix Metalloproteinase 2,MMP1 protein\, human,Matrix Metalloproteinase 1",,,,"BRAF V600 mutation,dysplastic nevus,matrix metalloproteinase,nodular melanoma,overall survival"
31677187,"Amemori S,Yamano HO,Tanaka Y,Yoshikawa K,Matsushita HO,Takagi R,Harada E,Yoshida Y,Tsuda K,Kato B,Tamura E,Eizuka M,Sugai T,Adachi Y,Yamamoto E,Suzuki H,Nakase H",Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months.,"Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.",Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society,vol.32:6:979-983,2020,Case Reports,,,"Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Gastroenterology\, Akita Red Cross Hospital\, Akita\, Japan.,Department of Pathology\, Iwate Medical University\, Iwate\, Japan.,Department of Pathology\, Iwate Medical University\, Iwate\, Japan.,Department of Gastroenterology and Hepatology\, Sapporo Medical University School of Medicine\, Hokkaido\, Japan.,Department of Gastroenterology and Hepatology\, Sapporo Medical University School of Medicine\, Hokkaido\, Japan.,Department of Molecular Biology\, Sapporo Medical University School of Medicine\, Hokkaido\, Japan.,Department of Gastroenterology and Hepatology\, Sapporo Medical University School of Medicine\, Hokkaido\, Japan.",,,,,"follow-up case,genetic and epigenetic analyses,magnifying endoscopy,serrated neoplastic pathway,sessile serrated adenoma/polyp"
32462249,"Zaremba A,Zimmer L,Griewank KG,Ugurel S,Roesch A,Schadendorf D,Livingstone E",[Immunotherapy for malignant melanoma].,"Although cutaneous melanoma accounts for only about 4% of all skin cancers (including nonmelanocytic skin cancer), it is responsible for 80% of all deaths caused by skin cancer. The introduction of immune checkpoint inhibitors led to a significant improvement in long-term survival of patients in an advanced stage regardless of BRAF mutation status. In addition to targeted therapy for patients with BRAF-mutated melanoma, immunotherapies are the therapies of choice in advanced stages and, since 2018, also in the adjuvant setting. The effectiveness of combination therapies and sequences of targeted and immunotherapies are currently being tested.",Der Internist,vol.61:7:669-675,2020,Review,"|Combined Modality Therapy|,|Humans|,|Immunotherapy|,|Melanoma|pathology|therapy|,|Molecular Targeted Therapy|methods|,|Skin Neoplasms|pathology|therapy|",,"Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland.,Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland.,Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland.,Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland.,Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland.,Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland. dirk.schadendorf@uk-essen.de.,Klinik und Poliklinik für Dermatologie\, Venerologie und Allergologie\, Universitätsklinikum Essen\, Hufelandstr. 55\, 45122\, Essen\, Deutschland.",,,,,"BRAF mutation,Drug therapy\, combination,Immune checkpoint inhibitors,Malignant melanoma\, pathogenesis,Targeted therapy"
32462295,"Esagian SM,Grigoriadou GΙ,Nikas IP,Boikou V,Sadow PM,Won JK,Economopoulos KP",Comparison of liquid-based to tissue-based biopsy analysis by targeted next generation sequencing in advanced non-small cell lung cancer: a comprehensive systematic review.,"To explore whether targeted next generation sequencing (NGS) of liquid biopsy in advanced non-small cell lung cancer (NSCLC) could potentially overcome the innate problems that arise with standard tissue biopsy\, like intratumoral heterogeneity and the inability to obtain adequate samples for analysis.,The Scopus\, Cochrane Library\, and MEDLINE (via PubMed) databases were searched for studies with matched tissue and liquid biopsies from advanced NSCLC patients\, analyzed with targeted NGS. The number of mutations detected in tissue biopsy only\, liquid biopsy only\, or both was assessed and the positive percent agreement (PPA) of the two methods was calculated for every clinically relevant gene.,A total of 644 unique relevant articles were retrieved and data were extracted from 38 studies fulfilling the inclusion criteria. The sample size was composed of 2000 mutations tested in matched tissue and liquid biopsies derived from 1141 patients. No studies analyzed circulating tumor cells. The calculated PPA rates were 53.6% (45/84) for ALK\, 53.9% (14/26) for BRAF\, 56.5% (13/23) for ERBB2\, 67.8% (428/631) for EGFR\, 64.2% (122/190) for KRAS\, 58.6% (17/29) for MET\, 54.6% (12/22) for RET\, and 53.3% (8/15) for ROS1. We additionally recorded data for 65 genes that are not recommended by current guidelines for mutational testing. An extra category containing results of unspecified genes was added\, with a PPA rate of 55.7% (122/219).,Despite many advantages\, liquid biopsy might be unable to fully substitute its tissue counterpart in detecting clinically relevant mutations in advanced NSCLC patients. However\, it may serve as a helpful tool when making therapeutic decisions. More studies are needed to evaluate its role in everyday clinical practice.",Journal of cancer research and clinical oncology,vol.146:8:2051-2066,2020,Systematic Review,"|Biopsy|methods|,|Carcinoma\, Non-Small-Cell Lung|blood|genetics|pathology|,|Circulating Tumor DNA|genetics|,|DNA Mutational Analysis|,|High-Throughput Nucleotide Sequencing|methods|,|Humans|,|Liquid Biopsy|methods|,|Lung Neoplasms|blood|genetics|pathology|,|Neoplastic Cells\, Circulating|pathology|",,"Oncology Working Group\, Society of Junior Doctors\, Athens\, Greece.,Oncology Working Group\, Society of Junior Doctors\, Athens\, Greece.,School of Medicine\, European University of Cyprus\, Nicosia\, Cyprus.,Oncology Working Group\, Society of Junior Doctors\, Athens\, Greece.,Department of Pathology\, Harvard Medical School\, Massachusetts General Hospital\, Boston\, MA\, USA.,Department of Pathology\, Seoul National University Hospital\, Seoul\, Republic of Korea.,http://orcid.org/0000-0003-4856-0405Oncology Working Group\, Society of Junior Doctors\, Athens\, Greece. economopoulos@sni.gr.",Circulating Tumor DNA,NCI NIH HHS,United States,P01 CA240239,"ALK fusion gene,BRAF testing,EGFR mutations,NGS,NSCLC,ROS1 translocation,ctDNA"
32462837,"Huber A,Latifyan S,Nikolopoulou A,Homicsko K,Berthod G,Michielin O,Özdemir BC",[Locally advanced and metastatic melanoma : novelties].,The standard of care of melanoma patients has evolved at a rapid pace with the advent of immune checkpoint inhibitors and BRAF and MEK inhibitors. ESMO guidelines were revised in September 2019 to integrate the results of recent studies that broaden the indication of these treatments to the adjuvant setting and validated new limitations to completion lymph node dissection in the case of a positive sentinel lymph node biopsy in locally advanced melanoma. We hereby detail the main novelties of the revised ESMO 2019 guidelines.,Revue medicale suisse,vol.16:695:1092-1097,2020,Review,"|Antineoplastic Agents|therapeutic use|,|Humans|,|Lymph Node Excision|,|Melanoma|therapy|,|Practice Guidelines as Topic|,|Sentinel Lymph Node Biopsy|,|Skin Neoplasms|therapy|",,"Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.,Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.,Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.,Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.,Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.,Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.,Service d'oncologie médicale\, Département d'oncologie\, CHUV\, 1011 Lausanne.",Antineoplastic Agents,,,,
32466585,"Diazzi S,Tartare-Deckert S,Deckert M",Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies.,"Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma.",Cancers,vol.12:6:,2020,Review,,,"Université Côte d'Azur\, INSERM\, C3M\, 06204 Nice\, France.,Université Côte d'Azur\, INSERM\, C3M\, 06204 Nice\, France.,0000-0003-2094-559XUniversité Côte d'Azur\, INSERM\, C3M\, 06204 Nice\, France.",,"Ligue Contre le Cancer,Institut National Du Cancer,Agence Nationale de la Recherche,Institut National de la Santé et de la Recherche Médicale",",,,","Labellisation d'équipe 2016,INCA_1267,ANR-11-LABX-0028-01,U1065","fibrosis,melanoma,resistance,targeted therapies"
32438756,"Lee SH,Kim H,Kim MJ,Kim B,Kim HS",Biphasic Thyroid-Like Low-Grade Nasopharyngeal Papillary Adenocarcinoma with a Prominent Spindle Cell Component: A Case Report.,"Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLG-NPPA) is a distinctly rare malignancy of the nasopharynx. Morphologically and immunophenotypically, TLLG-NPPA resembles papillary thyroid carcinoma (PTC) and is characterized by a papillary architecture with PTC-like nuclear features and thyroid transcription factor-1 expression. Recently, some cases of TLLG-NPPA with a spindle cell component have been reported. In this study, we report a very interesting case of biphasic TLLG-NPPA that was predominantly composed of spindle cells, with comprehensive analyses of its clinical, pathological, and immunophenotypical features. A 50-year-old woman presented with a sensation of a foreign body in the nasopharynx. Nasopharyngoscopy and computed tomography demonstrated a pedunculated mass arising from the nasopharyngeal roof. Based on the clinical impression of a nasopharyngeal tumor, an excisional biopsy was performed. At low-power magnification, the nasopharyngeal mass consisted of papillary tumor tissue, the growth pattern and architecture of which resembled those of PTC. The papillae were complex and packed tightly with fibrovascular cores. At high-power magnification, each papillary structure was lined with a pseudostratified cuboidal-to-columnar epithelium. The tumor cell nuclei frequently showed a ground-glass appearance, intranuclear grooves, pseudoinclusions, and membrane thickening and irregularity, resembling the characteristic nuclear morphology of PTC. These histological features were compatible with TLLG-NPPA. Intriguingly, in between the papillary components were spindle cells that appeared very similar to the glandular epithelial cells that imperceptibly merged with the papillary component. This spindle cell component comprised two-thirds of the entire tumor volume. The nuclear morphology of the spindle cell component was similar to that of the papillary component. On immunostaining, both the papillary and spindle cell components were diffusely and strongly positive for thyroid transcription factor-1, cytokeratin 7, cytokeratin 19, vimentin, and Hector Battifora mesothelial-1. In contrast, the tumor cells tested negative for p63, p40, smooth muscle actin, S-100, cytokeratin 5/6, thyroglobulin, BRAF V600E, and Epstein-Barr virus-encoded small RNAs. Only two cases of biphasic TLLG-NPPA exhibiting a prominent spindle cell component had been reported previously in the English literature. When the pathologist receives a primary nasopharyngeal mass with the aforementioned histological features, particularly biopsy specimens with predominant spindle cells, biphasic TLLG-NPPA should be considered in the differential diagnosis. By describing its detailed clinicopathological characteristics, we anticipate that this report will expand the existing knowledge on the spindle cell component associated with TLLG-NPPA.","Diagnostics (Basel, Switzerland)",vol.10:5:,2020,Case Reports,,,"0000-0003-2692-9881Pathology Center\, Seegene Medical Foundation\, Seoul 04805\, Korea.,Department of Pathology and Translational Genomics\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul 06351\, Korea.,Department of Pathology\, Soonchunhyang University College of Medicine\, Bucheon Hospital\, Bucheon 14584\, Korea.,Luke Ear\, Nose\, and Throat Clinic\, Donghae 25769\, Korea.,0000-0003-4730-221XDepartment of Pathology and Translational Genomics\, Samsung Medical Center\, Sungkyunkwan University School of Medicine\, Seoul 06351\, Korea.",,"Ministry of Science and ICT, South Korea",,2018R1C1B5043725,"immunohistochemistry,nasopharynx,prominent spindle cell component,thyroid transcription factor-1,thyroid-like low-grade nasopharyngeal papillary adenocarcinoma"
32440157,"Zeng Y,Zhu X,Wang Y,Liu B,Yang X,Wang Q,Du J,Ma Y,Lin L,Fu P,Xiao H,Guo QN","Clinicopathological, Immunohistochemical and Molecular Genetic Study on Epithelioid Glioblastoma: A Series of Fifteen Cases with Literature Review.","To observe the clinicopathological\, immunohistochemical\, and molecular genetic features of epithelioid glioblastoma (E-GBM)\, and identify tumor-associated prognostic factors.,The clinical and radiological data of fifteen cases of E-GBM were collected\, and their pathological\, immunohistochemical\, and molecular features were examined. A 1p/19q analysis via FISH\, MGMT promoter methylation by MS-PCR\, and IDH1 and BRAF V600E mutation analysis by HRM-PCR were performed. The level of EZH2 expression was valuated by immunohistochemistry in 15 E-GBM cases\, and the prognostic factors were analyzed in E-GBM patients. Fifteen non-E-GBM cases were used as a control.,The fifteen cases of E-GBM included twelve males and three females\, with fourteen cases supratentorially located. Headache was the main symptom. Microscopy revealed that the tumors were composed of epithelioid cells and some rhabdoid cells. The epithelioid and rhabdoid cells displayed focal discohesion\, scant intervening neuropil\, a distinct cell membrane\, eosinophilic cytoplasm\, and a laterally positioned nucleus. Most tumors showed high mitosis\, zonal necrosis\, and microvascular hyperplasia. Immunohistochemical findings included epithelioid cells positive for GFAP\, vimentin\, nestin\, S-100\, and INI-1. The molecular findings included no deletions of 1p/19q\, EGFR amplifications\, or IDH1 mutations in any case\, a methylated MGMT promoter in 46.7% (7/15) cases\, and a BRAFV600E mutation in 46.7% (7/15) cases. EZH2 overexpression occurred in 60.0% (9/15) of E-GBM cases. E-GBM patients with OS (≤12 months) exhibited extensive necrosis (6/6)\, EZH2 overexpression (6/6)\, MGMT promoter unmethylation (5/6)\, BRAFV600E mutation (3/6)\, and treatment (surgery4/6). E-GBM patients with OS (>12 months) exhibited focal or limited necrosis\, low or negative EZH2 expression\, MGMT promoter methylation (2/3)\, BRAFV600E mutation (3/3)\, and treatment (surgery+radiotherapy/chemo-radiotherapy\, 2/3).,E-GBM was a rare variant of glioblastoma\, with histological epithelioid features and poor prognosis. Extensive necrosis\, MGMT promoter unmethylation\, EZH2 overexpression\, and lack of adjuvant chemo-radiotherapy may indicate a poor prognosis.",OncoTargets and therapy,vol.13::3943-3952,2020,Journal Article,,,"Department of Pathology\, Second Affiliated Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400037\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Second Affiliated Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400037\, People's Republic of China.,Department of Pathology\, Second Affiliated Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400037\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,Department of Pathology\, Daping Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400042\, People's Republic of China.,0000-0002-5074-0838Department of Pathology\, Second Affiliated Hospital\, Amy Medical University (Third Military Medical University)\, Chongqing 400037\, People's Republic of China.",,,,,"central nervous system tumor,clinicopathological features,differential diagnosis,epithelioid glioblastoma,immunohistochemistry,molecular genetics"
32441371,"Medina BD,Choi BH,Rodogiannis KG,Moran U,Shapiro RL,Pavlick A,Osman I,Berman RS,Lee AY",Metastasectomy for melanoma is associated with improved overall survival in responders to targeted molecular or immunotherapy.,"Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly\, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies.,Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics\, response to treatment\, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method.,Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors\, 11 received targeted inhibitors\, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%)\, palliation (34%)\, and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months\, P = .018).,Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.",Journal of surgical oncology,vol.122:3:555-561,2020,Journal Article,"|Female|,|Humans|,|Immunotherapy|methods|,|Male|,|Melanoma|mortality|secondary|surgery|therapy|,|Metastasectomy|,|Molecular Targeted Therapy|methods|,|Neoplasm Staging|,|Retrospective Studies|",,"Division of Surgical Oncology\, Department of Surgery\, New York University Langone Health\, New York\, New York.,Division of Surgical Oncology\, Department of Surgery\, New York University Langone Health\, New York\, New York.,Interdisciplinary Melanoma Cooperative Group\, New York University Langone Health\, New York\, New York.,Interdisciplinary Melanoma Cooperative Group\, New York University Langone Health\, New York\, New York.,Division of Surgical Oncology\, Department of Surgery\, New York University Langone Health\, New York\, New York.,Interdisciplinary Melanoma Cooperative Group\, New York University Langone Health\, New York\, New York.,Interdisciplinary Melanoma Cooperative Group\, New York University Langone Health\, New York\, New York.,http://orcid.org/0000-0002-5026-5651Division of Surgical Oncology\, Department of Surgery\, New York University Langone Health\, New York\, New York.,http://orcid.org/0000-0002-8143-2635Division of Surgical Oncology\, Department of Surgery\, New York University Langone Health\, New York\, New York.",,,,,"checkpoint blockade,melanoma,metastasectomy,targeted molecular therapy"
32441577,"Maity P,Halder A,Ghosh R,Chatterjee U,Barman S,Sarkar R",Immunohistochemistry as a Surrogate Marker of Underlying Molecular Derangements in Sporadic Colorectal Carcinoma in Children - A Series of Three Cases.,"Background: Colorectal carcinomas (CRCs) are uncommon tumors in children. Here, we elucidate three cases of childhood CRCs with their underlying molecular derangements using immunohistochemistry (IHC) with emphasis on BRAF mutation. Case summary: All three CRCs were sporadic tumors involving the left colon with two of them having a mucinous phenotype. We performed IHC for BRAF, p53 and β-catenin along with markers of microsatellite instability (MSI) in all three tumors. All the tumors had diffuse strong cytoplasmic BRAF positivity, with focal p53 positivity in two cases and cytoplasmic β-catenin staining in one case. One case showed CpG island hypermethylation with isolated loss of PMS2 staining. None of the cases had any family history of CRC. Conclusions: IHC can be used as a surrogate marker for determining the underlying molecular derangements in CRC. Sporadic CRCs in children are a cumulative effect of multiple mutations, of which BRAF mutation is significant and critical for planning targeted therapy.",Fetal and pediatric pathology,vol.::1-9,2020,Journal Article,,,"Department of Pathology\, Institute of Postgraduate Medical Education and Research\, Kolkata\, India.,Department of GI Pathology\, Institute of Postgraduate Medical Education and Research\, Kolkata\, India.,Department of GI Pathology\, Institute of Postgraduate Medical Education and Research\, Kolkata\, India.,Department of Pathology\, Institute of Postgraduate Medical Education and Research\, Kolkata\, India.,Department of Pediatric Surgery\, Institute of Postgraduate Medical Education and Research\, Kolkata\, India.,Department of Pediatric Surgery\, Institute of Postgraduate Medical Education and Research\, Kolkata\, India.",,,,,"BRAF,IHC,MSI,colorectal carcinoma,pediatric tumors"
32441866,"Roncarati R,Lupini L,Miotto E,Saccenti E,Mascetti S,Morandi L,Bassi C,Rasio D,Callegari E,Conti V,Rinaldi R,Lanza G,Gafà R,Papi A,Frassoldati A,Sabbioni S,Ravenna F,Casoni GL,Negrini M",Molecular testing on bronchial washings for the diagnosis and predictive assessment of lung cancer.,"Cytopathological analyses of bronchial washings (BWs) collected during fibre-optic bronchoscopy are often inconclusive for lung cancer diagnosis. To address this issue, we assessed the suitability of conducting molecular analyses on BWs, with the aim to improve the diagnosis and outcome prediction of lung cancer. The methylation status of RASSF1A, CDH1, DLC1 and PRPH was analysed in BW samples from 91 lung cancer patients and 31 controls, using a novel two-colour droplet digital methylation-specific PCR (ddMSP) technique. Mutations in ALK, BRAF, EGFR, ERBB2, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1 and TP53 and gene fusions of ALK, RET and ROS1 were also investigated, using next-generation sequencing on 73 lung cancer patients and 14 tumour-free individuals. Our four-gene methylation panel had significant diagnostic power, with 97% sensitivity and 74% specificity (relative risk, 7.3; odds ratio, 6.1; 95% confidence interval, 12.7-127). In contrast, gene mutation analysis had a remarkable value for predictive, but not for diagnostic, purposes. Actionable mutations in EGFR, HER2 and ROS1 as well as in other cancer genes (KRAS, PIK3CA and TP53) were detected. Concordance with gene mutations uncovered in tumour biopsies was higher than 90%. In addition, bronchial-washing analyses permitted complete patient coverage and the detection of additional actionable mutations. In conclusion, BWs are a useful material on which to perform molecular tests based on gene panels: aberrant gene methylation and mutation analyses could be performed as approaches accompanying current diagnostic and predictive assays during the initial workup phase. This study establishes the grounds for further prospective investigation.",Molecular oncology,vol.14:9:2163-2175,2020,"Research Support, Non-U.S. Gov't",,,"0000-0002-2371-3316Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Azienda Ospedaliero-Universitaria di Ferrara\, Division of Respiratory Endoscopy\, S. Anna Hospital\, Cona\, Italy.,Azienda Ospedaliero-Universitaria di Ferrara\, Division of Respiratory Endoscopy\, S. Anna Hospital\, Cona\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Department of Clinical and Molecular Medicine\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Pneumology Division\, State Hospital\, San Marino\, Republic of San Marino.,Division of Anatomic Pathology\, Carlo Poma Hospital\, Mantova\, Italy.,Azienda Ospedaliero-Universitaria di Ferrara\, Division of Anatomic Pathology\, S. Anna Hospital\, Cona\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Azienda Ospedaliero-Universitaria di Ferrara\, Division of Respiratory Endoscopy\, S. Anna Hospital\, Cona\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.,Laboratorio per le Tecnologie delle Terapie Avanzate\, Tecnopolo\, University of Ferrara\, Italy.,Division of Pneumology and Intensive Respiratory Unit\, Carlo Poma Hospital\, Mantova\, Italy.,Azienda Ospedaliero-Universitaria di Ferrara\, Division of Respiratory Endoscopy\, S. Anna Hospital\, Cona\, Italy.,Department of Morphology\, Surgery and Experimental Medicine\, University of Ferrara\, Italy.",,,,,"early diagnosis,liquid biopsy,lung cancer,molecular test,therapeutic decision-making"
32445930,"Loo K,Soliman I,Renzetti M,Li T,Wu H,Reddy S,Olszanski AJ,Farma JM",Impact of Sun Exposure and Tanning Patterns on Next-Generation Sequencing Mutations in Melanoma.,"For the past 30 y\, the incidence rate of malignant melanoma has risen steadily. Ultraviolet radiation exposure has been identified as the most prevalent modifiable risk factor for melanoma. Here\, next-generation sequencing was used to analyze the relationship between multiple sun exposure factors and select cancer-related genes to determine the relationship of sun exposure on the molecular profiles of melanomas.,The collection and analysis of study samples were approved by the institutional review board. The patient cohort consisted of 173 patients whose melanoma tissue samples underwent next-generation sequencing analysis for somatic mutations of 50 cancer-related genes. Univariate and multivariate analyses were conducted.,Patients with a history of blistering sunburn had an absolute mutation incidence of 1.67 mutations per patient\, compared with patients without a history of blistering sunburn\, who had an absolute mutation incidence of 1.16 mutations per patient (P = 0.028). A BRAF mutation was found in more tumors of patients who reported visiting a tanning salon (57.14%)\, compared with those who had not (18.75%; P = 0.0463). Patients with a previous history of skin cancer were more likely to have a CDKN2A mutation (20.83%)\, compared with those without a previous history of skin cancer (7.76%; P = 0.0292).,The trends seen in the molecular profiles of melanomas with respect to various sun exposure factors suggest that sun exposure impacts genetic makeup. Considering the increase in absolute mutation incidence in patients with a history of blistering sunburn suggests that additional genes may contribute to the pathology of malignancy. Future studies will use the unique molecular profiles of melanomas to personalize patient treatments.",The Journal of surgical research,vol.254::147-153,2020,"Research Support, Non-U.S. Gov't","|Adult|,|Aged|,|Aged\, 80 and over|,|Cyclin-Dependent Kinase Inhibitor p16|genetics|,|Female|,|High-Throughput Nucleotide Sequencing|,|Humans|,|Male|,|Melanoma|epidemiology|genetics|,|Middle Aged|,|Mutation|genetics|,|Proto-Oncogene Proteins B-raf|genetics|,|Skin Neoplasms|epidemiology|genetics|,|Sunbathing|statistics & numerical data|,|Sunburn|genetics|,|Sunlight|adverse effects|,|Tanning|,|Tumor Suppressor Protein p53|genetics|,|Ultraviolet Rays|adverse effects|",,"Department of Surgical Oncology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania; Lewis Katz School of Medicine at Temple University\, Philadelphia\, Pennsylvania.,Department of Surgical Oncology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania.,Department of Surgical Oncology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania; Lewis Katz School of Medicine at Temple University\, Philadelphia\, Pennsylvania.,Department of Statistics\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania.,Department of Pathology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania.,Department of Surgical Oncology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania.,Department of Medical Oncology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania.,Department of Surgical Oncology\, Fox Chase Cancer Center\, Philadelphia\, Pennsylvania. Electronic address: Jeffrey.Farma@fccc.edu.","CDKN2A protein\, human,Cyclin-Dependent Kinase Inhibitor p16,TP53 protein\, human,Tumor Suppressor Protein p53,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"Melanoma,Next-generation sequencing,Sun exposure"
32355756,"Song LB,Zhang QJ,Hou XY,Xiu YY,Chen L,Song NH,Lu Y",A twelve-gene signature for survival prediction in malignant melanoma patients.,"Melanoma is defined as a highly mutational heterogeneous disease containing numerous alternations of the molecule. However\, due to the phenotypically and genetically heterogeneity of malignant melanoma\, conventional clinical characteristics remain restricted or limited in the ability to accurately predict individual outcomes and survival. This study aimed to establish an accurate gene expression signature to predict melanoma prognosis.,In this study\, we established an RNA sequencing-based 12-gene signature data of melanoma patients obtained from 2 independent databases: the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. We evaluated the quality of each gene to predict survival conditions in each database by employing univariate and multivariate regression models. A prognostic risk score based on a prognostic signature was determined. This prognostic gene signature further classified patients into low-risk and high-risk groups.,Based on a prognostic signature\, a prognostic risk score was determined. This prognostic gene signature further divided the patients into low-risk and high-risk groups. In the chemotherapy and radiotherapy groups of the TCGA cohort and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) expression group in the GEO cohort\, patients in the low-risk group had a longer survival duration compared to patients in the high-risk group. Nevertheless\, the immunotherapy group in the TCGA database and neuroblastoma RAS viral oncogene homolog (NRAS) expression group in the GEO database had no significant differences in statistics. Moreover\, this gene signature was associated with patient prognosis regardless of whether the Breslow depth was greater than or less than 3.75 mm. Stratified gene set enrichment analysis (GSEA) revealed that certain immune-related pathways\, such as the T-cell signaling pathway\, chemokine signaling pathway\, and primary immunodeficiency\, were significantly enriched in the low-risk group of both TCGA and GEO cohorts. This information implied the immune-related properties of the 12-gene signature.,Our study emphasizes the significance of the gene expression signature in that it may be an indispensable prognostic predictor in melanoma and has great potential for application in personalized treatment.",Annals of translational medicine,vol.8:6:312,2020,Journal Article,,,"Department of Dermatology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.,Department of Urology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.,Department of Dermatology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.,Department of Dermatology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.,Department of Dermatology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.,Department of Urology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.,Department of Dermatology\, The First Affiliated Hospital of Nanjing Medical University\, Nanjing 210029\, China.",,,,,"Melanoma,gene expression signature,prognostic prediction,treatment"
32348888,"Kim SH,Hwang K,Lee KS,Choe G,Kim CY",Cerebellar Pleomorphic Xanthoastrocytoma with BRAF V600E Mutation.,"Pleomorphic xanthoastrocytoma (PXA) is a rare type of astrocytoma with a peak incidence from 10 to 19 years of age. PXA is found most commonly in the supratentorium. When it is present in atypical areas such as the infratentorium\, it is often overlooked as a potential differential diagnosis.,This report discusses the case of an 18-year-old woman with a pure PXA in the left cerebellum. The case consists of interesting pathologic and molecular features which do not align with the literature about PXA: a positive finding for BRAF V600E mutation and a negative finding for cluster of differentiation 34 expression. A review of pure PXA cases in the infratentorium has also been completed.,To our knowledge\, this is the first case of PXA in the infratentorium with BRAF V600E mutation. The case also highlights the clinical relevance of including PXA as a differential diagnosis for lesions of the infratentorium.",World neurosurgery,vol.139::577-581,2020,Review,"|Adolescent|,|Astrocytoma|diagnostic imaging|genetics|surgery|,|Cerebellar Neoplasms|diagnostic imaging|genetics|surgery|,|Female|,|Follow-Up Studies|,|Humans|,|Mutation|genetics|,|Proto-Oncogene Proteins B-raf|genetics|",,"School of Medicine\, The University of Auckland\, Auckland\, New Zealand; Department of Neurosurgery\, Seoul National University Bundang Hospital\, Seongnam-si\, Republic of Korea.,Department of Neurosurgery\, Seoul National University Bundang Hospital\, Seongnam-si\, Republic of Korea. Electronic address: ns.kihwan@gmail.com.,Department of Pathology\, Seoul National University Bundang Hospital\, Seongnam-si\, Republic of Korea.,Department of Pathology\, Seoul National University Bundang Hospital\, Seongnam-si\, Republic of Korea; Department of Neurosurgery\, Seoul National University College of Medicine\, Seongnam-si\, Republic of Korea.,Department of Neurosurgery\, Seoul National University Bundang Hospital\, Seongnam-si\, Republic of Korea; Department of Neurosurgery\, Seoul National University College of Medicine\, Seongnam-si\, Republic of Korea.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF V600E mutation,Cerebellum,Infratentorium,Pleomorphic xanthoastrocytoma"
32350854,"Chung YC,Chiu HH,Wei WC,Chang KJ,Chao WT",Application of trastuzumab emtansine in HER-2-positive and KRAS/BRAF-mutated colon cancer cells.,"Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) for the treatment of human epidermal growth factor receptor 2 (HER-2)-positive breast cancer. T-DM1 is based on the trastuzumab antibody and delivers a toxic agent into breast cancer cells through endocytic mechanism. This study evaluated whether T-DM1 can be used in HER-2-positive colon cancer cells which harbour KRAS/ BRAF mutation with limited treatment.,LS174T and HT-29 which are KRAS and BRAF mutant HER-2-positive colon cancer cells were used in this study. Cells were first treated with T-DM1; cetuximab and trastuzumab were applied for comparison\, the effect of drug sensitivity was determined. Cells were then transfected with plasmid to overexpress HER-2 or the endocytic protein\, caveolin-1 or furthermore pretreated with metformin to examine the effect of T-DM1 efficacy. Finally\, a xenograft mouse model was used to evaluate the drug efficacy in vivo.,The results showed that T-DM1 had better inhibitory effect than cetuximab and trastuzumab on LS174T and HT-29 cells. HER-2 or caveolin-1 overexpression with plasmid in the cells to increase T-DM1 recognition or internalization can increase the sensitivity to T-DM1. When cells were pretreated with metformin\, caveolin-1 expression was induced and promoted T-DM1 uptake and enhanced cell toxicity. In xenograft mouse model\, combined treatment of T-DM1 and metformin had apparent inhibitory effect on subcutaneous tumour growth.,The results of this study suggested that T-DM1 has potential in the treatment of HER-2-positive colon cancer cells\, and application of metformin has therapeutic benefits during T-DM1 treatment.",European journal of clinical investigation,vol.::e13255,2020,Journal Article,,,"Department of Surgery\, Cheng-Ching General Hospital\, Taichung\, Taiwan.,Department of Proctology\, Cheng-Ching General Hospital\, Taichung\, Taiwan.,Department of Surgery\, Cheng-Ching General Hospital\, Taichung\, Taiwan.,Department of Breast Surgery\, Cardinal Tien Hospital\, Taipei\, Taiwan.,https://orcid.org/0000-0003-4122-2198Department of Life Science\, Tunghai University\, Taichung\, Taiwan.",,Cheng-Ching hospital,,CH10600204A,"KRAS mutation,T-DM1,caveolin-1,colon cancer,metformin"
32351561,"Pastoricchio M,Cubisino A,Lanzaro A,Troian M,Zanconati F,Bernardi S,Fabris B,de Manzini N,Dobrinja C",Impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology Classification of Thyroid Nodules in the Treatment of Indeterminate Follicular Lesions: Five-Year Results at a Single Center.,"Aim of the study was to assess the impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology (SIAPEC) classification of 2014\, on the treatment of indeterminate thyroid lesions (TIR3).,We retrospectively analyzed patients undergoing thyroid surgery for TIR3 lesions between 2013 and 2018\, at the General Surgery Department of Trieste University Hospital. According to the SIAPEC classification\, patients were divided into TIR3A and TIR3B groups. All patients treated before 2014 underwent surgical treatment\, and surgical specimens were retrospectively classified after revision of fine-needle aspiration cytology. Starting 2014\, TIR3A patients were treated only when symptomatic (i.e.\, coexistent bilateral thyroid goiter or growing TIR3A nodules)\, whereas TIR3B patients always received surgical treatment. Hemithyroidectomy (HT) was the procedure of choice. Total thyroidectomy (TT) was performed in case of concurrent bilateral goiter\, autoimmune thyroid disease\, and/or presence of BRAF and/or RAS mutation. Lastly\, we analyzed the malignancy rate in the two groups.,29 TIR3A and 90 TIR3B patients were included in the study. HT was performed in 10 TIR3A patients and 37 TIR3B patients\, respectively\, with need for reoperation in 4 TIR3B (10.8%) patients due to histological findings of follicular thyroid carcinoma >1  cm. The malignancy rates were 17.2% in TIR3A and 31.1% in TIR3B\, (p = 0.16). Predictability of malignancy was almost 89% in BRAF mutation and just 47% in RAS mutation.,The new SIAPEC classification in association with biomolecular markers has improved diagnostic accuracy\, patient selection\, and clinical management of TIR3 lesions.",International journal of endocrinology,vol.2020::7325260,2020,Journal Article,,,"https://orcid.org/0000-0002-5192-7231Division of Clinical Surgery\, Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Cattinara Teaching Hospital\, Trieste 34149\, Italy.,Division of Clinical Surgery\, Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Cattinara Teaching Hospital\, Trieste 34149\, Italy.,Division of Clinical Surgery\, Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Cattinara Teaching Hospital\, Trieste 34149\, Italy.,https://orcid.org/0000-0001-7867-1646Division of Clinical Surgery\, Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Cattinara Teaching Hospital\, Trieste 34149\, Italy.,Department of Medical\, Surgical and Health Sciences\, Università Degli Studi di Trieste\, Cattinara Teaching Hospital\, Strada di Fiume 447\, 34149 Trieste\, Italy.,https://orcid.org/0000-0002-7429-3075Department of Medical\, Surgical and Health Sciences\, Università Degli Studi di Trieste\, Cattinara Teaching Hospital\, Strada di Fiume 447\, 34149 Trieste\, Italy.,Department of Medical\, Surgical and Health Sciences\, Università Degli Studi di Trieste\, Cattinara Teaching Hospital\, Strada di Fiume 447\, 34149 Trieste\, Italy.,https://orcid.org/0000-0002-8362-9044Division of Clinical Surgery\, Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Cattinara Teaching Hospital\, Trieste 34149\, Italy.,Division of Clinical Surgery\, Department of Medical\, Surgical and Health Sciences\, University of Trieste\, Cattinara Teaching Hospital\, Trieste 34149\, Italy.",,,,,
31759151,"Zeng X,Zhan Q,Gao Y,Cui N,Dong M,Feng L,Chu L,Liu J",The Coexistence of Gliosarcoma and Arteriovenous Malformation with the BRAF V600E Mutation.,"The authors report a case of a woman aged 33 years who suffered from the combination of primary gliosarcoma and arteriovenous malformation as the first clinical presentation of intracranial hemorrhage.,Subsequently\, gene examination rarely finds BRAF V600E mutation in the surgical specimen. The lesion was not completely identified with magnetic resonance imaging and digital subtraction angiography.,This case illustrates the occult and unusual feature of gliosarcoma. The pathogenesis of such coexistence might be related to underlying genetic alterations.",World neurosurgery,vol.134::594-597,2020,Case Reports,"|Adult|,|Angiography\, Digital Subtraction|methods|,|Arteriovenous Malformations|genetics|pathology|,|Astrocytoma|diagnosis|genetics|pathology|,|Female|,|Gliosarcoma|diagnosis|genetics|pathology|,|Humans|,|Intracranial Hemorrhages|diagnosis|pathology|,|Proto-Oncogene Proteins B-raf|genetics|",,"Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Department of Neurosurgery\, the Affiliated Hospital of Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Department of Neurosurgery\, the Affiliated Hospital of Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Department of Neurosurgery\, the Affiliated Hospital of Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China.,Guizhou Medical University\, Guiyang\, Guizhou\, People's Republic of China. Electronic address: luzicaipseudonym@outlook.com.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"Arteriovenous malformation,BRAF V600E,Gliosarcoma"
31765065,"Bergdorf KN,Lee LA,Weiss VL","BRAF molecular testing in cytopathology: Implications for diagnosis, prognosis, and targeted therapeutics.",,Cancer cytopathology,vol.128:1:9-11,2020,Journal Article,"|Antineoplastic Agents|pharmacology|therapeutic use|,|Genetic Testing|,|Humans|,|MAP Kinase Signaling System|drug effects|genetics|,|Molecular Targeted Therapy|methods|,|Mutation|,|Neoplasms|diagnosis|drug therapy|genetics|mortality|,|Phosphorylation|,|Precision Medicine|methods|,|Prognosis|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|",,",,0000-0003-0874-3207","Antineoplastic Agents,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,
31769323,"Mezheyeuski A,Ponten F,Edqvist PH,Sundström M,Thunberg U,Qvortrup C,Pfeiffer P,Sorbye H,Glimelius B,Dragomir A",Metastatic colorectal carcinomas with high SATB2 expression are associated with better prognosis and response to chemotherapy: a population-based Scandinavian study.,"Background: Survival and response to therapy in patients with metastatic colorectal cancer (mCRC) are very heterogeneous. There is an unmet need for better markers of prognosis and treatment benefit for mCRC patients. The homeobox 2 gene SATB2 has a highly specific expression in colorectal tissue and is associated with better prognosis in non-metastatic CRC.Material and methods: A population-based cohort of 798 mCRC patients was analysed. From primary tumour material, protein expression was assessed by immunohistochemistry. BRAF and KRAS mutation status was also determined. Associations with clinicopathological data, overall and progression-free survival and response to first-line chemotherapy were analysed.Results: Tumour tissue and clinical data were available from 467 patients. SATB2 was strongly expressed in 58% of cases, significantly more in left-sided, low-grade and wild-type BRAF tumours. Patients with high SATB2 tumours had longer overall survival compared with low SATB2 tumours (median 13 vs 8 months respectively, p < .001). Chemotherapy was given to 282 patients (63%). Patients with high SATB2 tumours had longer OS (median 22 vs 15 months respectively, p = .001) and more often responded to chemotherapy than those with low SATB2 (objective response 43% vs 29%, p = .02; clinical response 83% vs 67%, p = .004). Progression-free survival on first-line irinotecan chemotherapy was longer in high SATB2 cases (median 8 vs 4 months respectively, p = .019). Patients with both low SATB2 expression and mutated BRAF (n = 69) had particularly poor survival compared to the rest (median 8 and 12 months respectively, p = .001). In multivariable analysis, the SATB2 findings were independent of known clinicopathological prognostic markers, including BRAF mutation status.Conclusion: Patients with mCRC expressing high level of SATB2 have better prognosis and response to chemotherapy than those with low SATB2 expression. Patients with both low SATB2 expression and mutated BRAF had particularly poor prognosis and could thus benefit from more aggressive therapies.","Acta oncologica (Stockholm, Sweden)",vol.59:3:284-290,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Antineoplastic Agents|therapeutic use|,|Cohort Studies|,|Colorectal Neoplasms|drug therapy|genetics|metabolism|pathology|,|Female|,|Humans|,|Immunochemistry|,|Male|,|Matrix Attachment Region Binding Proteins|analysis|,|Middle Aged|,|Mutation|,|Neoplasm Metastasis|,|Prognosis|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Scandinavian and Nordic Countries|,|Transcription Factors|analysis|,|raf Kinases|genetics|",,"http://orcid.org/0000-0002-4394-2634Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.,Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.,Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.,Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.,Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.,Department of Oncology\, Odense University Hospital\, Odense C\, Denmark.,Department of Oncology\, Odense University Hospital\, Odense C\, Denmark.,Department of Oncology\, Haukeland University Hospital\, Bergen\, Norway.,Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.,http://orcid.org/0000-0003-2777-8114Department of Immunology\, Genetics and Pathology\, Uppsala University\, Uppsala\, Sweden.","Antineoplastic Agents,KRAS protein\, human,Matrix Attachment Region Binding Proteins,SATB2 protein\, human,Transcription Factors,raf Kinases,Proto-Oncogene Proteins p21(ras)",,,,
31773354,"Igarashi T,Shimizu K,Usui K,Yokobori T,Ohtaki Y,Nakazawa S,Obayashi K,Yajima T,Nobusawa S,Ohkawa T,Katoh R,Motegi Y,Ogawa H,Harimoto N,Ichihara T,Mitani Y,Yokoo H,Mogi A,Shirabe K",Significance of RAS mutations in pulmonary metastases of patients with colorectal cancer.,"RAS/BRAF mutations of colorectal cancer (CRC) play a crucial role in carcinogenesis and cancer progression and need to be considered for the therapeutic strategy choice. We used next-generation-sequencing (NGS) technology to assess RAS/BRAF mutation differences between primary CRC and corresponding pulmonary metastases (PMs).,We examined the mutation statuses of the KRAS 12/13/61/146\, NRAS 12/13/61/146\, and BRAF 600 codons in genomic DNA from fresh-frozen or formalin-fixed paraffin-embedded tissues derived from 34 primary lesions and 52 corresponding PMs from 36 patients with CRC.,We found RAS mutations in 76% (26/34) of primary CRC lesions and in 86% (31/36) of PMs. While 27% (7/26) of the primary CRC RAS mutations were heterogeneous\, all the RAS mutations in PMs were homogeneous. Of the mutations in PMs\, 71% (22/31) were KRAS G>A transitions\, of which 82% (18/22) were KRAS G12D or G13D. The RAS mutation discordance between primary tumors and PMs was 12.1% (4/33). RAS mutations with the same genotyping were detected in all synchronous and metachronous PMs from 9 patients. We found no BRAF mutations in either primary or pulmonary tissues.,Our NGS analysis suggests that RAS mutations of PM of patients with CRC are more common than initially thought. The presence of KRAS mutations in CRC specimens\, especially G12D or G13D mutations\, seems to promote PM formation.",International journal of clinical oncology,vol.25:4:641-650,2020,Journal Article,"|Aged|,|Aged\, 80 and over|,|Colorectal Neoplasms|genetics|pathology|,|Female|,|GTP Phosphohydrolases|genetics|,|High-Throughput Nucleotide Sequencing|,|Humans|,|Lung Neoplasms|genetics|secondary|,|Male|,|Membrane Proteins|genetics|,|Middle Aged|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|",,"Department of Hepatobiliary and Pancreatic Surgery\, Gunma University Graduate School of Medicine\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan. kmshimizu@gmail.com.,Genetic Diagnosis Technology Unit\, RIKEN Center of Integrative Medical Sciences\, 1-7-22 Suehiro-cho\, Tsurumi-ku\, Yokohama\, Kanagawa\, 230-0045\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Department of Human Pathology\, Gunma University Graduate School of Medicine\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Genetic Diagnosis Technology Unit\, RIKEN Center of Integrative Medical Sciences\, 1-7-22 Suehiro-cho\, Tsurumi-ku\, Yokohama\, Kanagawa\, 230-0045\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Department of Hepatobiliary and Pancreatic Surgery\, Gunma University Graduate School of Medicine\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,K.K. DNAFORM\, 75-1 Ono-machi\, Tsurumi-ku\, Yokohama\, Kanagawa\, 230-0046\, Japan.,K.K. DNAFORM\, 75-1 Ono-machi\, Tsurumi-ku\, Yokohama\, Kanagawa\, 230-0046\, Japan.,Department of Human Pathology\, Gunma University Graduate School of Medicine\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Integrative Center of General Surgery\, Gunma University Hospital\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.,Department of Hepatobiliary and Pancreatic Surgery\, Gunma University Graduate School of Medicine\, 3-39-22 Showa-machi\, Maebashi\, Gunma\, 371-8511\, Japan.","KRAS protein\, human,Membrane Proteins,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human,Proto-Oncogene Proteins p21(ras)","Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science,Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science",",","22590516,19390359","Colorectal cancer,Pulmonary metastasis,Rat sarcoma viral oncogene homolog (RAS)"
31774543,"Pellegrini C,Cardelli L,Padova M,Nardo LD,Ciciarelli V,Rocco T,Cipolloni G,Clementi M,Cortellini A,Ventura A,Leocata P,Fargnoli MC",Intra-patient Heterogeneity of BRAF and NRAS Molecular Alterations in Primary Melanoma and Metastases.,"Mutations in MAPK signalling genes are driver events in melanoma, and have therapeutic relevance in the metastatic and adjuvant setting. This study evaluated the intra-patient heterogeneity of BRAF, NRAS and c-KIT mutational status between 30 primary melanomas and 39 related metastases, using molecular analysis and immunohistochemistry. BRAF mutations were identified in 46.7% of primary melanomas and 48.7% of metastases and NRAS mutations in 20% and 25.6%, respectively. Intra-patient heterogeneity was detected in 13.3% of patients for both BRAF and NRAS genes and was not associated with clinico-pathological characteristics of melanomas or metastases. High consistency was observed between immunostaining and molecular methods for BRAFV600E (k = 0.90; p < 0.001) and NRASQ61R (k = 0.87; p < 0.001). These findings demonstrate a relevant intra-patient heterogeneity between primary and metastatic lesions that is independent of clinical variables and methodological approach.",Acta dermato-venereologica,vol.100:1:adv00040,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Biomarkers\, Tumor|genetics|,|DNA Mutational Analysis|,|Female|,|GTP Phosphohydrolases|genetics|,|Genetic Heterogeneity|,|Genetic Predisposition to Disease|,|Humans|,|Male|,|Melanoma|genetics|secondary|,|Membrane Proteins|genetics|,|Middle Aged|,|Mutation|,|Phenotype|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins c-kit|genetics|,|Skin Neoplasms|genetics|pathology|",,"Dermatology Unit\, Department of Biotechnological and Applied Clinical Science \, University of L'Aquila\, Via Vetoio\, Coppito\, IT-67100 L'Aquila\, Italy.,,,,,,,,,,,","Biomarkers\, Tumor,Membrane Proteins,KIT protein\, human,Proto-Oncogene Proteins c-kit,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human",,,,"BRAF,NRAS,c-KIT,heterogeneity,melanoma,metastases"
31783291,"Wu CC,Wang JH,Lin PC,Liang CA,Huang CY,Lien HC,Chen CY,Chou KJ,Su YC",Tumor sidedness and efficacy of first-line therapy in patients with RAS/BRAF wild-type metastatic colorectal cancer: A network meta-analysis.,"We conducted a systemic search of several databases for randomized controlled trials (RCTs) that reported efficacy and safety outcomes of drugs for left-sided and right-sided metastatic colorectal cancer (mCRC), to identify the best available treatment. A network meta-analysis with mixed comparisons was created to interpret the best treatment option using the surface under the cumulative ranking curve. In the left-sided rat sarcoma (RAS) wild-type (WT) mCRC patients, bevacizumab, panitumumab, or cetuximab with chemotherapy groups showed a significantly better objective response rate than the chemotherapy alone group. The progression-free survival (PFS) and overall survival were better with panitumumab or cetuximab with chemotherapy than with chemotherapy alone. In the right-sided RAS WT mCRC patients, PFS for bevacizumab with chemotherapy was significantly better than that for cetuximab with chemotherapy. Cetuximab, closely followed by panitumumab, is the most effective treatment in left-sided RAS WT mCRC. Bevacizumab is more effective in right-sided mCRC.",Critical reviews in oncology/hematology,vol.145::102823,2020,Meta-Analysis,"|Antibodies\, Monoclonal|,|Antineoplastic Combined Chemotherapy Protocols|,|Bevacizumab|,|Cetuximab|,|Colorectal Neoplasms|drug therapy|genetics|pathology|,|Disease-Free Survival|,|Functional Laterality|,|Humans|,|Network Meta-Analysis|,|Proto-Oncogene Proteins B-raf|",,"Division of Colorectal Surgery\, Department of Surgery\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan; School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan.,Division of Colorectal Surgery\, Department of Surgery\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan.,Department of Medical Education and Research\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan; Department of Pharmacy\, School of Pharmacy\, Kaohsiung Medical University\, Kaohsiung\, Taiwan. Electronic address: jia.love70@vghks.gov.tw.,Department of Pharmacy\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan.,Department of Pharmacy\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan.,Institute of Epidemiology and Preventive Medicine\, College of Public Health\, National Taiwan University\, Taipei\, Taiwan.,Department of Pharmacy\, School of Pharmacy\, Kaohsiung Medical University\, Kaohsiung\, Taiwan; Master Program in Clinical Pharmacy\, School of Pharmacy\, Kaohsiung Medical University\, Kaohsiung\, Taiwan; Department of Medical Research\, Kaohsiung Medical University\, Kaohsiung\, Taiwan.,School of Medicine\, National Yang-Ming University\, Taipei\, Taiwan; Division of Nephrology\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan.,Department of Pharmacy\, Kaohsiung Veterans General Hospital\, Kaohsiung\, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences\, College of Medicine\, National Cheng-Kung University\, Tainan\, Taiwan. Electronic address: pauleoswu@hotmail.com.","Antibodies\, Monoclonal,Bevacizumab,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Cetuximab",,,,"First-line therapy,Metastatic colorectal cancer,Network meta-analysis,Targeted agents,Tumor sidedness"
31784187,"Kaoud TS,Mohassab AM,Hassan HA,Yan C,Van Ravenstein SX,Abdelhamid D,Dalby KN,Abdel-Aziz M",NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth.,"Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazole/oxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC50 of ∼ 0.5 μM. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-naïve (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c.",European journal of medicinal chemistry,vol.186::111885,2020,Journal Article,"|Antineoplastic Agents|chemical synthesis|chemistry|pharmacology|,|Apoptosis|drug effects|,|Cell Cycle|drug effects|,|Cell Line\, Tumor|,|Cell Proliferation|drug effects|,|Dose-Response Relationship\, Drug|,|Drug Screening Assays\, Antitumor|,|Humans|,|Melanoma|drug therapy|metabolism|pathology|,|Molecular Docking Simulation|,|Molecular Structure|,|Nitric Oxide|analysis|metabolism|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|metabolism|,|STAT3 Transcription Factor|antagonists & inhibitors|metabolism|,|Structure-Activity Relationship|",,"Division of Chemical Biology and Medicinal Chemistry\, College of Pharmacy\, The University of Texas at Austin\, Austin\, TX\, 78712\, USA.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia\, 61519\, Egypt.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia\, 61519\, Egypt.,Department of Chemistry\, Georgia State University\, Atlanta\, GA\, 30302\, USA.,Division of Chemical Biology and Medicinal Chemistry\, College of Pharmacy\, The University of Texas at Austin\, Austin\, TX\, 78712\, USA.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia\, 61519\, Egypt. Electronic address: dalia_abdelhameed@mu.edu.eg.,Division of Chemical Biology and Medicinal Chemistry\, College of Pharmacy\, The University of Texas at Austin\, Austin\, TX\, 78712\, USA. Electronic address: dalby@austin.utexas.edu.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia\, 61519\, Egypt.","Antineoplastic Agents,STAT3 Transcription Factor,STAT3 protein\, human,Nitric Oxide,BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"Acquired resistance to BRAF-Inhibition,BRAF V600E mutant,Melanoma,NO donors,Quinolines,STAT3,Triazoles"
31785018,"Escandon Brehm J,Bedogni B",Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator.,"Melanoma is a deadly tumor, which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors. However, immunotherapy poses deleterious side effects and pursuit of new therapeutic targets is warranted. As knowledge of tumor immunology advances, such targets are being recognized. C-motif chemokine receptor-5 (CCR5) is a receptor found on immune cells whose effects impact the immune response both to induce inflammation and to activate suppressor cells causing an anti-inflammatory effect. CCR5 is well known as a target for HIV therapy where its blockade is efficient and safe, it is also known that its mutation CCR5delta32 is for the most part non-pathological to its carriers. In oncology, activation of the CCR5 receptor has been observed in high-stage disease and CCR5 blockade has been associated with an increased immune response. In this letter, we build up the rationale to utilize CCR5 as a therapeutic target for metastatic melanoma.",Experimental dermatology,vol.29:2:196,2020,Journal Article,,,"0000-0003-3444-1253Dr Philip Frost Department of Dermatology and Cutaneous Surgery\, University of Miami\, Miami\, FL\, USA.,Dr Philip Frost Department of Dermatology and Cutaneous Surgery\, University of Miami\, Miami\, FL\, USA.",,NCI NIH HHS,United States,R21 CA187695,"cancer,immunotherapy,inflammation,melanoma"
31630459,"Fukuoka K,Mamatjan Y,Ryall S,Komosa M,Bennett J,Zapotocky M,Keith J,Myrehaug S,Hazrati LN,Aldape K,Laperriere N,Bouffet E,Tabori U,Hawkins C",BRAF V600E mutant oligodendroglioma-like tumors with chromosomal instability in adolescents and young adults.,"We performed genome-wide methylation analysis on 136 pediatric low-grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma-like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken-wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high-grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co-deletion or IDH1 p.R132H mutation. Hierarchical clustering and t-stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric-type low-grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow-up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild-type low-grade gliomas which may be confused with ""molecular GBM."" Further, they highlight the heterogeneity of IDH wild-type gliomas and the relatively indolent behavior of ""pediatric-type"" gliomas.","Brain pathology (Zurich, Switzerland)",vol.30:3:515-523,2020,"Research Support, Non-U.S. Gov't",,,"0000-0003-2568-0877Division of Haematology/Oncology\, Department of Paediatrics\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Princess Margaret Cancer Centre and MacFeeters\, Hamilton Centre for Neuro-Oncology Research\, Toronto\, ON\, Canada.,Department of Laboratory Medicine and Pathobiology\, University of Toronto\, Toronto\, ON\, Canada.,Program in Genetics and Genome Biology\, The Arthur and Sonia Labatt Brain Tumour Research Centre\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Division of Haematology/Oncology\, Department of Paediatrics\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Division of Haematology/Oncology\, Department of Paediatrics\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Department of Pathology\, Sunnybrook Health Sciences Centre\, Toronto\, ON\, Canada.,Department of Radiation Oncology\, Sunnybrook Health Sciences Centre\, Toronto\, ON\, Canada.,Division of Pathology\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Princess Margaret Cancer Centre and MacFeeters\, Hamilton Centre for Neuro-Oncology Research\, Toronto\, ON\, Canada.,Department of Radiation Oncology\, Princess Margaret Hospital\, Toronto\, ON\, Canada.,Division of Haematology/Oncology\, Department of Paediatrics\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Division of Haematology/Oncology\, Department of Paediatrics\, The Hospital for Sick Children\, Toronto\, ON\, Canada.,Division of Pathology\, The Hospital for Sick Children\, Toronto\, ON\, Canada.",,"Tokyo Children's Cancer Study Group (TCCSG) scholarship of the Gold Ribbons Network of Japan,RESTRACOMP of the Hospital for Sick Children,Canadian Institute of Health Research (CIHR) CGS-M scholarship,Ontario Graduate Scholarship (OGS),A Kids' Brain Tumor Cure Foundation","International,International,International,International,International",,"BRAF V600E mutation,chromosomal instability,low grade glioma,oligodendroglioma"
31678973,Müller HL,The Diagnosis and Treatment of Craniopharyngioma.,"Craniopharyngioma (CP) is a rare embryonic malformation of the sellar/parasellar region with a low histological grade. Clinical manifestations are related to hypothalamic/pituitary deficiencies, visual impairment, and increased intracranial pressure. Recent insight into the molecular pathogenesis of CP opens new perspectives on targeted therapy in papillary CP harboring BRAF-V600E mutations. Further research to elucidate pathogenic mechanisms and hopefully prevent hypothalamic involvement of CP is warranted. If the tumor is favorably localized, the therapy of choice is complete resection, with care taken to preserve the optical and hypothalamic functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), the recommended therapy is a limited hypothalamus-sparing surgical strategy followed by local irradiation. Surgical treatment strategies should be based on a multidisciplinary approach involving experienced teams. Centralizing the treatment of CP in experienced ""centers of excellence"" and multicenter-based networks for reference assessments should be considered to assure a high standard of treatment quality. CP recurrence and progression are frequent. Irradiation has proven effective in reducing recurrences and progression. Proton beam therapy, available in a wider range in the near future, will help to avoid radio-oncological side effects. Anatomical involvement and/or surgical lesions of posterior hypothalamic areas can result in serious sequelae that compromise quality of life (QoL), such as hypothalamic obesity and psychopathological symptoms. Novel insights into neuropsychological sequelae after CP occurrence should be the basis for the development of therapeutic neuropsychological interventions. CP should be managed as a frequently chronic disease, providing ongoing care of pediatric and adult patients' clinical and QoL consequences by experienced multidisciplinary teams.",Neuroendocrinology,vol.110:9-10:753-766,2020,"Research Support, Non-U.S. Gov't",,,"Department of Pediatrics and Pediatric Hematology/Oncology, University Children's Hospital, Klinikum Oldenburg AöR, Oldenburg, Germany, mueller.hermann@klinikum-oldenburg.de.",,,,,"Craniopharyngioma,Hypothalamus,Irradiation,Neurosurgery,Pituitary"
31401046,"Zhou S,Liang Y,Zhang X,Liao L,Yang Y,Ouyang W,Xu H",SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway.,"SHARPIN, as a tumor-associated gene, is involved in the metastatic process of many kinds of tumors. Herein, we studied the function of Shank-associated RH domain interacting protein (SHARPIN) in melanoma metastasis and the relevant molecular mechanisms. We found that SHARPIN expression was increased in melanoma tissues and activated the process of proliferation, migration, and invasion in vitro and in vivo, resulting in a poor prognosis of the disease. Functional analysis demonstrated that SHARPIN promoted melanoma migration and invasion by regulating Ras-associated protein-1(Rap1) and its downstream pathways, including p38 and JNK/c-Jun. Rap1 activator (8-pCPT-2'-O-Me-cAMP) and inhibitor (ESI-09 and farnesylthiosalicylic acid-amide) treatments could partially rescue invasion and migration of tumor cells. Additionally, SHARPIN expression in cell lines and public datasets also indicated that molecules other than BRAF and N-RAS may contribute to SHARPIN activation. In conclusion, our broad-in-depth work suggests that SHARPIN promotes melanoma development via p38 and JNK/c-Jun pathways through upregulation of Rap1 expression.",The Journal of investigative dermatology,vol.140:2:395-403.e6,2020,"Research Support, Non-U.S. Gov't","|Adult|,|Aged\, 80 and over|,|Animals|,|Cell Line\, Tumor|,|Cell Movement|drug effects|,|Datasets as Topic|,|Disease Progression|,|Gene Expression Regulation\, Neoplastic|,|Gene Knockdown Techniques|,|Humans|,|Kaplan-Meier Estimate|,|MAP Kinase Signaling System|drug effects|,|Male|,|Melanoma|mortality|pathology|,|Mice|,|Middle Aged|,|Neoplasm Invasiveness|pathology|,|Prognosis|,|Skin|pathology|,|Skin Neoplasms|mortality|pathology|,|Telomere-Binding Proteins|agonists|antagonists & inhibitors|metabolism|,|Ubiquitins|genetics|metabolism|,|Up-Regulation|,|Xenograft Model Antitumor Assays|",,"Department of Dermatology\, Cosmetology and Venereology\, Shenzhen Hospital\, Southern Medical University\, Shenzhen\, Guangdong\, China.,Department of Dermatology\, Cosmetology and Venereology\, Shenzhen Hospital\, Southern Medical University\, Shenzhen\, Guangdong\, China. Electronic address: liangdoctor@163.com.,Department of Dermatology\, Cosmetology and Venereology\, Shenzhen Hospital\, Southern Medical University\, Shenzhen\, Guangdong\, China.,Department of Dermatology\, Cosmetology and Venereology\, Shenzhen Hospital\, Southern Medical University\, Shenzhen\, Guangdong\, China.,Department of Dermatology\, Cosmetology and Venereology\, Shenzhen Hospital\, Southern Medical University\, Shenzhen\, Guangdong\, China.,The Second Clinical Medical College\, Zhujiang Hospital\, Southern Medical University\, Guangzhou\, Guangdong\, China.,Department of Bone and Soft Tissue Surgery\, Sun Yat-Sen University Cancer Center\, Guangzhou\, Guangdong\, China.","SHARPIN protein\, human,TERF2IP protein\, human,Telomere-Binding Proteins,Ubiquitins",,,,
31096734,"Bae JM,Wen X,Kim TS,Kwak Y,Cho NY,Lee HS,Kang GH",Fibroblast Growth Factor Receptor 1 (FGFR1) Amplification Detected by Droplet Digital Polymerase Chain Reaction (ddPCR) Is a Prognostic Factor in Colorectal Cancers.,"The purpose of this study was to reveal the clinicopathological characteristics and prognostic implications associated with fibroblast growth factor receptor 1 (FGFR1) amplification in colorectal cancers (CRCs).,We measured the copy number of FGFR1 by droplet digital polymerase chain reaction (ddPCR)\, and analyzed the FGFR1 expression by immunohistochemistry\, in 764 surgically resected CRCs (SNUH2007 dataset\, 384 CRCs; SNUH Folfox dataset\, 380 CRCs).,CRCs with ≥ 3.3 copies of the FGFR1 gene were classified as FGFR1 amplified. FGFR1 amplification was found in 10 of the 384 CRCs (2.6%) in the SNUH2007 dataset\, and in 28 of the 380 CRCs (7.4%) in the SNUH Folfox dataset. In the SNUH2007 dataset\, there was no association between the FGFR1 copy number status and sex\, gross appearance\, stage\, or differentiation. High FGFR1 expression was associated with female sex and KRAS mutation. At the molecular level\, FGFR1 amplification was mutually exclusive with BRAF mutation\, microsatellite instability\, and MLH1 methylation\, in both SNUH2007 and SNUH Folfox datasets. Survival analysis revealed that FGFR1 amplification was associated with significantly worse clinical outcome compared with no FGFR1 amplification\, in both SNUH2007 and SNUH Folfox datasets. Within the SNUH2007 dataset\, CRC patients with high FGFR1 expression had an inferior progression-free survival compared with those with low FGFR1 expression. The FGFR inhibitor\, PD173074\, repressed the proliferation of a CRC cell line overexpressing FGFR1\, but not of cells with FGFR1 amplification.,FGFR1 amplification measured by ddPCR can be a prognostic indicator of poor clinical outcome in patients with CRCs.",Cancer research and treatment : official journal of Korean Cancer Association,vol.52:1:74-84,2020,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Biomarkers\, Tumor|,|Cell Survival|,|Colorectal Neoplasms|diagnosis|genetics|mortality|,|DNA Copy Number Variations|,|DNA Methylation|,|Databases\, Factual|,|Female|,|Gene Amplification|,|Gene Expression|,|Humans|,|Immunohistochemistry|,|In Situ Hybridization\, Fluorescence|,|Kaplan-Meier Estimate|,|Male|,|Middle Aged|,|Mutation|,|Neoplasm Staging|,|Polymerase Chain Reaction|methods|standards|,|Prognosis|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Receptor\, Fibroblast Growth Factor\, Type 1|genetics|metabolism|",,"Department of Pathology\, Seoul National University Hospital\, Seoul National University College of Medicine\, Seoul\, Korea.,Laboratory of Epigenetics\, Cancer Research Institute\, Seoul National University College of Medicine\, Seoul\, Korea.,Laboratory of Epigenetics\, Cancer Research Institute\, Seoul National University College of Medicine\, Seoul\, Korea.,Department of Pathology\, Seoul National University Bundang Hospital\, Seoul National University College of Medicine\, Seongnam\, Korea.,Laboratory of Epigenetics\, Cancer Research Institute\, Seoul National University College of Medicine\, Seoul\, Korea.,Department of Pathology\, Seoul National University Bundang Hospital\, Seoul National University College of Medicine\, Seongnam\, Korea.,Department of Pathology\, Seoul National University Hospital\, Seoul National University College of Medicine\, Seoul\, Korea.","Biomarkers\, Tumor,KRAS protein\, human,FGFR1 protein\, human,Receptor\, Fibroblast Growth Factor\, Type 1,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)","SNUH Research Fund,National Research Foundation of Korea,Ministry of Science\, ICT and Future Planning,Korea Health Industry Development Institute,Ministry of Health and Welfare",",,,,","04-2017-0830,2016M3A9B6026921,2011-0030049,HI14C1277","Colorectal neoplasms,Copy number alteration,Droplet digital polymerase chain reaction,Fibroblast growth factor receptor 1,Prognosis"
31862522,"Gui X,Köbel M,Ferraz JGP,Iacucci M,Ghosh S,Demetrick DJ",Newly recognized non-adenomatous lesions associated with enteric carcinomas in inflammatory bowel disease - Report of six rare and unique cases.,"It is the current view that the inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous (with classic cytologic dysplasia) and non-adenomatous (without frank cytologic dysplasia), and the latter ones are in various histomorphologies including serrated, mucinous, eosinophilic (goblet cell deficient), and differentiated (dysplasia with terminal epithelial differentiation) types. By retrospectively reviewing the surgically resected IBD-associated colorectal and ileal carcinomas (×53), analyzing the background epithelial changes/lesions in the mucosa surrounding and adjacent to invasive carcinomas, and testing the key molecular profile (KRAS, BRAF, PIK3CA, NRAS, p53, mismatch repair proteins, and SAT-B2) known to be involved in colorectal carcinogenesis, we identified 6 representative, rare and unique cases, in which non-adenomatous lesions were clearly in vicinity and in transition to invasive carcinomas. Furthermore, we identified certain colonic carcinoma-related molecular alterations, and thus further confirmed the neoplastic nature of various non-adenomatous lesions. It was also revealed that non-adenomatous lesions are heterogeneous in both morphology and molecular alterations, and that it is common to have more than one type of lesions be associated with a carcinoma. Moreover, mixed focal adenomatous dysplasia was common, which may be the necessary step in the malignant transformation of the non-adenomatous lesions.",Annals of diagnostic pathology,vol.44::151455,2020,Journal Article,"|Aged|,|Aged\, 80 and over|,|Carcinoma|diagnosis|pathology|,|Cell Transformation\, Neoplastic|,|Colitis|complications|pathology|,|Colonic Neoplasms|diagnosis|pathology|,|Female|,|Humans|,|Inflammatory Bowel Diseases|diagnosis|pathology|,|Male|,|Middle Aged|,|Precancerous Conditions|",,"Department of Pathology and Laboratory Medicine\, University of Calgary\, Canada; Alberta Precision Laboratories\, Calgary\, Canada; Department of Pathology\, University of Washington School of Medicine\, USA. Electronic address: xgui@uw.edu.,Department of Pathology and Laboratory Medicine\, University of Calgary\, Canada; Alberta Precision Laboratories\, Calgary\, Canada.,Division of Gastroenterology and Hepatology\, University of Calgary\, Canada.,Division of Gastroenterology and Hepatology\, University of Calgary\, Canada; NIHR Biomedical Research Centre\, Institute of Translational Medicine\, University of Birmingham\, UK.,Division of Gastroenterology and Hepatology\, University of Calgary\, Canada; NIHR Biomedical Research Centre\, Institute of Translational Medicine\, University of Birmingham\, UK.,Department of Pathology and Laboratory Medicine\, University of Calgary\, Canada; Alberta Precision Laboratories\, Calgary\, Canada.",,,,,"Colitis-associated colorectal carcinoma (CACRC),Colitis-associated dysplasia (CAD),Dysplasia,IBD-associated dysplasia,Inflammatory bowel diseases (IBD),Precancerous lesion"
31865250,"Cubero Rego D,Lee H,Boguniewicz A,Jennings TA","Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study.","Rigid diagnostic criteria for NIFTP have been recently proposed. The frequency of NIFTP using the new criteria is unknown\, and whether abortive papillae are associated with BRAFV600E mutation has not been studied. The aim of this study is to identify NIFTP by a retrospective review of Follicular Variant of Papillary Thyroid Carcinoma (FVPTC)\, and to study its incidence as well as the association between immunohistochemical BRAFV600E expression and abortive papillae in NIFTP.,Thyroid tumors diagnosed as FVPTC or NIFTP over a period of 18 years (2000-2017) were identified using the laboratory information system. The final pathology reports were reviewed and potential NIFTP were retrieved. The archived slides for these cases were independently reviewed by 2 pathologists. BRAFV600E (clone: VE1) immunostain was performed on representative tumor blocks. Clinical information including follow-up data was obtained from the electronic medical records.,Among the 1918 cases with the diagnosis of papillary thyroid carcinoma (PTC)\, 589 (30.7%) of FVPTC and 136 cases of potential NIFTP were identified. After the review of the archived pathology slides\, 29 lesions were morphologically reclassified as NIFTP. Four (13.7%) of these were positive for BRAFV600E; no association was found between the presence of abortive papillae and BRAFV600Eexpression (p=0.3). Exclusion of the 4 cases with BRAFV600Eexpression resulted in 25 lesions of final NIFTP\, representing 4.2% of the FVPTC and 1.3% of the PTC. The mean age of the NIFTP patients was 50 years\, 87.5% were females. The mean size of the lesions was 1.4 cm (0.1-4.0 cm). Intranuclear pseudoinclusions were not identified\, and abortive papillae were identified in 60% of NIFTP. The average follow-up was 70 (28-166) months. There were no adverse events (recurrence or metastasis) in the NIFTP group.,When strictly defined\, NIFTP comprises 1.3% of cases perviously classified as PTC. In morphological NIFTP\, no correlation is found between the presence of abortive papillae and the BRAFV600E expression. Intranuclear pseudo-inclusions are not observed in NIFTP. Modification of current morphological criteria to include BRAFV600E immunohistochemistry test may stratify NIFTP with benign outcome.",Annals of diagnostic pathology,vol.44::151439,2020,Journal Article,"|Adenocarcinoma\, Follicular|classification|genetics|pathology|,|Humans|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Retrospective Studies|,|Thyroid Cancer\, Papillary|classification|genetics|pathology|,|Thyroid Neoplasms|classification|genetics|pathology|",,"Anatomic Pathology\, Albany Medical College\, Albany\, NY 12208\, USA. Electronic address: cuberod@amc.edu.,Anatomic Pathology\, Albany Medical College\, Albany\, NY 12208\, USA.,Anatomic Pathology\, Albany Medical College\, Albany\, NY 12208\, USA.,Anatomic Pathology\, Albany Medical College\, Albany\, NY 12208\, USA.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF(V600E),NIFTP,Papillary thyroid carcinoma"
31866016,"Garbe C,Amaral T,Peris K,Hauschild A,Arenberger P,Bastholt L,Bataille V,Del Marmol V,Dréno B,Fargnoli MC,Grob JJ,Höller C,Kaufmann R,Lallas A,Lebbé C,Malvehy J,Middleton M,Moreno-Ramirez D,Pellacani G,Saiag P,Stratigos AJ,Vieira R,Zalaudek I,Eggermont AMM",European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2019.,"A unique collaboration of multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with 1- to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumour thickness ≥1.0 mm or ≥0.8 mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team (""Tumor Board""). Adjuvant therapies in stage III/IV patients are primarily anti-PD-1, independent of mutational status, or dabrafenib plus trametinib for BRAF-mutant patients. In distant metastasis, either resected or not, systemic treatment is indicated. For first-line treatment, particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In particular scenarios for patients with stage IV melanoma and a BRAF-V600 E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy. In patients with primary resistance to immunotherapy and harbouring a BRAF-V600 E/K mutation, this therapy shall be offered in second-line. Systemic therapy in stage III/IV melanoma is a rapidly changing landscape, and it is likely that these recommendations may change in the near future.","European journal of cancer (Oxford, England : 1990)",vol.126::159-177,2020,Journal Article,"|Combined Modality Therapy|,|Consensus|,|Diagnostic Imaging|standards|,|European Union|,|Humans|,|Interdisciplinary Communication|,|Melanoma|classification|diagnosis|therapy|,|Neoplasm Staging|,|Practice Guidelines as Topic|standards|",,"Center for Dermatooncology\, Department of Dermatology\, Eberhard Karls University\, Tuebingen\, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de.,Center for Dermatooncology\, Department of Dermatology\, Eberhard Karls University\, Tuebingen\, Germany; Portuguese Air Force Health Care Direction\, Lisbon\, Portugal.,Institute of Dermatology\, Università Cattolica\, Rome\, Italy; Fondazione Policlinico Universitario A\, Gemelli - IRCCS\, Rome\, Italy.,Department of Dermatology\, University Hospital Schleswig-Holstein (UKSH)\, Campus Kiel\, Kiel\, Germany.,Department of Dermatovenerology\, Third Faculty of Medicine\, Charles University of Prague\, Prague\, Czech Republic.,Department of Oncology\, Odense University Hospital\, Denmark.,Twin Research and Genetic Epidemiology Unit\, School of Basic & Medical Biosciences\, King's College London\, London\, SE1 7EH\, UK.,Department of Dermatology\, Erasme Hospital\, Université Libre de Bruxelles\, Brussels\, Belgium.,Dermatology Department\, CHU Nantes\, CIC 1413\, CRCINA\, University Nantes\, Nantes\, France.,Department of Dermatology\, University of L'Aquila\, Italy.,University Department of Dermatology\, Marseille\, France.,Department of Dermatology\, Medical University of Vienna\, Austria.,Department of Dermatology\, Venerology and Allergology\, Frankfurt University Hospital\, Frankfurt\, Germany.,First Department of Dermatology\, Aristotle University\, Thessaloniki\, Greece.,APHP Department of Dermatology\, INSERM U976\, University Paris 7 Diderot\, Saint-Louis University Hospital\, Paris\, France.,Melanoma Unit\, Department of Dermatology\, Hospital Clinic\, IDIBAPS\, Barcelona\, Spain.,NIHR Biomedical Research Centre\, University of Oxford\, UK.,Medical-&-Surgical Dermatology Service\, Hospital Universitario Virgen Macarena\, Sevilla\, Spain.,Dermatology Unit\, University of Modena and Reggio Emilia\, Modena\, Italy.,University Department of Dermatology\, Université de Versailles-Saint Quentin en Yvelines\, APHP\, Boulogne\, France.,1st Department of Dermatology\, University of Athens School of Medicine\, Andreas Sygros Hospital\, Athens\, Greece.,Department of Dermatology and Venereology\, Centro Hospitalar Universitário de Coimbra\, Coimbra\, Portugal.,Dermatology Clinic\, Maggiore Hospital\, University of Trieste\, Trieste\, Italy.,Princess Máxima Center\, 3584\, CS Utrecht\, the Netherlands.",,,,,"Adjuvant treatment,Cutaneous melanoma,Excisional margins,Interferon-α,Metastasectomy,Sentinel lymph node dissection,Systemic treatment,Tumour thickness"
31866097,"Wu M,Kim YS,Ryu HS,Choi SC,Kim KY,Park WC,Kim MS,Myung JY,Choi HS,Kim EJ,Lee MY",MSI status is associated with distinct clinicopathological features in BRAF mutation colorectal cancer: A systematic review and meta-analysis.,"Microsatellite stable (MSS) BRAF p.V600E mutation colorectal cancer (BRAF-CRC) has a poor prognosis\, whereas microsatellite instability (MSI) in BRAF-CRC is associated with a favorable prognosis. Although usually considered a single clinical entity\, the MSI BRAF-CRC subtype shows some distinct characteristics in comparison with the MSS BRAF-CRC subtype.,We conducted a meta-analysis to investigate the influence of clinicopathological features on MSI status in BRAF-CRC. We searched publications up to March 2019 from PubMed\, Embase\, and the Cochrane Library. The effect of MSI status on outcome parameters was assessed using odds ratios (ORs) with 95% confidence intervals (CIs) and fixed- or random-effects models according to the heterogeneity.,After reviewing 2839 reports\, 16 eligible studies including 1381 patients with BRAF-CRC met the criteria. The MSI BRAF-CRC subtype was associated with older age\, female sex (OR = 1.70; 95% CI = 1.35-2.14; P < 0.00001)\, proximal tumor location (OR = 5.10; 95% CI = 3.70-7.03; P < 0.00001)\, early TNM stage (OR = 5.28; 95% CI = 3.93-7.09; P < 0.00001)\, and poor differentiation (OR = 2.29; 95% CI = 1.60-3.28; P < 0.00001).,MSI was significantly correlated with distinct favorable clinicopathological characteristics in BRAF-CRC. These results suggest that MSI status should be considered as a stratification factor for better management of the BRAF-CRC.","Pathology, research and practice",vol.216:1:152791,2020,Systematic Review,"|Adolescent|,|Adult|,|Aged|,|Child|,|Colonic Neoplasms|diagnosis|genetics|,|Colorectal Neoplasms|diagnosis|genetics|pathology|,|Female|,|Humans|,|Kaplan-Meier Estimate|,|Male|,|Microsatellite Instability|,|Middle Aged|,|Mutation|genetics|,|Prognosis|,|Proto-Oncogene Proteins B-raf|genetics|,|Young Adult|",,"Department of Medical Laboratory\, Affiliated Hospital of Jiujiang University\, Jiujiang\, 332000\, China; Department of Physiology\, School of Medicine\, Wonkwang University\, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science\, Iksan 54538\, Republic of Korea.,Department of Gastroenterology\, Wonkwang University\, School of Medicine\, Wonkwang Digestive Disease Research Institute\, Iksan\, 54538\, Republic of Korea.,Department of Gastroenterology\, Wonkwang University\, School of Medicine\, Wonkwang Digestive Disease Research Institute\, Iksan\, 54538\, Republic of Korea.,Department of Gastroenterology\, Wonkwang University\, School of Medicine\, Wonkwang Digestive Disease Research Institute\, Iksan\, 54538\, Republic of Korea.,Department of General Surgery\, Wonkwang University\, School of Medicine\, Wonkwang Digestive Disease Research Institute\, Iksan 54538\, Republic of Korea.,Department of General Surgery\, Wonkwang University\, School of Medicine\, Wonkwang Digestive Disease Research Institute\, Iksan 54538\, Republic of Korea.,Department of Physiology\, School of Medicine\, Wonkwang University\, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science\, Iksan 54538\, Republic of Korea.,Department of Physiology\, School of Medicine\, Wonkwang University\, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science\, Iksan 54538\, Republic of Korea.,Department of Physiology\, School of Medicine\, Wonkwang University\, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science\, Iksan 54538\, Republic of Korea.,Department of Physiology\, School of Medicine\, Wonkwang University\, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science\, Iksan 54538\, Republic of Korea.,Department of Physiology\, School of Medicine\, Wonkwang University\, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science\, Iksan 54538\, Republic of Korea. Electronic address: lmy6774@hanmail.net.","BRAF protein\, human,Proto-Oncogene Proteins B-raf",,,,"BRAF p.V600E mutation,Clinicopathological features,Colorectal cancer,Microsatellite instability,Microsatellite stable"
31867109,"Takahashi S,Murata S,Seki R,Kuriyama S,Kaji M,Nakamura M",The first case of micropapillary adenocarcinoma associated with cystic airspace in a non-smoking man.,"Lung cancers associated with cystic airspaces are attracting increasing attention because of delayed diagnosis. The cancers that usually occur in smokers comprise lepidic, papillary, and/or acinar adenocarcinoma, but a micropapillary type has not been described to date. Pulmonary micropapillary adenocarcinoma was added to the 2015 World Health Organization (WHO) classification system as a new subtype with a notably poor prognosis. We describe the first micropapillary adenocarcinoma of the lung associated with cystic airspaces in a 79-year-old non-smoking man.",Respirology case reports,vol.8:2:e00513,2020,Case Reports,,,"https://orcid.org/0000-0002-5490-4203Department of Pulmonary Medicine Tokyo Saiseikai Central Hospital Tokyo Japan.,Department of Pulmonary Medicine Tokyo Saiseikai Central Hospital Tokyo Japan.,Division of Diagnostic Pathology Tokyo Saiseikai Central Hospital Tokyo Japan.,Department of Thoracic Surgery Tokyo Saiseikai Central Hospital Tokyo Japan.,Department of Thoracic Surgery Tokyo Saiseikai Central Hospital Tokyo Japan.,Department of Pulmonary Medicine Tokyo Saiseikai Central Hospital Tokyo Japan.",,,,,"BRAF mutation,EGFR mutation,lung cancers associated with cystic airspaces,micropapillary adenocarcinoma"
31869447,"Poklepovic AS,Luke JJ",Considering adjuvant therapy for stage II melanoma.,"Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti-CTLA-4 and anti-PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti-PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node-negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma-specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk-stratification and treatment-benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma.",Cancer,vol.126:6:1166-1174,2020,Review,"|Antineoplastic Agents|adverse effects|therapeutic use|,|Antineoplastic Agents\, Immunological|therapeutic use|,|Chemotherapy\, Adjuvant|,|Humans|,|Immunotherapy|methods|,|Interferons|therapeutic use|,|MAP Kinase Kinase 1|antagonists & inhibitors|,|Medical Illustration|,|Melanoma|drug therapy|genetics|pathology|surgery|,|Neoplasm Recurrence\, Local|,|Neoplasm Staging|methods|,|Numbers Needed To Treat|,|Programmed Cell Death 1 Receptor|antagonists & inhibitors|,|Proto-Oncogene Proteins B-raf|antagonists & inhibitors|genetics|,|Risk Assessment|,|Skin Neoplasms|drug therapy|genetics|pathology|surgery|",,"0000-0002-4015-5037Department of Medicine\, Virginia Commonwealth University\, Richmond\, Virginia.,0000-0002-1182-4908Department of Medicine\, University of Pittsburgh Medical Center\, Pittsburgh\, Pennsylvania.","Antineoplastic Agents,Antineoplastic Agents\, Immunological,PDCD1 protein\, human,Programmed Cell Death 1 Receptor,Interferons,BRAF protein\, human,Proto-Oncogene Proteins B-raf,MAP Kinase Kinase 1,MAP2K1 protein\, human",NCI NIH HHS,United States,P30 CA014599,"BRAF,PD1,adjuvant therapy,immunotherapy,melanoma,pd-1,risk stratification,stage II,targeted therapy"
31869749,"Jing W,Li L,Zhang X,Wu S,Zhao J,Hou Q,Wu H,Ma W,Li S,Liu H,Yang B",Genetic Profiling of Breast Cancer with and Without Preexisting Metabolic Disease.,"Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women. Various mechanisms are involved in the initiation and progression of breast cancer. Metabolic dysregulation has been associated with increasing breast cancer incidence and mortality. However, little is known about how metabolic disease regulates the development and progression of breast cancer at the molecular level. Here, using a hybridization capture-based panel including 124 cancer-associated genes, we performed targeted next-generation sequencing of tumor tissues and matched blood samples from 20 postmenopausal patients with primary breast cancer, in which 6 cases suffered from preexisting metabolic disorders including hypertension, type 2 diabetes, and coronary heart disease. We took only the protein-altering variants and identified 170 somatic mutations of 59 genes. Among these, 40 mutated genes were found in the metabolic disease group, and 33 mutated genes were found in the non-metabolic disease group. Importantly, nonsynonymous mutations of 26 genes (MSH3, BRAF, MLH3, MTOR, DDR2, ALK, etc.) were uniquely present in the metabolic disease group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to investigate biological functions and key pathways of somatic mutations. TP53, PIK3CA, and PTEN were the top three commonly mutated genes at a higher frequency compared with the Cancer Genome Atlas (TCGA) data, and several novel but infrequent mutations in other genes were also found. Although further studies are required to validate these variants, our results are the first to suggest a specific molecular profile of breast cancer with preexisting metabolic disease.",Translational oncology,vol.13:2:245-253,2020,Journal Article,,,"Department of Oncology\, The Aviation Hanzhong 3201 Hospital\, Xi'an Jiao Tong University\, Hanzhong 723000\, Shaanxi\, China.,Department of Oncology\, Tengzhou Central People's Hospital\, Jining Medical University\, Tengzhou 277500\, Shandong\, China.,Department of Pathology\, People's Hospital of Xinghua City\, Xinghua 225700\, Jiangsu\, China.,Biotecan Medical Diagnostics Co.\, Ltd.\, Zhangjiang Center for Translational Medicine\, Shanghai 201203\, China.,Biotecan Medical Diagnostics Co.\, Ltd.\, Zhangjiang Center for Translational Medicine\, Shanghai 201203\, China.,Biotecan Medical Diagnostics Co.\, Ltd.\, Zhangjiang Center for Translational Medicine\, Shanghai 201203\, China.,Biotecan Medical Diagnostics Co.\, Ltd.\, Zhangjiang Center for Translational Medicine\, Shanghai 201203\, China.,Department of Oncology\, The Aviation Hanzhong 3201 Hospital\, Xi'an Jiao Tong University\, Hanzhong 723000\, Shaanxi\, China.,Department of Thyroid and Breast Surgery\, Tengzhou Central People's Hospital\, Jining Medical University\, Tengzhou 277500\, Shandong\, China.,Biotecan Medical Diagnostics Co.\, Ltd.\, Zhangjiang Center for Translational Medicine\, Shanghai 201203\, China. Electronic address: hmliu@biotecan.com.,Department of Orthopaedic\, The Aviation Hanzhong 3201 Hospital\, Xi'an Jiao Tong University\, Hanzhong 723000\, Shaanxi\, China. Electronic address: ybh3201@163.com.",,,,,
31874374,"Reger de Moura C,Vercellino L,Jouenne F,Baroudjian B,Sadoux A,Louveau B,Delyon J,Serror K,Goldwirt L,Merlet P,Bouquet F,Battistella M,Lebbé C,Mourah S",Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma.,"The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.",Translational oncology,vol.13:2:275-286,2020,Journal Article,,,"Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Pharmacogenomics\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Department of Nuclear Medicine\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Pharmacogenomics\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Department of Dermatology\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Pharmacogenomics\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Pharmacogenomics\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Department of Dermatology\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Department of Plastic\, Reconstructive and Aesthetic Surgery\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Pharmacogenomics\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Department of Nuclear Medicine\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Roche Institute\, Boulogne Billancourt\, France.,Department of Pathology\, Hôpital Saint-Louis\, AP-HP\, Paris\, France; Université de Paris\, Inserm\, UMR_S1165\, Paris\, France.,Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Dermatology\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Université de Paris\, Inserm\, UMR_S976\, Paris\, France; Department of Pharmacogenomics\, Hôpital Saint-Louis\, AP-HP\, Paris\, France. Electronic address: samia.mourah@aphp.fr.",,,,,
31875302,"Xu H,Chen F,Zhu H,Luo L,Zhang R",Diffuse leptomeningeal glioneuronal tumor in a Chinese adult: a novel case report and review of literature.,"Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioma tumor classified by the World Health Organization as a central nervous system tumor in 2016. DLGNT is most common in children and adolescents but is rare in adults. A 25-year-old male patient was admitted due to recurrent seizures. Head magnetic resonance imaging revealed lesions in the right temporal lobe, which were considered to be intracranial tumors with variable properties. The patient was admitted for surgical treatment. After admission, it was confirmed that seizures were associated with right temporal lobe lesions. Right temporal epileptogenic focus resection was performed by craniotomy. Immunohistochemistry revealed that tumor cells were reactive for oligodendrocyte transcription factor 2, synaptophysin, S100 proteins, and α-thalassemia mental retardation X-linked; and partially reactive for neuronal nuclei, glial fibrillary acidic protein, and nestin. The vascular wall was reactive for vimentin, CD34, CD31, and smooth muscle actin. Ki-67 was 4%. Molecular detection demonstrated 1p36 deletion, O6-methylguanine-DNA-methyltransferase methylation, and positive v-raf murine sarcoma viral oncogene homolog B mutation. DLGNT. The patient recovered well after surgery and received 54 Gy/27f radiotherapy without neurological dysfunction and seizures. In this study, onset age, tumor site, tumor increment coefficient, molecular detection, treatment methods, and prognosis of 54 patients were summarized from 19 studies. DLGNT patients are characterized by more singular tumor site, smaller volume, lower increment coefficient, and longer stable disease period. Patients with DLGNT may also have a longer stable condition in cases of molecular detection of 1p/19q deletion, or BRAF fusion.",Acta neurologica Belgica,vol.120:2:247-256,2020,Review,"|Adult|,|Asian Continental Ancestry Group|,|Brain Neoplasms|pathology|surgery|,|Humans|,|Male|,|Meningeal Neoplasms|pathology|surgery|,|Oligodendroglioma|pathology|surgery|",,"Department of Functional Neurosurgery\, The Brain Hospital Affiliated to Nanjing Medical University\, Nanjing\, 210029\, China.,Department of Functional Neurosurgery\, The Brain Hospital Affiliated to Nanjing Medical University\, Nanjing\, 210029\, China.,Department of Functional Neurosurgery\, The Brain Hospital Affiliated to Nanjing Medical University\, Nanjing\, 210029\, China.,Department of Functional Neurosurgery\, The Brain Hospital Affiliated to Nanjing Medical University\, Nanjing\, 210029\, China.,Department of Functional Neurosurgery\, The Brain Hospital Affiliated to Nanjing Medical University\, Nanjing\, 210029\, China. neurosurgeonzr@njmu.edu.cn.",,"Medical Science and Technology Development Foundation, Nanjing Municipality Health Bureau",,YKK17136,"Cerebral tumor,Glioneuronal,Leptomeningeal,Prognosis"
32375301,"Collins KL,Pollack IF",Pediatric Low-Grade Gliomas.,"Brain tumors constitute the largest source of oncologic mortality in children and low-grade gliomas are among most common pediatric central nervous system tumors. Pediatric low-grade gliomas differ from their counterparts in the adult population in their histopathology, genetics, and standard of care. Over the past decade, an increasingly detailed understanding of the molecular and genetic characteristics of pediatric brain tumors led to tailored therapy directed by integrated phenotypic and genotypic parameters and the availability of an increasing array of molecular-directed therapies. Advances in neuroimaging, conformal radiation therapy, and conventional chemotherapy further improved treatment outcomes. This article reviews the current classification of pediatric low-grade gliomas, their histopathologic and radiographic features, state-of-the-art surgical and adjuvant therapies, and emerging therapies currently under study in clinical trials.",Cancers,vol.12:5:,2020,Review,,,"Department of Pediatric Neurosurgery\, University of Pittsburgh\, Pittsburgh\, PA 15224\, USA.,Department of Pediatric Neurosurgery\, University of Pittsburgh\, Pittsburgh\, PA 15224\, USA.",,NIH HHS,United States,NIH-1R01CA187219,"BRAF mutation,diffuse astrocytoma,molecularly-targeted therapy,neuroepithelial tumor,pediatric low-grade glioma,pilocytic astrocytoma,pleomorphic xanthoastrocytoma,subependymal giant cell astrocytoma"
32376239,"Gonçalves de Oliveira-Júnior R,Marcoult-Fréville N,Prunier G,Beaugeard L,Beserra de Alencar Filho E,Simões Mourão ED,Michel S,Quintans-Júnior LJ,Guedes da Silva Almeida JR,Grougnet R,Picot L",Polymethoxyflavones from Gardenia oudiepe (Rubiaceae) induce cytoskeleton disruption-mediated apoptosis and sensitize BRAF-mutated melanoma cells to chemotherapy.,"A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC50 = 3.92 and 8.18 μM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (½IC50) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 μM vs. >100 μM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs.",Chemico-biological interactions,vol.325::109109,2020,Journal Article,"|Antineoplastic Agents|pharmacology|,|Apoptosis|drug effects|,|Caspase 3|metabolism|,|Cell Cycle Checkpoints|drug effects|,|Cell Line\, Tumor|,|Cell Movement|drug effects|,|Cell Proliferation|drug effects|,|Cytoskeleton|drug effects|metabolism|,|Drug Synergism|,|Enzyme Activation|drug effects|,|Flavones|chemistry|metabolism|pharmacology|,|Gardenia|chemistry|,|Humans|,|Melanoma|pathology|,|Molecular Docking Simulation|,|Mutation|,|Protein Conformation|,|Proto-Oncogene Proteins B-raf|genetics|,|Structure-Activity Relationship|,|Tubulin|chemistry|metabolism|",,"LIENSs UMRi CNRS 7266\, La Rochelle Université\, 17042\, La Rochelle\, France. Electronic address: rgonca01@univ-lr.fr.,LIENSs UMRi CNRS 7266\, La Rochelle Université\, 17042\, La Rochelle\, France.,LIENSs UMRi CNRS 7266\, La Rochelle Université\, 17042\, La Rochelle\, France.,LIENSs UMRi CNRS 7266\, La Rochelle Université\, 17042\, La Rochelle\, France.,Department of Pharmacy\, Universidade Federal do Vale do São Francisco\, 56304-205\, Petrolina\, Pernambuco\, Brazil.,Department of Pharmacy\, Universidade Federal do Vale do São Francisco\, 56304-205\, Petrolina\, Pernambuco\, Brazil.,Equipe Produits Naturels\, Analyse\, Synthèse\, UMR CNRS 8038\, Université Paris Descartes\, 75006\, Paris\, France.,LANEF\, Universidade Federal de Sergipe\, 49100-000\, São Cristóvão\, Sergipe\, Brazil.,NEPLAME\, Universidade Federal do Vale do São Francisco\, 56304-205\, Petrolina\, Pernambuco\, Brazil.,Equipe Produits Naturels\, Analyse\, Synthèse\, UMR CNRS 8038\, Université Paris Descartes\, 75006\, Paris\, France.,LIENSs UMRi CNRS 7266\, La Rochelle Université\, 17042\, La Rochelle\, France.","Antineoplastic Agents,Flavones,Tubulin,Proto-Oncogene Proteins B-raf,Caspase 3",,,,"Apoptosis,Cancer,Cytoskeleton,Flavonoids,Melanoma,Multidrug resistance"
32378970,"Ramos Perez J,Ravandi-Kashani F",The pharmacological management of hairy cell leukemia.,"Hairy cell leukemia (HCL) is a B-cell lymphoid malignancy that accounts for approximately 2% of all leukemias. Treatment with purine nucleoside analogs (PNA) results in a high response rate and remains the standard of care. Long term follow-up shows that most patients relapse and require retreatment. Newer combination strategies and agents have emerged to try to reduce the relapse rate and to address cases of PNA refractoriness.,The authors reviewed the literature on the pharmacological management of HCL\, including recent studies that led to new agents being incorporated into practice.,Combination of cladribine plus rituximab produces a high rate of measurable residual disease-negative complete remission. In our center\, newly diagnosed patients are offered cladribine followed by 8 weekly doses of rituximab in an ongoing phase II trial. Patients in first relapse are also offered this combination if they were initially treated with a single-agent PNA\, or if the remission duration was ≥5 years after first-line cladribine plus rituximab. Patients who relapse within 5 years are offered therapy with a novel agent that may include the BRAF inhibitor vemurafenib\, alone or in combination with rituximab\, dabrafenib in combination with trametinib\, the BTK inhibitor ibrutinib\, or moxetumomab pasudotox.",Expert opinion on pharmacotherapy,vol.21:11:1337-1344,2020,Review,"|Antineoplastic Combined Chemotherapy Protocols|administration & dosage|adverse effects|therapeutic use|,|Bacterial Toxins|administration & dosage|adverse effects|therapeutic use|,|Cladribine|administration & dosage|adverse effects|therapeutic use|,|Clinical Trials\, Phase II as Topic|,|Exotoxins|administration & dosage|adverse effects|therapeutic use|,|Humans|,|Interferon-alpha|administration & dosage|adverse effects|therapeutic use|,|Leukemia\, Hairy Cell|drug therapy|pathology|,|Remission Induction|,|Rituximab|administration & dosage|adverse effects|therapeutic use|,|Splenectomy|",,"Department of Leukemia\, The University of Texas MD Anderson Cancer Center \, Houston\, TX\, USA.,Department of Leukemia\, The University of Texas MD Anderson Cancer Center \, Houston\, TX\, USA.","Bacterial Toxins,Exotoxins,Interferon-alpha,immunotoxin HA22,Cladribine,Rituximab",,,,"Hairy Cell Leukemia,cladribine,pharmacological management,rituximab"
31273418,"Dettmer MS,Schmitt A,Komminoth P,Perren A",Poorly differentiated thyroid carcinoma : An underdiagnosed entity.,"Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10%of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas. The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.",Der Pathologe,vol.41:Suppl 1:1-8,2020,Review,"|Carcinoma|pathology|,|Humans|,|Missed Diagnosis|,|Thyroid Neoplasms|pathology|,|Undiagnosed Diseases|",,"Institute of Pathology\, University of Bern\, Murtenstraße 31\, 3010\, Bern\, Switzerland. dettmerms@gmail.com.,Institute of Pathology\, University of Bern\, Murtenstraße 31\, 3010\, Bern\, Switzerland.,Institute of Pathology\, City Hospital Triemli\, 8063\, Zürich\, Switzerland.,Institute of Pathology\, University of Bern\, Murtenstraße 31\, 3010\, Bern\, Switzerland.",,,,,"MicroRNA,Poorly differentiated thyroid carcinoma,Prognosis,Thyroid neoplasm,Tyrosine kinase inhibitor"
31848314,"Salem ME,Battaglin F,Goldberg RM,Puccini A,Shields AF,Arguello D,Korn WM,Marshall JL,Grothey A,Lenz HJ",Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer.,"The incidence of colorectal cancer (CRC)\, particularly left-sided tumors (LT)\, in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression\, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA.,A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS)\, protein expression\, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data.,RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%)\, KRAS (64.1% vs. 45.5%)\, PIK3CA (27% vs. 11.2%)\, and RNF43 (24.2% vs. 2.9%). Notably\, additional mutations in distinct genes involved in histone modification and chromatin remodeling\, as well as genes associated with DNA repair and cancer-predisposing syndromes\, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%)\, ARID1A (53.3% vs. 21.4%)\, MSH6 (11.1% vs. 2.3%)\, MLH1 (10.5% vs. 2.3%)\, MSH2 (10.5% vs. 1.2%)\, POLE (5.9% vs. 0.6%)\, PTEN (10.8% vs. 2.3%)\, and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status.,Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA.,Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right- and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right- and left-sided CRC show distinct molecular features in AYA\, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair\, as well as epigenetic mechanisms\, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.",The oncologist,vol.25:5:404-413,2020,Journal Article,,,"Department of Medical Oncology\, Levine Cancer Institute\, Atrium Health\, Charlotte\, North Carolina\, USA.,Division of Medical Oncology\, Norris Comprehensive Cancer Center\, Keck School of Medicine\, University of Southern California\, Los Angeles\, California\, USA.,West Virginia University Cancer Institute\, Morgantown\, West Virginia\, USA.,Division of Medical Oncology\, Norris Comprehensive Cancer Center\, Keck School of Medicine\, University of Southern California\, Los Angeles\, California\, USA.,Department of Oncology\, Karmanos Cancer Institute\, Wayne State University\, Detroit\, Michigan\, USA.,Caris Life Sciences\, Phoenix\, Arizona\, USA.,Caris Life Sciences\, Phoenix\, Arizona\, USA.,The Ruesch Center and Georgetown Lombardi Comprehensive Cancer Center\, Washington\, DC\, USA.,West Cancer Center\, Germantown\, Tennessee\, USA.,Division of Medical Oncology\, Norris Comprehensive Cancer Center\, Keck School of Medicine\, University of Southern California\, Los Angeles\, California\, USA.",,NIGMS NIH HHS,United States,U54 GM104942,"Adolescents and young adults,Colorectal cancer,Molecular profiling,Tumor sidedness"
31062130,"Tashiro K,Oikawa M,Miki Y,Takahashi T,Kumamoto H","Immunohistochemical assessment of growth factor signaling molecules: MAPK, Akt, and STAT3 pathways in oral epithelial precursor lesions and squamous cell carcinoma.","Several growth factors and their receptors, such as epidermal growth factor receptor, have been studied as prognostic biomarkers for many epithelial malignancies. The signal transduction cascade of those receptors includes RAS/RAF/ERK, PI3K/Akt/mTOR, and STAT3 pathways. The aim of this study was to investigate the expression levels of several key proteins of those pathways in patients with oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), and to correlate the expressions of these proteins with clinicopathologic features and prognosis. Fifteen leukoplakia (LP), 15 low-grade epithelial dysplasia, 15 high-grade epithelial dysplasia (HD), and 132 OSCC specimens were immunohistochemically examined for KRAS, HRAS, NRAS, BRAF, pERK1/2, pAkt, pmTOR, and pSTAT3 expression. Immunoreactivity for these molecules predominantly occurred in regions OEPL basal to prickle layers and in most OSCC cells. KRAS and NRAS expression was significantly lower in OSCC than in OEPLs, while pAkt and pmTOR showed higher expression in OSCC than in OEPLs. pERK1/2 expression was significantly higher in HD than in LP. In OSCC, KRAS and NRAS immunoreactivity was significantly higher in advanced age and male gender. In addition, higher immunoreactivity was shown in pERK1/2 in female gender and advanced TNM stage, pAkt in advanced T classification and cases without postoperative metastasis, pmTOR in advanced mode of invasion, and pSTAT3 in invasion depth. Correlations between these markers and clinicopathological variables were also noted. MAPK, Akt, and STAT3 pathways might play diverse roles in oral carcinogenesis.",Odontology,vol.108:1:91-101,2020,Journal Article,"|Carcinoma\, Squamous Cell|genetics|,|Female|,|Humans|,|Male|,|Mouth Neoplasms|genetics|,|Phosphatidylinositol 3-Kinases|,|Proto-Oncogene Proteins c-akt|,|STAT3 Transcription Factor|,|Signal Transduction|",,"Division of Oral and Maxillofacial Surgery\, Department of Oral Medicine and Surgery\, Tohoku University Graduate School of Dentistry\, 4-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan. kazuki.tasiro.r5@dc.tohoku.ac.jp.,Division of Oral Pathology\, Department of Oral Medicine and Surgery\, Tohoku University Graduate School of Dentistry\, 4-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan.,Department of Disaster Obstetrics and Gynecology\, International Research Institute of Disaster Science\, Tohoku University\, 468-1\, Aoba\, Aramaki aza\, Aoba-ku\, Sendai\, Miyagi\, 980-8572\, Japan.,Division of Oral and Maxillofacial Surgery\, Department of Oral Medicine and Surgery\, Tohoku University Graduate School of Dentistry\, 4-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan.,Division of Oral Pathology\, Department of Oral Medicine and Surgery\, Tohoku University Graduate School of Dentistry\, 4-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan.","STAT3 Transcription Factor,STAT3 protein\, human,Proto-Oncogene Proteins c-akt",,,,"Akt,MAPK,Oral epithelial precursor lesions (OEPLs),Oral squamous cell carcinoma (OSCC),STAT3"
32394048,"Yamada T,Matsuda A,Takahashi G,Iwai T,Takeda K,Ueda K,Kuriyama S,Koizumi M,Shinji S,Yokoyama Y,Ohta R,Yoshida H","Emerging RAS, BRAF, and EGFR mutations in cell-free DNA of metastatic colorectal patients are associated with both primary and secondary resistance to first-line anti-EGFR therapy.","Oncogenic RAS mutations are negative biomarkers of response to epidermal growth factor receptor (EGFR) blockade. RAS mutations are usually detected in biopsies of primary colorectal tumors. However, the genomic profiles of primary tumors and metastases are not always concordant, and chemotherapeutic agents can alter the tumor molecular landscape. Cell-free DNA (cfDNA) is a novel tool to detect molecular heterogeneity. This study evaluated the clinical utility of cfDNA to predict primary or secondary resistance to EGFR blockade in patients with metastatic colorectal cancer. Thirty metastatic colorectal cancer patients without RAS and BRAF mutations were prospectively enrolled and treated with cytotoxic agents and EGFR blockade as first-line therapy. cfDNA was analyzed for the presence of RAS, BRAF, and EGFR (S492R) point mutations before initiating chemotherapy and every 2 months during chemotherapy. The analysis was performed in 223 plasma samples from all 30 patients. Of the 30 patients, five had RAS mutations in their cfDNA before starting chemotherapy and did not respond. Twenty-four of the remaining 25 patients without cfDNA RAS mutations had a response. Twenty of the 24 responders developed secondary resistance and cfDNA RAS mutations were found in 17 of the 20. cfDNA BRAF mutations were found in seven, and EGFR mutations were found in eight of the 20 patients. Emerging RAS, BRAF, and EGFR mutations occurred in patients with primary and secondary resistance to EGFR blockade. The detection of these mutations in cfDNA is a promising approach to predict treatment response and secondary resistance.",International journal of clinical oncology,vol.25:8:1523-1532,2020,Journal Article,"|Aged|,|Aged\, 80 and over|,|Antineoplastic Combined Chemotherapy Protocols|therapeutic use|,|Cell-Free Nucleic Acids|genetics|,|Cetuximab|administration & dosage|,|Colorectal Neoplasms|drug therapy|genetics|mortality|pathology|,|Drug Resistance\, Neoplasm|drug effects|genetics|,|ErbB Receptors|antagonists & inhibitors|genetics|,|Female|,|Fluorouracil|therapeutic use|,|Humans|,|Leucovorin|therapeutic use|,|Male|,|Middle Aged|,|Mutation|,|Organoplatinum Compounds|therapeutic use|,|Panitumumab|administration & dosage|,|Pilot Projects|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Treatment Outcome|",,"http://orcid.org/0000-0002-1436-7482Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan. y-tak@nms.ac.jp.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery\, Nippon Medical School\, 1-1-5 Sendagi\, Bunkyo-ku\, Tokyo\, 113-8603\, Japan.","Cell-Free Nucleic Acids,Organoplatinum Compounds,Panitumumab,EGFR protein\, human,ErbB Receptors,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras),Cetuximab,Leucovorin,Fluorouracil",Kakenhi,,17K10657,"BRAF,Cell-free DNA,Circulating tumor DNA,EGFR blockade,KRAS,Liquid biopsy,RAS"
32397295,"Ferrara MG,Di Noia V,D'Argento E,Vita E,Damiano P,Cannella A,Ribelli M,Pilotto S,Milella M,Tortora G,Bria E",Oncogene-Addicted Non-Small-Cell Lung Cancer: Treatment Opportunities and Future Perspectives.,"Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3-7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients.",Cancers,vol.12:5:,2020,Review,,,"U.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,U.O.C. Medical Oncology\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,0000-0001-8802-9876U.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,0000-0003-4546-547XU.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,U.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,U.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,U.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,U.O.C. Oncology\, Azienda Ospedaliera Universitaria Integrata\, University and Hospital Trust of Verona\, 37126 Verona\, Italy.,U.O.C. Oncology\, Azienda Ospedaliera Universitaria Integrata\, University and Hospital Trust of Verona\, 37126 Verona\, Italy.,U.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.,0000-0002-2333-704XU.O.C. Medical Oncology\, Comprehensive Cancer Center\, Fondazione Policlinico Universitario Agostino Gemelli IRCCS\, Università Cattolica del Sacro Cuore\, 00168 Rome\, Italy.",,,,,"ALK,EGFR,ROS1,addiction,lung,oncogene"
32399264,"Kasi PM,Kamatham S,Shahjehan F,Li Z,Johnson PW,Merchea A,Colibaseanu DT",BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.,"Early identification of colorectal cancer (CRC) patients that are BRAF-V600E mutant and/or microsatellite instability-high (MSI-High)\, has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple\, rapid and universally available lab tests\, i.e.\, carbohydrate cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) tumor markers\, the ratio (CA-19-9/CEA) of which can distinctly identify these patients from other molecular subsets of CRC.,All patients with metastatic CRC from December 2016 to February 2019 were identified\, and included in the study if they had both CA19-9 and CEA tests available. Circulating tumor DNA (ctDNA) testing and tissue genetic testing results were used to categorize patients into BRAF V600E microsatellite stable (MSS)\, MSI-High\, RAS mutant MSS and RAS/RAF wild type CRCs. Kruskal-Wallis test was used to compare the CA19-9/CEA ratio between mutation types and the pairwise p values were adjusted for multiple comparisons with Holm method. For sensitivity analysis\, the same analysis was repeated for the mean and median ratio of each patient. All tests were two-sided with alpha level set at 0.05 for statistical significance.,BRAF-V600E MSS CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. Patients in the BRAF V600E MSS subset had the highest median CA19-9/CEA ratio versus the least median ratio in MSI-High patients. The median of maximum CA-19-9/CEA ratio was 28.92 (range\, 2.76-707.27) in BRAF-V600E MSS patients and 4.06 (range\, 0.46-166.74) in MSI-High subset of patients.,To date\, this is the first report utilizing the ratio of tumor markers CA19-9/CEA as a predictive rather than just prognostic tool to identify BRAF-V600E MSS and MSI-High CRC patients.",Journal of gastrointestinal oncology,vol.11:2:236-241,2020,Journal Article,,,"Division of Oncology/Hematology\, Division of Internal Medicine\, University of Iowa\, Holden Comprehensive Cancer Center\, Iowa City\, IA\, USA.,Division of Pathology\, Wayne State University\, Detroit\, MI\, USA.,Division of Internal Medicine\, Conemaugh Memorial Medical Center\, Johnstown\, PA\, USA.,Division of Biomedical Statistics and Informatics\, Mayo Clinic\, Jacksonville\, FL\, USA.,Division of Biomedical Statistics and Informatics\, Mayo Clinic\, Jacksonville\, FL\, USA.,Division of Colorectal Surgery\, Mayo Clinic\, Jacksonville\, FL\, USA.,Division of Colorectal Surgery\, Mayo Clinic\, Jacksonville\, FL\, USA.",,,,,"BRAF-V600E,Colorectal cancer (CRC),cancer antigen 19-9 (CA19-9),ctDNA,microsatellite instability-high (MSI-High)"
32399739,"de Blank P,Fouladi M,Huse JT",Molecular markers and targeted therapy in pediatric low-grade glioma.,"Recently discovered molecular alterations in pediatric low-grade glioma have helped to refine the classification of these tumors and offered novel targets for therapy. Genetic aberrations may combine with histopathology to offer new insights into glioma classification\, gliomagenesis and prognosis. Therapies targeting common genetic aberrations in the MAPK pathway offer a novel mechanism of tumor control that is currently under study.,We have reviewed common molecular alterations found in pediatric low-grade glioma as well as recent clinical trials of MEK and BRAF inhibitors.,In this topic review\, we examine the current understanding of molecular alterations in pediatric low-grade glioma\, as well as their role in diagnosis\, prognosis and therapy. We summarize current data on the efficacy of targeted therapies in pediatric low-grade gliomas\, as well as the many unanswered questions that these new discoveries and therapies raise.,The identification of driver alterations in pediatric low-grade glioma and the development of targeted therapies have opened new therapeutic avenues for patients with low-grade gliomas.",Journal of neuro-oncology,vol.150:1:5-15,2020,Review,,,"http://orcid.org/0000-0001-6623-3040Department of Pediatrics\, University of Cincinnati College of Medicine and the Cincinnati Children's Hospital Medical Center\, 3333 Burnet Avenue\, Cincinnati\, OH\, 45229\, USA. peter.deblank@cchmc.org.,Department of Pediatrics\, University of Cincinnati College of Medicine and the Cincinnati Children's Hospital Medical Center\, 3333 Burnet Avenue\, Cincinnati\, OH\, 45229\, USA.,Departments of Pathology and Translational Molecular Pathology\, University of Texas MD Anderson Cancer Center\, Houston\, TX\, USA.",,,,,"Low-grade glioma,Molecular markers,Pediatric brain tumor,Targeted therapy"
32402358,"Giustini NP,Jeong AR,Buturla J,Bazhenova L",Advances in Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer: Targeted Therapy.,"The treatment of metastatic non-small cell lung cancer (NSCLC) is constantly evolving. Although the advent of immunotherapy has played an important role in the treatment of patients with NSCLC, the identification of driver mutations and the subsequent specific treatment of these targets often lead to durable responses while maintaining quality of life. This review delves into targeted therapies available for epidermal growth factor receptor, anaplastic lymphoma kinase, ROS1, neurotrophic tropomyosin receptor kinase, and BRAF- mutated NSCLC patients, as well as other mutations with promising novel drugs under clinical investigation.",Clinics in chest medicine,vol.41:2:223-235,2020,Review,"|Carcinoma\, Non-Small-Cell Lung|pathology|therapy|,|Humans|,|Lung Neoplasms|pathology|therapy|,|Neoplasm Metastasis|",,"UCSD Moores Cancer Center\, 3855 Health Sciences Drive MC #0987\, La Jolla\, CA 92093-0829\, USA. Electronic address: ngiustini@health.ucsd.edu.,UCSD Moores Cancer Center\, 3855 Health Sciences Drive MC #0987\, La Jolla\, CA 92093-0829\, USA.,UCSD Moores Cancer Center\, 3855 Health Sciences Drive MC #0987\, La Jolla\, CA 92093-0829\, USA.,UCSD Moores Cancer Center\, 3855 Health Sciences Drive MC #0987\, La Jolla\, CA 92093-0829\, USA.",,,,,"ALK,BRAF,EGFR,Lung cancer,NTRK,Non–small cell lung cancer (NSCLC),ROS1,Targeted therapy,Tyrosine kinase inhibitor (TKI)"
32402656,"Sukari A,Kukreja G,Nagasaka M,Shukairy MK,Yoo G,Lin HS,Hotaling J,Kim H",The role of immune checkpoint inhibitors in anaplastic thyroid cancer (Case Series).,"Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid neoplasm. However, it is one of the most aggressive forms of malignancy accounting for approximately 50% of mortality associated with all thyroid cancers. Here we report two cases of ATC treated with immune checkpoint inhibitors. Next generation sequencing identified BRAFV600E mutation in one of the patients who also derived benefit from BRAF targeted therapy. We here discuss these cases highlighting the importance of expert pathological review, utilizing molecular testing to identify the underlying genetic targets for personalized therapy, and the potential role of PD-1 inhibitors for the treatment of ATC.",Oral oncology,vol.109::104744,2020,Letter,,,"Department of Oncology\, Karmanos Cancer Institute/Wayne State University\, Detroit\, MI\, USA. Electronic address: sukaria@karmanos.org.,Division of Hematology and Oncology\, Department of Internal Medicine\, Henry Ford Medical Group\, Detroit\, MI\, USA.,Department of Oncology\, Karmanos Cancer Institute/Wayne State University\, Detroit\, MI\, USA; Division of Neurology\, Department of Internal Medicine\, St. Marianna University Graduate School of Medicine\, Kawasaki\, Japan.,Wayne State University School of Medicine\, Detroit\, MI\, USA.,Department of Otolaryngology Head and Neck Surgery\, Wayne State University\, Detroit\, MI\, USA.,Department of Otolaryngology Head and Neck Surgery\, Wayne State University\, Detroit\, MI\, USA.,Department of Otolaryngology Head and Neck Surgery\, Wayne State University\, Detroit\, MI\, USA.,Division of Radiation Oncology\, Department of Oncology\, Karmanos Cancer Institute/Wayne State University\, Detroit\, MI\, USA.",,,,,"Anaplastic thyroid carcinoma,BRAF,Chemo-immunotherapy,Molecular testing,PD1 inhibitors"
32403192,"Bhave P,Haydon A",Treatment of High Risk Resected Melanoma in Australia: Current Landscape and Practises.,"Stage III melanoma involves regional lymph nodes and/or in-transit or satellite disease, without spread to distant metastatic sites. Stage IIIA melanoma includes a T1a-T2a primary lesion with N1a or N2a nodal involvement, whilst stage IIID melanoma includes a T4b primary lesion with N3a-N3c nodal involvement. With surgery alone, patients with stage IIIA melanoma have 10-year survival rates of ~88%; however, patients with stage IIID melanoma have 10-year survival rates of only ~24%. Targeted therapy and immunotherapy are being explored in stage III disease as adjuvant therapy after surgical resection, to eliminate micro-metastatic disease and thereby prevent relapse of melanoma and increase patient survival. A number of pivotal trials published in the last two years have shown improved relapse-free survival (RFS) and overall survival in patients with stage III melanoma treated with adjuvant therapy. COMBI-AD showed adjuvant dabrafenib and trametinib improving RFS compared with placebo (HR 0.49; 95% CI 0.40-0.59). Checkmate-238 demonstrated an improvement in RFS of adjuvant nivolumab over ipilimumab (HR 0.68, P < 0.001) whilst Keynote-054 demonstrated an improvement in RFS with adjuvant pembrolizumab over placebo (HR 0.57, P < 0.001). Many nuances need to be considered when interpreting this data, including implications of an updated staging system, which patients are suitable for adjuvant therapy and the choice between adjuvant targeted therapy and immunotherapy in BRAF mutant patients. This review article summaries the currently available literature on adjuvant targeted therapy and provides a guide on applying this data in everyday practise.",The Australasian journal of dermatology,vol.61:3:203-209,2020,Review,,,"https://orcid.org/0000-0001-9084-8467Alfred Health\, Melbourne\, Victoria\, Australia.,Alfred Health\, Melbourne\, Victoria\, Australia.",,,,,"adjuvant therapy,immunotherapy,melanoma,melanoma recurrence,targeted therapy"
31939681,"Nguyen HT,Tran DH,Ngo QD,Pham HT,Tran TT,Tran VU,Pham TN,Le TK,Le NT,Nguyen NM,Vo BT,Nguyen LT,Nguyen TV,Bui QTN,Nguyen HN,Luong BA,Le LGH,Do DM,Do TT,Hoang AV,Dinh KT,Phan MD,Tran LS,Giang H,Nguyen HN",Evaluation of a Liquid Biopsy Protocol using Ultra-Deep Massive Parallel Sequencing for Detecting and Quantifying Circulation Tumor DNA in Colorectal Cancer Patients.,"The identification and quantification of actionable mutations are critical for guiding targeted therapy and monitoring drug response in colorectal cancer. Liquid biopsy (LB) based on plasma cell-free DNA analysis has emerged as a noninvasive approach with many clinical advantages over conventional tissue sampling. Here, we developed a LB protocol using ultra-deep massive parallel sequencing and validated its clinical performance for detection and quantification of actionable mutations in three major driver genes (KRAS, NRAS and BRAF). The assay showed a 92% concordance for mutation detection between plasma and paired tissues and great reliability in quantification of variant allele frequency.",Cancer investigation,vol.38:2:85-93,2020,Journal Article,"|Circulating Tumor DNA|genetics|,|Colorectal Neoplasms|blood|genetics|,|GTP Phosphohydrolases|genetics|,|High-Throughput Nucleotide Sequencing|methods|,|Humans|,|Liquid Biopsy|methods|,|Membrane Proteins|genetics|,|Mutation|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Reproducibility of Results|",,"University Medical Center\, Ho Chi Minh City\, Vietnam.,University Medical Center\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,University Medical Center\, Ho Chi Minh City\, Vietnam.,University Medical Center\, Ho Chi Minh City\, Vietnam.,University Medical Center\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.,Medical Genetics Institute\, Ho Chi Minh City\, Vietnam.,http://orcid.org/0000-0002-3426-1044Gene Solutions\, Ho Chi Minh City\, Vietnam.,http://orcid.org/0000-0002-5382-3903Gene Solutions\, Ho Chi Minh City\, Vietnam.,Gene Solutions\, Ho Chi Minh City\, Vietnam.,University of Medicine and Pharmacy\, Ho Chi Minh City\, Vietnam.","Circulating Tumor DNA,KRAS protein\, human,Membrane Proteins,BRAF protein\, human,Proto-Oncogene Proteins B-raf,GTP Phosphohydrolases,NRAS protein\, human,Proto-Oncogene Proteins p21(ras)",,,,"Liquid biopsy,actionable mutation,circulating tumor DNA,colorectal cancer,ultra-deep sequencing"
32392586,"Scarpino S,Taccogna S,Pepe G,Papini E,D'Angelo M,Cascone F,Nicoletti D,Guglielmi R,Palermo A,Trombetta M,Rainer A,Taffon C,Crescenzi A",Morphological and Molecular Assessment in Thyroid Cytology Using Cell-Capturing Scaffolds.,"The increased frequency of thyroid nodules is paralleled by the rise of thyroid cancer diagnosis. To define the nature of most thyroid nodules, fine needle aspiration (FNA) followed by cytological evaluation is considered the method of choice. About 20% of FNA biopsies on thyroid nodules, however, show indeterminate cytological features and may require diagnostic surgery. Several immunocytochemical and molecular markers have been proposed to improve classification of thyroid nodules, but these tests require adequate cell amount and cytological paraffin inclusion. Polymeric matrices were recently proposed for the collection of cells for diagnostic purposes. In this study, we evaluated the diagnostic use of a new matrix (CytoMatrix). Morphological, molecular and immunohistochemical investigations were carried out on 23 FNA samples included in CytoMatrix and compared with data obtained from the definitive histology of surgical samples. Our results showed that CytoMatrix is suitable to capture and preserve the cellularity of the samples harvested by FNA and that its paraffin sections mimic the morphology of those obtained from real histological tissue. Immunohistochemistry on CytoMatrix samples was consistent with the immunophenotypical profile of the corresponding histological surgical specimens. Mutational analysis of the BRAF (V600E) gene performed on CytoMatrix inclusions and paired surgical tissue matched in all but one cases while matrix immunohistochemistry identified 91.6% of BRAF mutated samples. In conclusion, we suggest that CytoMatrix could be a reliable tool to overcome the current limits of traditional collection methods for the study of thyroid cytology, thereby improving their reliability for a conclusive diagnostic interpretation.",Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme,vol.::,2020,Journal Article,,,"Department of Clinical and Molecular Medicine\, Pathology Unit\, Sant'Andrea Hospital\, Sapienza University of Rome\, Albano Laziale (RM)\, Italy.,Pathology Unit\, Regina Apostolorum Hospital\, Albano Laziale (RM)\, Italy.,Department of Clinical and Molecular Medicine\, Pathology Unit\, Sant'Andrea Hospital\, Sapienza University of Rome\, Albano Laziale (RM)\, Italy.,Endocrinology and Metabolism Unit\, Regina Apostolorum Hospital\, Albano Laziale (RM)\, Italy.,Pathology Unit\, Regina Apostolorum Hospital\, Albano Laziale (RM)\, Italy.,Pathology Unit\, University Hospital Campus Bio-Medico of Rome\, Rome\, Italy.,Pathology Unit\, University Hospital Campus Bio-Medico of Rome\, Rome\, Italy.,Endocrinology and Metabolism Unit\, Regina Apostolorum Hospital\, Albano Laziale (RM)\, Italy.,Unit of Endocrinology and Diabetes\, University Hospital Campus Bio-Medico of Rome\, Rome\, Italy.,Department of Engineering\, University Campus Bio-Medico of Rome\, Rome\, Italy.,Department of Engineering\, University Campus Bio-Medico of Rome\, Rome\, Italy.,Pathology Unit\, University Hospital Campus Bio-Medico of Rome\, Rome\, Italy.,Pathology Unit\, University Hospital Campus Bio-Medico of Rome\, Rome\, Italy.",,,,,
32392931,"Wang B,Zhang XY,Li J,Chen H,Wang XW,Zhong DR",[Clinicopathological and genetic characteristics of lung cancer in the lungs of explanted from lung transplant recipients].,"Objective: To describe the clinicopathological features of the lung cancers in the lungs explanted from lung transplant recipients, and to understand the molecular alterations of these cancers. Methods: The patients who underwent lung transplantation in China-Japan Friendship Hospital from March 2017 to December 2018 were reviewed. Clinical data of the patients with lung cancer associated with end-stage interstitial lung diseases (ILD) were collected. Hematoxylin-eosin staining and immunohistochemistry were performed to evaluate the pathological feature. Real-time quantitative PCR was performed to analyze the hotspots and targeted regions of 9 cancer-associated genes. Results: Among the 154 identified patients, 10 met the inclusion criteria and were included. The detection rate of lung cancer in the lung transplantation patients was 6.5%(10/154). All of the included 10 patients were male, with an average age of 59 years. They all had a history of heavy smoking. Three cases had a lung cancer diagnosed before operation, while the other 7 cases were concealed in the specimen of end-stage ILD. All of lung cancers were non-small-cell carcinoma, including 8 cases of adenocarcinoma and 2 cases of squamous cell carcinoma. The proportion of mucinous adenocarcinoma components was 3/10. The mutations in KRAS gene exon 2 were detected in two patients with mucous adenocarcinoma, while no alterations in NRAS, EGFR, ALK, ROS1, BRAF, HER2, PI3KCA and RET were detected in the remaining patients. Conclusions: Lung cancers are difficult to detect in patients with end-stage ILD. They are mainly adenocarcinomas and associated with a higher frequency of mutations in KRAS gene. These cancers have limited treatment options and a poor prognosis.",Zhonghua bing li xue za zhi = Chinese journal of pathology,vol.49:5:464-470,2020,Journal Article,"|China|,|Humans|,|Lung Neoplasms|surgery|,|Lung Transplantation|,|Male|,|Middle Aged|,|Mutation|,|Protein-Tyrosine Kinases|,|Proto-Oncogene Proteins|,|Transplant Recipients|",,"Department of Pathology\, China-Japan Friendship Hospital\, Beijing 100029\, China.,Department of Pulmonary and Critical Care Medicine\, Center of Respiratory Medicine\, China-Japan Friendship Hospital\, Beijing 100029\, China.,Department of Pathology\, China-Japan Friendship Hospital\, Beijing 100029\, China.,Department of Pathology\, China-Japan Friendship Hospital\, Beijing 100029\, China.,Department of Pathology\, China-Japan Friendship Hospital\, Beijing 100029\, China.,Department of Pathology\, China-Japan Friendship Hospital\, Beijing 100029\, China.","Proto-Oncogene Proteins,Protein-Tyrosine Kinases",,,,"Genes\, neoplasm,Lung diseases\, interstitial,Lung neoplasms,Lung transplantation"
33261504,"Sánchez Cánovas M,López Martín A",SEVERE GASTROINTESTINAL TOXICITY SECONDARY TO FLUOROPYRIMIDINES: ACUTE ESOPHAGEAL NECROSIS ASSOCIATED EXTENSIVE DUODENAL MUCOSITIS.,"A 68-year-old male with stage IV sigmoid adenocarcinoma (liver metastases). KRAS and BRAF wild type. No other medical-surgical history of interest. In first line treatment with 5-Fluoracil, oxaliplatin and cetuximab. One week after the administration of the third cycle of therapy, the patient presented vomits which looked like coffee grounds. Gastroscopy showed an esophagus with ulcers, in its proximal third, which converged distally, appearing a black esophagus (Image 1), while gastric cavity had not relevant alterations. On duodenal bulb there were abundant ulcerations in different stages, radially distributed, without active bleeding or visible vessel, suggesting extensive mucositis (Image 2). Acute esophageal necrosis (AEN) is defined endoscopically by a circumferential black-appearing esophageal mucosa with nearly universal involvement of the distal esophagus and abrupt transition at the gastroesophageal junction, with variable proximal extension (1). The 10% of patients with AEN have a history of malignancy (2). Cancer is associated with cachexia and immune dysregulation, thereby decreasing mucosal regenerative ability and increasing susceptibility. AEN often follows chemotherapy administration (1). Mucositis, stomatitis, or esophagopharyngitis (which may lead to mucosal sloughing or ulceration) may occur with fluorouracil (3). In this patient, severity of the adverse event forced the withhold of this drug.",Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva,vol.::,2020,Journal Article,,,"Hematología y Oncología Médica\, Hospital Universitario Jose María Morales Meseguer\, España.,Digestivo\, Hospital Universitario Jose María Morales Meseguer.",,,,,
33269152,"Rittberg R,Banerji S,Green S,Qing G,Dawe DE",Immunotherapy Benefit in a Patient With Non-Small Cell Lung Cancer and a Rare BRAF Mutation.,"Immunotherapy is less effective in non-small cell lung cancer (NSCLC) with driver mutations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) and some may extrapolate this trend to other driver mutations. Up to 4% of NSCLC cases contain a BRAF mutation. Most BRAF mutations are V600E, and little is known about the impact of treatment in rare BRAF G469A mutations. We present a case of a patient found to have BRAF G469A mutated NSCLC. She was diagnosed with Stage IIIB NSCLC and treated with concurrent chemotherapy and radiation. Post-treatment imaging demonstrated disease progression and she was started on nivolumab, resulting in a dramatic and prolonged response which is ongoing after 76 cycles. Her substantial response and prolonged benefit suggest that BRAF-mutated NSCLC may respond better than EGFR- or ALK-driven disease to immunotherapy. Due to the rarity of specific mutations, this case adds to the limited current published literature on NSCLC harbouring a BRAF G469A mutation and suggests that immunotherapy is a reasonable treatment option.",Cureus,vol.12:10:e11224,2020,Case Reports,,,"Oncology and Hematology\, University of Manitoba\, Winnipeg\, CAN.,Oncology and Hematology\, CancerCare Manitoba\, University of Manitoba\, Winnipeg\, CAN.,Oncology and Hematology\, CancerCare Manitoba\, Winnipeg\, CAN.,Pathology\, University of Manitoba\, Winnipeg\, CAN.,Oncology and Hematology\, CancerCare Manitoba\, University of Manitoba\, Winnipeg\, CAN.",,,,,"braf,driver mutation,immune checkpoint inhibitor,nivolumab,non-small cell lung cancer"
33277344,"Iaccarino A,Pisapia P,Pepe F,Sgariglia R,Nacchio M,Russo G,Gragnano G,De Luca C,Troncone G,Malapelle U",Liquid biopsy for mutations testing in non-small cell lung cancer: a retrospective study.,"V-Raf murine sarcoma viral oncogene homolog B (BRAF) gene mutations have recently been approved to select advanced stages non-small cell lung cancer (NSCLC) patients for tyrosine kinase inhibitors treatments. In this setting, liquid biopsy may represent a valuable option for BRAF mutational testing in patients without tissue availability. Here, we reviewed 196 plasma based liquid biopsies analysed by an in-house developed next generation sequencing panel, termed SiRe. On the overall, 6 (3.1%) out of 196 BRAF mutated cases were identified, with an overall median allelic frequency of 3.4%. Exon 15 p.V600E was the most common detected mutation (2/6, 33.3%). Our data highlighted that the SiRe panel is a robust tool for BRAF mutation assessment on circulating tumour DNA. Further investigation is required to develop a diagnostic algorithm to harmonise BRAF testing on tissue and blood in advanced stages NSCLC patients.",Journal of clinical pathology,vol.::,2020,Journal Article,,,"Public Health\, University of Naples Federico II\, Naples\, Italy.,http://orcid.org/0000-0002-6429-0620Public Health\, University of Naples Federico II\, Naples\, Italy.,Public Health\, University of Naples Federico II\, Naples\, Italy.,Public Health\, University of Naples Federico II\, Naples\, Italy.,Public Health\, University of Naples Federico II\, Naples\, Italy.,Public Health\, University of Naples Federico II\, Naples\, Italy.,Public Health\, University of Naples Federico II\, Naples\, Italy.,Public Health\, University of Naples Federico II\, Naples\, Italy.,http://orcid.org/0000-0003-1630-5805Public Health\, University of Naples Federico II\, Naples\, Italy giancarlo.troncone@unina.it.,http://orcid.org/0000-0003-3211-9957Public Health\, University of Naples Federico II\, Naples\, Italy.",,,,,"biomarkers,lung neoplasms,molecular,pathology,tumour"
33282585,"Dominic JL,Feroz SH,Muralidharan A,Ahmed A,Thirunavukarasu P",Aberrant Partial Chromosomal Instability With Chemotherapeutically Resistant Metachronous Colorectal Cancer Following a Synchronous Primary Colorectal Cancer: A Case Report.,"The diagnosis of synchronous colorectal cancer (CRC) is crucial as the management, including the extent of surgical resection, depends on it. There have been numerous studies on the clinicopathological features of synchronous CRC; however, only a few studies have discussed synchronous cancer treatment. The guidelines to best manage the synchronous and metachronous CRC are limited, especially the most appropriate surgical treatment and chemotherapy based on mutational analysis of mismatch repair genes and the carcinoma sequence model. We present a rare case of a metachronous CRC with intact nuclear expression of microsatellite instability markers following a synchronous CRC, and it failed to show any significant response to surgical resection and chemoradiotherapy. A 53-year-old female presented in June 2016 with bleeding per rectum for one month, weight loss, and a recent history of altered bowel habits. The per rectal examination revealed a circumferential growth. Colonoscopy and biopsy yielded multiple polyps throughout the colon and invasive adenocarcinoma in the upper and lower one-third of the rectum. The above features were highly suggestive of synchronous CRC. Serologic studies revealed elevated carcinoembryonic antigen (CEA). Excisional biopsy of mesenteric and retroperitoneal lymph nodes during proctocolectomy and end ileostomy was negative for metastasis, including the other metastatic workup preoperatively-eight months post-resection and adjuvant chemotherapy patient developed metachronous CRC. Mutational analysis showed positivity only for adenomatous polyposis coli (APC) while negative for KRAS, NRAS, and BRAF. Immunohistochemistry (IHC) markers for mismatch repair (MMR) proteins showed intact protein expression. The patient was given multiple chemotherapy cycles throughout her course, including oral capecitabine, XELOX (capecitabine + oxaliplatin), cetuximab-capecitabine, cetuximab-irinotecan, and FOLFIRI (5-fluorouracil [5-FU] + irinotecan + folinic acid)-bevacizumab, as is the standard chemotherapy regimen for these tumors. The diagnosis of metachronous CRC with intensive follow up is crucial. IHC markers for MMR proteins showed intact protein expression ruling out the possibility of microsatellite instability and Lynch Syndrome. The only presence of APC mutation indicates a partial chromosomal instability. During the course, the patient had either stable size of the masses or developed new metastatic growth despite intensive chemotherapeutic regimes. Unfortunately, there are no precise guidelines based on aberrant mutational analysis regarding synchronous and metachronous CRCs management.",Cureus,vol.12:11:e11308,2020,Case Reports,,,"General Surgery\, South Texas Health System\, McAllen\, USA.,General Surgery\, Jawaharlal Nehru Medical College\, Aligarh\, IND.,Internal Medicine\, Kiruba Hospital\, Coimbatore\, IND.,General Surgery\, Ramaiah Medical College and Hospital\, Bangalore\, IND.,Surgical Oncology\, Cape Fear Valley Medical Center\, Fayetteville\, USA.",,,,,"capecitabine,cetuximab,chemotherapeutic resistance,chromosomal instability,irinotecan,metachronous colorectal cancer,metastatic colorectal cancer,microsatellite instability,primary colorectal cancer,synchronous colorectal cancer"
33282733,"Appay R,Fina F,Barets D,Gallardo C,Nanni-Metellus I,Scavarda D,Henaff D,Vincent J,Grewis L,Pourquier P,Colin C,Figarella-Branger D",Multiplexed Droplet Digital PCR Assays for the Simultaneous Screening of Major Genetic Alterations in Tumors of the Central Nervous System.,"The increased integration of molecular alterations to define tumor type or grade in central nervous system (CNS) tumor classification brings new challenges for the pathologist to make the best use of a precious limited tissue specimen for molecular studies. Within the different methods available to identify gene alterations, the droplet digital PCR (dPCR) constitutes a rapid, cost-effective, and very sensitive tool. In this study, we describe the development and validation of five multiplexed dPCR assays to detect major CNS biomarkers by using only small amounts of DNA extracted from formalin-fixed paraffin-embedded specimens. When compared to HRM-sequencing, NGS-sequencing, RNA-sequencing, or simplex digital PCR assays used as ""gold standard"" methods, these multiplexed dPCR assays displayed 100% specificity and sensitivity for the simultaneous detection of: 1/BRAF V600E mutation and KIAA1549:BRAF fusion; 2/FGFR1 N546K and K656E mutations and FGFR1 duplication; 3/H3F3A K27M and G34R/V mutations; 4/IDH1 R132X and IDH2 R172X mutations; and 5/TERT promoter mutations C228T and C250T. In light of the increased integration of molecular alteration, we believe that such strategies might help laboratories to optimize their screening strategies for routine diagnosis of pediatric and adult CNS tumors.",Frontiers in oncology,vol.10::579762,2020,Journal Article,,,"APHM\, CHU Timone\, Service d'Anatomie Pathologique et de Neuropathologie\, Marseille\, France.,APHM\, CHU Timone\, Service d'Anatomie Pathologique et de Neuropathologie\, Marseille\, France.,APHM\, CHU Timone\, Service d'Anatomie Pathologique et de Neuropathologie\, Marseille\, France.,APHM\, CHU Timone\, Service d'Anatomie Pathologique et de Neuropathologie\, Marseille\, France.,APHM\, CHU Nord\, Service de Transfert d'Oncologie Biologique\, Laboratoire de Biologie Médicale\, Marseille\, France.,APHM\, CHU Timone\, Service de Neurochirurgie pédiatrique\, Marseille\, France.,ID Solutions\, Research and Development\, Grabels\, France.,ID Solutions\, Research and Development\, Grabels\, France.,ID Solutions\, Research and Development\, Grabels\, France.,ID Solutions\, Research and Development\, Grabels\, France.,Aix-Marseille Univ\, CNRS\, INP\, Inst Neurophysiopathol\, Marseille\, France.,APHM\, CHU Timone\, Service d'Anatomie Pathologique et de Neuropathologie\, Marseille\, France.",,,,,"biomarkers,formaldehyde-fixed sample tissue,glial and glioneuronal tumors,molecular screening test,multiplexed droplet digital PCR assay,tumors of the central nervous system"
33284897,"Wang S,He F,Li Z,Hu Y,Huangfu N,Xie D",Long non-coding RNA BANCR promotes interferon-β-induced cardiomyocyte apoptosis by targeting signal transducer and activator of transcription 1 .,"Myocardium functions as an immune organ, and myocardial ischemia-reperfusion (I/R) is known to initiate myocardial innate immune response to induce myocardial injury. However, the mechanisms underlying interferon-β (IFN-β)-mediated myocardial injury during I/R and whether long non-coding RNAs (lncRNAs) are involved in IFN-β-mediated myocardial injury remain unknown. This study identified that I/R significantly induced IFN-β expression in induced pluripotent stem cell-derived cardiomyocytes, and IFN-β further enhanced I/R-induced myocardial apoptosis. Furthermore, it was demonstrated that the lncRNA BRAF-activated non-coding RNA (BANCR) was highly expressed in cardiomyocytes, and BANCR-knockdown suppressed signal transducer and activator of transcription 1 (STAT1) phosphorylation and IFN-β-induced cardiomyocyte apoptosis. Furthermore, it was identified that BANCR specifically interacted with STAT1 to promote IFN-β-STAT1 signaling and enhanced the expression of pro-apoptotic interferon stimulated genes. Overall, the present study reports that lncRNA BANCR promotes IFN-β-mediated cardiomyocyte apoptosis following I/R injury by interacting with STAT1, suggesting lncRNA BANCR is involved in IFN-β-induced cardiomyocyte apoptosis.",International journal of clinical and experimental pathology,vol.13:11:2840-2852,2020,Journal Article,,,"Department of Cardiology\, Ningbo First Hospital No. 59\, Liuding Street\, Ningbo 315000\, PR China.,Department of Cardiology\, Ningbo First Hospital No. 59\, Liuding Street\, Ningbo 315000\, PR China.,Department of Cardiology\, Ningbo First Hospital No. 59\, Liuding Street\, Ningbo 315000\, PR China.,Department of Cardiology\, Ningbo First Hospital No. 59\, Liuding Street\, Ningbo 315000\, PR China.,Department of Cardiology\, Ningbo First Hospital No. 59\, Liuding Street\, Ningbo 315000\, PR China.,Department of Cardiology\, Ningbo Ninth Hospital No. 68\, Xiajia Road\, Ningbo 315000\, PR China.",,,,,"Long non-coding RNA BRAF-activated non-coding RNA,interferon-β,myocardial infarction,signal transducer and activator of transcription 1"
32380762,"Diukendjieva A,Zaharieva MM,Mori M,Alov P,Tsakovska I,Pencheva T,Najdenski H,Křen V,Felici C,Bufalieri F,Di Marcotullio L,Botta B,Botta M,Pajeva I",Dual SMO/BRAF Inhibition by Flavonolignans from .,"Silymarin is the standardized extract from the fruits of Silybum marianum (L.) Gaertn., a well-known hepatoprotectant and antioxidant. Recently, bioactive compounds of silymarin, i.e., silybins and their 2,3-dehydro derivatives, have been shown to exert anticancer activities, yet with unclear mechanisms. This study combines in silico and in vitro methods to reveal the potential interactions of optically pure silybins and dehydrosilybins with novel protein targets. The shape and chemical similarity with approved drugs were evaluated in silico, and the potential for interaction with the Hedgehog pathway receptor Smoothened (SMO) and BRAF kinase was confirmed by molecular docking. In vitro studies on SMO and BRAF V600E kinase activity and in BRAF V600E A-375 human melanoma cell lines were further performed to examine their effects on these proteins and cancer cell lines and to corroborate computational predictions. Our in silico results direct to new potential targets of silymarin constituents as dual inhibitors of BRAF and SMO, two major targets in anticancer therapy. The experimental studies confirm that BRAF kinase and SMO may be involved in mechanisms of anticancer activities, demonstrating dose-dependent profiles, with dehydrosilybins showing stronger effects than silybins. The results of this work outline the dual SMO/BRAF effect of flavonolignans from Silybum marianum with potential clinical significance. Our approach can be applied to other natural products to reveal their potential targets and mechanism of action.","Antioxidants (Basel, Switzerland)",vol.9:5:,2020,Journal Article,,,"0000-0003-3159-9872Department of QSAR and Molecular Modelling\, Institute of Biophysics and Biomedical Engineering\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.,Department of Infectious Microbiology\, Stephan Angeloff Institute of Microbiology\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.,0000-0003-2398-1254Department of Biotechnology\, Chemistry and Pharmacy\, Department of Excellence 2018-2022\, University of Siena\, 53100 Siena\, Italy.,Department of QSAR and Molecular Modelling\, Institute of Biophysics and Biomedical Engineering\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.,0000-0003-1389-1685Department of QSAR and Molecular Modelling\, Institute of Biophysics and Biomedical Engineering\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.,0000-0002-1439-8895Department of QSAR and Molecular Modelling\, Institute of Biophysics and Biomedical Engineering\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.,Department of Infectious Microbiology\, Stephan Angeloff Institute of Microbiology\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.,0000-0002-1091-4020Laboratory of Biotransformation\, Institute of Microbiology of the Czech Academy of Sciences\, 14220 Prague\, Czech Republic.,Department of Molecular Medicine\, Sapienza University of Rome\, 00161 Rome\, Italy.,0000-0002-9571-318XDepartment of Molecular Medicine\, Sapienza University of Rome\, 00161 Rome\, Italy.,0000-0003-0274-7178Department of Molecular Medicine\, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti\, Sapienza University of Rome\, 00185 Rome\, Italy.,0000-0001-8707-4333Department of Chemistry and Technology of Drugs\, Sapienza University of Rome\, 00185 Rome\, Italy.,Department of Biotechnology\, Chemistry and Pharmacy\, Department of Excellence 2018-2022\, University of Siena\, 53100 Siena\, Italy.,0000-0001-5412-1586Department of QSAR and Molecular Modelling\, Institute of Biophysics and Biomedical Engineering\, Bulgarian Academy of Sciences\, 1113 Sofia\, Bulgaria.",,"Bulgarian Ministry of Education and Science\, National Research Program ""Healthy Foods for a Strong Bio-Economy and Quality of Life"",COST Action CM 1407 ""Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery"",Associazione Italiana Ricerca Cancro (AIRC),Czech Science Foundation",",,,","DCM#577/17.08.2018,STSM grant to Antonia Diukendjieva,#IG20801 to Lucia Di Marcotullio,18-00150S to Vladimir Kren","BRAF kinase,Smoothened,cytotoxicity,in silico methods,silybins"
32382617,"Zhao K,Lu Y,Chen Y,Cheng J,Zhang W",RNA sequencing data of Vemurafenib-resistant melanoma cells and parental cells.,"Melanoma is a type of malignant tumor derived from melanocytes, most of which occur in the skin, and a few occur in the mucosa and choroid. BRAF mutations occur in approximately 50% of melanoma patients. Vemurafenib is a specific and potent BRAF inhibitor that significantly prolongs progression-free survival in patients with BRAF mutant melanoma. But most patients have tumor recurrence after 7-9 months. Drug resistance severely limits the long-term clinical effects of targeted drugs. To explore the mechanism of melanoma resistance to Vemurafenib, the transcripts of Vemurafenib-resistant melanoma A375R cells and the parental A375 cells were sequenced. For more insight please see Transcripts 202 and 205 of IL-6 confer resistance to Vemurafenib by reactivating the MAPK pathway in BRAF(V600E) mutant melanoma cells [1]. RNA-seq data has been uploaded to Sequence Read Archive (SRA), which allows researchers to obtain RNA sequence data for these cells.",Data in brief,vol.30::105610,2020,Journal Article,,,"Key Laboratory of Transplant Engineering and Immunology\, NHFPC; Regenerative Medicine Research Center\, West China Hospital\, Sichuan University\, Chengdu\, Sichuan\, China.,Key Laboratory of Transplant Engineering and Immunology\, NHFPC; Regenerative Medicine Research Center\, West China Hospital\, Sichuan University\, Chengdu\, Sichuan\, China.,Key Laboratory of Transplant Engineering and Immunology\, NHFPC; Regenerative Medicine Research Center\, West China Hospital\, Sichuan University\, Chengdu\, Sichuan\, China.,Key Laboratory of Transplant Engineering and Immunology\, NHFPC; Regenerative Medicine Research Center\, West China Hospital\, Sichuan University\, Chengdu\, Sichuan\, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Center\, West China Hospital\, Sichuan University\, Chengdu\, Sichuan\, China.",,,,,"BRAF,Melanoma,RNA-seq,Vemurafenib,resistance"
32382835,"Roberto M,Marchetti P,Arrivi G,Di Pietro FR,Cascinu S,Gelsomino F,Caputo F,Cerma K,Ghidini M,Ratti M,Pizzo C,Ficorella C,Parisi A,Cortellini A,Urbano F,Calandrella ML,Botticelli A,Dell'Aquila E,Minelli A,Fulgenzi C,Montori A,Pilozzi E,Mazzuca F",The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference.,"BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations\, with the aim to identify any predictive factors of response to targeted-based therapy.,A retrospective study of RCC patients\, with BRAF known mutation status\, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers\, was conducted.,We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%\, p = 0.016)\, undifferentiated (71.4% v 44.0%\, p = 0.004)\, KRAS wt (90.5% v 38.2%\, p < 0.001)\, and MSI-H (41.7% v 16.2%\, p = 0.019) tumors\, with synchronous (52.4% v 31.5%\, p = 0.018) and peritoneal metastases (38.1% v 22.4%\, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting\, BRAF-mutant showed a 2ys OS of 80% in clinical trials\, 32% in anti-VEGF\, 14% in epidermial growth factor receptor (EGFR)\, and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival\, regardless of targeted therapy administered. However\, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months\, P = 0.005 in BRAF mutant v BRAF wt\, respectively).,Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore\, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.",International journal of colorectal disease,vol.35:8:1513-1527,2020,Journal Article,,,"Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy. paolo.marchetti@uniroma1.it.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Department of Oncology and Hematology\, Division of Oncology\, University Hospital of Modena\, Modena\, Italy.,Department of Oncology and Hematology\, Division of Oncology\, University Hospital of Modena\, Modena\, Italy.,Department of Oncology and Hematology\, Division of Oncology\, University Hospital of Modena\, Modena\, Italy.,Department of Oncology and Hematology\, Division of Oncology\, University Hospital of Modena\, Modena\, Italy.,Oncology Unit\, Oncology Department\, ASST of Cremona\, Cremona\, Italy.,Oncology Unit\, Oncology Department\, ASST of Cremona\, Cremona\, Italy.,Oncology Unit\, Oncology Department\, ASST of Cremona\, Cremona\, Italy.,Department of Biotechnological and Applied Clinical Sciences\, Medical Oncology\, St. Salvatore Hospital\, University of L'Aquila\, L'Aquila\, Italy.,Department of Biotechnological and Applied Clinical Sciences\, Medical Oncology\, St. Salvatore Hospital\, University of L'Aquila\, L'Aquila\, Italy.,Department of Biotechnological and Applied Clinical Sciences\, Medical Oncology\, St. Salvatore Hospital\, University of L'Aquila\, L'Aquila\, Italy.,Department of Radiology\, Oncology and Pathology\, Policlinico Umberto I\, Sapienza University\, Rome\, Italy.,Department of Radiology\, Oncology and Pathology\, Policlinico Umberto I\, Sapienza University\, Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Oncologia Medica\, Policlinico Universitario ""Campus Bio-Medico di Roma""\, Rome\, Italy.,Oncologia Medica\, Policlinico Universitario ""Campus Bio-Medico di Roma""\, Rome\, Italy.,Oncologia Medica\, Policlinico Universitario ""Campus Bio-Medico di Roma""\, Rome\, Italy.,Department of Clinical and Molecular Medicine\, UOC Anatomia Patologica\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Department of Clinical and Molecular Medicine\, UOC Anatomia Patologica\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.,Department of Clinical and Molecular Medicine\, Oncology Unit\, Sant' Andrea Hospital\, University ""La Sapienza""\, Rome\, Italy.",,,,,"Anti-EGFR,BRAF,Colorectal cancer,RCC,Sidedness"
32384640,"Huynh JC,Schwab E,Ji J,Kim E,Joseph A,Hendifar A,Cho M,Gong J",Recent Advances in Targeted Therapies for Advanced Gastrointestinal Malignancies.,"The treatment of advanced gastrointestinal (GI) cancers has become increasingly molecularly driven. Molecular profiling for HER2 and PD-L1 status is standard for metastatic gastroesophageal (GEJ) cancers to predict benefits from trastuzumab (HER2-targeted therapy) and pembrolizumab (anti-PD-1 therapy), while extended RAS and BRAF testing is standard in metastatic colorectal cancer to predict benefits from epidermal growth factor receptor (EGFR)-targeted therapies. Mismatch repair (MMR) or microsatellite instability (MSI) testing is standard for all advanced GI cancers to predict benefits from pembrolizumab and in metastatic colorectal cancer, nivolumab with or without ipilimumab. Here we review recent seminal trials that have further advanced targeted therapies in these cancers including Poly (adenosine diphosphate-ribose) polymerases (PARP) inhibition in pancreas cancer, BRAF inhibition in colon cancer, and isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) inhibition in biliary tract cancer. Targeted therapies in GI malignancies constitute an integral component of the treatment paradigm in these advanced cancers and have widely established the need for standard molecular profiling to identify candidates.",Cancers,vol.12:5:,2020,Review,,,"0000-0003-4481-2783Hematology Oncology\, University of California\, Davis\, Sacramento\, CA 95817\, USA.,Hematology Oncology\, University of California\, Davis\, Sacramento\, CA 95817\, USA.,Internal Medicine\, University of California\, Davis\, Sacramento\, CA 95817\, USA.,Hematology Oncology\, University of California\, Davis\, Sacramento\, CA 95817\, USA.,Hematology Oncology\, University of California\, Davis\, Sacramento\, CA 95817\, USA.,Hematology Oncology\, Cedars-Sinai Medical Center\, Los Angeles\, CA 90048\, USA.,0000-0002-7152-0017Hematology Oncology\, University of California\, Davis\, Sacramento\, CA 95817\, USA.,Hematology Oncology\, Cedars-Sinai Medical Center\, Los Angeles\, CA 90048\, USA.",,,,,"gastrointestinal cancer,molecular targets"
32384699,"Fennell LJ,Kane A,Liu C,McKeone D,Fernando W,Su C,Bond C,Jamieson S,Dumenil T,Patch AM,Kazakoff SH,Pearson JV,Waddell N,Leggett B,Whitehall VLJ"," Mutation Marks an Aggressive Subtype of Mutant Colorectal Cancers.","WNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers\, and the role of mutations in WNT signaling regulators in this context is unclear. Here\, we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers.,we performed exome-sequencing on 24 BRAF mutant colorectal cancers and analyzed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators\, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled\, in vivo\, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse\, respectively.,RNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade\, including MEN1\, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (p < 2 × 10-5)\, advanced stage (p < 0.01)\, and poor survival (p = 0.026). Apcmin/+/BrafV637 animals had more numerous and