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
33262833,"Nguyen HT,Le DT,Duong QH,Tatipamula VB,Van Nguyen B",High frequency of microsatellite instability and its substantial co-existence with and mutations in Vietnamese patients with colorectal cancer.,"Tumor heterogeneity and resistance to chemotherapy have been recognized as two major obstacles in the diagnosis and treatment of colorectal cancer (CRC). Microsatellite instability (MSI) and KRAS and BRAF mutations are common diagnostic factors that have been widely used to classify CRC for therapeutics. In the present study, 151 patients with CRC were analyzed from the two most populous ethnic groups of Vietnam, Kinh and Muong, for their MSI status, frequency of KRAS and BRAF mutations, and their clinical implications. MSI-high (MSI-H) was detected in 45.0% (68/151), while mutated KRAS and BRAF were identified in 37.1% (56/151) and 2.6% (4/151) of the cases, respectively. There was a substantial co-existence of MSI-H with KRAS (27/56; 48.2%) and BRAF (3/4; 75.0%) mutations. Statistical analysis showed that MSI-H tumors were significantly associated with colon location (P=0.011) and more advanced T stages (P=0.016). KRAS exon 2 mutations were significantly more likely to be detected in patients who belonged to the Muong ethnic group (P=0.013) or those with no/fewer lymph node metastasis (P=0.048) as compared with their counterparts. In summary, the data revealed typical molecular features of Vietnamese patients with CRC, including a strikingly high rate of MSI-H and its high co-existence with KRAS and BRAF mutations, which should be carefully considered in the future therapeutics for this type of cancer.",Oncology letters,vol.21:1:41,2021,Journal Article,,,"Institute of Research and Development\, Duy Tan University\, Danang 550000\, Vietnam.,Institute for Global Health Innovations\, Duy Tan University\, Danang 550000\, Vietnam.,Laboratory Center\, Hanoi University of Public Heath\, Hanoi 100000\, Vietnam.,Institute of Research and Development\, Duy Tan University\, Danang 550000\, Vietnam.,Anapathology Department\, Hue Central Hospital\, Hue 530000\, Vietnam.",,,,,"BRAF mutation,KRAS mutation,clinical implications,colorectal cancer,microsatellite instability"
33299797,"Rabinowitz MJ,Kohn TP,Peña VN,Samarska IV,Matoso A,Herati AS",Onset of azoospermia in man treated with ipilimumab/nivolumab for BRAF negative metastatic melanoma.,"Azoospermia is classified as the complete absence of sperm in ejaculate and accounts for 10-15% of male infertility. Many anticancer drugs are known to cause defects in spermatogenesis, but the effects of immune checkpoint inhibitor cancer therapy on spermatogenesis remains largely unknown. Presented here is a normozoospermic man (60 million sperm/cc of ejaculate) who received a trial combination treatment of Ipilimumab/Nivolumab to treat BRAF negative, stage IV metastatic melanoma. Two years after the treatment, the patient presented as completely azoospermic. The patient subsequently underwent microdissection testicular sperm extraction, during which no sperm was retrieved, and sertoli-only pathology was elucidated.",Urology case reports,vol.34::101488,2021,Case Reports,,,"Brady Urological Institute\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.,Brady Urological Institute\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.,Brady Urological Institute\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.,Department of Pathology\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.,Department of Pathology\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.,Brady Urological Institute\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, USA.",,,,,"Azoospermia,BRAF,CTLA-4\, Cytotoxic T-Lymphocyte antigen-4,ICI\, immune checkpoint inhibitor,Immunotherapy,Infertility,Male,SA\, semen analysis,immune Checkpoint inhibitor therapy,mTESE\, microscopic testicular sperm extraction"
32951290,"Bubola J,Antonescu CR,Weinreb I,Swanson D,De Almeida JR,MacMillan CM,Dickson BC",A novel low-grade nasopharyngeal adenocarcinoma characterized by a GOLGB1-BRAF fusion gene.,"Nasopharyngeal adenocarcinoma is a rare malignancy that is classified into conventional/surface- and salivary-types. Herein we report the case of a 52-year-old male who presented with a right nasopharyngeal mass and right-sided hearing loss. Diagnostic imaging revealed a circumscribed 1.7 cm mass centred in the right antero-lateral aspect of the nasopharynx. A biopsy showed a gland-forming neoplasm that was in continuity with the surface epithelium. The tumor exhibited a nested to micro-papillary architecture, with mild cytologic atypia. Immunohistochemistry demonstrated diffuse staining for CK7, SOX10, and p16; the abluminal layer was highlighted by CK5 and p63, while the luminal cells expressed CD117. The tumor was not amenable to subclassification and was diagnosed as a low-grade nasopharyngeal adenocarcinoma, not otherwise specified (NOS). Subsequent RNA sequencing was performed which identified a novel GOLGB1-BRAF fusion product. Based on its unique morphology and molecular findings, this is presumed to represent a novel subtype of nasopharyngeal adenocarcinoma. In addition to being of diagnostic relevance, this fusion may ultimately represent a potential therapeutic target.","Genes, chromosomes & cancer",vol.60:1:49-53,2021,Journal Article,,,"Department of Pathology and Laboratory Medicine\, Mount Sinai Hospital\, Toronto\, Ontario\, Canada.,https://orcid.org/0000-0002-9717-8205Department of Pathology\, Memorial Sloan Kettering Cancer Center\, New York\, New York\, USA.,https://orcid.org/0000-0001-9552-3549Department of Pathology\, University Health Network\, Toronto\, Ontario\, Canada.,Department of Pathology and Laboratory Medicine\, Mount Sinai Hospital\, Toronto\, Ontario\, Canada.,Department of Otolaryngology Head and Neck Surgery\, Department of Surgical Oncology\, University Health Network\, Toronto\, Ontario\, Canada.,Department of Pathology and Laboratory Medicine\, Mount Sinai Hospital\, Toronto\, Ontario\, Canada.,https://orcid.org/0000-0003-2269-6216Department of Pathology and Laboratory Medicine\, Mount Sinai Hospital\, Toronto\, Ontario\, Canada.",,Panov 2 Research Fund,,,"BRAF,GOLGB1,nasopharyngeal adenocarcinoma"
33469371,"Miao X,Liu Y,Fan Y,Wang G,Zhu H",LncRNA BANCR Attenuates the Killing Capacity of Cisplatin on Gastric Cancer Cell Through the ERK1/2 Pathway.,"Chemotherapy-based comprehensive treatments are the most important therapeutic methods for patients with advanced gastric cancer\, but chemoresistance often cause treatment failure. Long non-coding RNA (LncRNA) BRAF-activated non-coding RNA (BANCR) has been shown to participate in many biological behaviors of multiple cancers. However\, the biological roles of LncRNA BANCR in chemoresistance of gastric cancer remain unclear. Here\, we aimed to evaluate the functions of LncRNA BANCR on the therapy of gastric cancer.,In this study\, LncRNA BANCR expression was detected in gastric cancer patient samples and cell lines by quantity polymerase chain reaction (qPCR). Cell proliferation and viability in cisplatin-treated cells were measured using clonogenic survival assay and cell counting kit-8. The levels of ERK1/2 pathway molecules were tested with Western blot. Ly3214996\, an inhibitor of ERK signal pathway\, was administered to assess the effects of BANCR overexpression on gastric cancer cell with cisplatin-treated resistance. Moreover\, the role of BANCR in cisplatin resistance of gastric cancer was validated in xenograft mouse models in vivo.,Our study revealed that LncRNA BANCR expression was also significantly increased in gastric cancer tissues compared with adjacent normal tissues. Furthermore\, we found that BANCR overexpression promoted gastric cancer cell resistance to cisplatin in vitro. Ly3214996 treatment abolished the BANCR overexpression-mediated gastric cancer cell cisplatin resistance via regulating the phosphorylation of ERK protein. Knock-down of BANCR significantly delayed tumor growth in xenograft mouse models.,BANCR promoted cisplatin resistance of gastric cancer cells by activating ERK1/2 pathway. Inhibition of BANCR markedly suppressed the growth of gastric cancer cells in vitro as well as in vivo. These results provided a new strategy for gastric cancer therapy via targeting BANCR.",Cancer management and research,vol.13::287-296,2021,Journal Article,,,"0000-0002-9299-8415Department of General Surgery\, Lianyungang Municipal Oriental Hospital\, Lianyungang\, Jiangsu 222042\, People's Republic of China.,0000-0002-9262-1837Department of General Surgery\, Lianyungang Municipal Oriental Hospital\, Lianyungang\, Jiangsu 222042\, People's Republic of China.,0000-0003-2276-8152Department of General Surgery\, Lianyungang Municipal Oriental Hospital\, Lianyungang\, Jiangsu 222042\, People's Republic of China.,0000-0001-7849-6139Department of General Surgery\, Lianyungang Municipal Oriental Hospital\, Lianyungang\, Jiangsu 222042\, People's Republic of China.,0000-0002-1928-8505Department of General Surgery\, Lianyungang Municipal Oriental Hospital\, Lianyungang\, Jiangsu 222042\, People's Republic of China.",,,,,"BANCR,ERK1/2 pathway,chemoresistance,cisplatin,gastric cancer"
33469503,"Dolatkhah R,Dastgiri S,Eftekhar Sadat AT,Farassati F,Nezamdoust M,Somi MH",Impact of mutations on clinical and prognostic outcomes in metastatic colorectal cancer.,"Introduction: Early-activated RAS/RAF mutation status is a key molecular finding in colorectal cancer (CRC), while these mutations have been proposed as predictive and prognostic biomarkers. The present study has been designed as a longitudinal study to evaluate and summarize the different genotypes of metastatic CRC (mCRC), and assessing any association with the disease prognosis and clinicopathological characteristics. This study was performed in two main referral hospitals of Tabriz University of Medical Sciences, over three years (2016-2018). Methods: Mutations were detected by Idylla tests of KRAS/NRAS/BRAF among a total of 173 mCRCs, using surgically-resected specimens or biopsied samples. To evaluate the factors associated with overall survival (OS) and prognosis, the Cox proportional hazards model was used in two steps to estimate the outcome measures (hazard ratio, or HR) with a 95% confidence interval (CI). Results: The nominal 1 to 5-year OS rates were 78%, 65%, 55%, 46%, and 42%, respectively. KRAS mutations in codon 12 was an independent significant prognostic factor, as the patients with codon 12 mutations had a significantly lower OS (P Log-rank=0.049) and a higher hazard of mortality (HR=2.30; 95% CI: 0.95-5.58; P =0.066). Also, the mCRC patients with liver metastasis (HR=2.49; 95% CI: 1.49-12.52; P =0.002) and tumors of the distal colon (HR=3.36; 95% CI: 1.07-10.49; P =0.037) had a significantly worse prognosis. Conclusion: KRAS mutation in codon 12 was an independent significant poor prognostic factor, and patients with liver metastasis had a significantly worse prognosis. Routinely performing specific oncogenic tests may help improve the patients' prognosis and life expectancy.",BioImpacts : BI,vol.11:1:5-14,2021,Journal Article,,,"https://orcid.org/0000-0002-6897-7120Hematology and Oncology Research Center\, Tabriz University of Medical Sciences\, Tabriz\, Iran.,https://orcid.org/0000-0002-8129-9125Tabriz Health Services Management Research Center\, Tabriz University of Medical Sciences\, Tabriz\, Iran.,Liver and Gastrointestinal Diseases Research Center\, Tabriz University of Medical Sciences\, Tabriz\, Iran.,Midwest Biomedical Research Foundation\, Kansas City\, MO\, USA.,Tabriz University of Medical Sciences\, Tabriz\, Iran.,https://orcid.org/0000-0002-6611-9958Liver and Gastrointestinal Diseases Research Center\, Tabriz University of Medical Sciences\, Tabriz\, Iran.",,,,,"Colorectal cancer,Hazard ratio,KRAS,Oncogene,Overall survival"
32602215,"Zhang W,Mathisen M,Goodman GR,Forbes H,Song Y,Bertran E,Demidov L,Shin SJ","Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady-State Pharmacokinetics of Vemurafenib in Patients With BRAF Mutation-Positive Malignancies.","The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.",Clinical pharmacology in drug development,vol.10:1:39-45,2021,Journal Article,,,"F. Hoffmann-La Roche Ltd.\, New York\, New York\, USA.,Genentech\, Inc.\, South San Francisco\, California\, USA.,Genentech\, Inc.\, South San Francisco\, California\, USA.,F. Hoffmann-La Roche Ltd.\, Mississauga\, Ontario\, Canada.,F. Hoffmann-La Roche Ltd.\, Mississauga\, Ontario\, Canada.,F. Hoffmann-La Roche Ltd.\, Basel\, Switzerland.,N. N. Blokhin Medical Research Center of Oncology\, Moscow\, Russia.,Division of Medical Oncology\, Yonsei University College of Medicine\, Seoul\, Republic of Korea.",,,,,"CYP3A4,drug-drug interactions,itraconazole,pharmacokinetics,vemurafenib"
32984984,"Zhao W,He L,Zhu J,Su A",A nomogram model based on the preoperative clinical characteristics of papillary thyroid carcinoma with Hashimoto's thyroiditis to predict central lymph node metastasis.,"Preoperative prediction of central lymph node (LN) metastasis in papillary thyroid carcinoma (PTC) with Hashimoto's thyroiditis (HT) provides an important basis for surgical decision-making\, especially regarding the extent of tumour resection. We aimed to develop and validate a nomogram model for the preoperative assessment of central LN metastasis.,We retrospectively collected the data of 994 PTC patients with HT who underwent surgery at the West China Hospital from January 2008 to December 2017. Among them\, 606 patients who underwent surgeries relatively earlier comprised the training cohort for nomogram development\, while the other 388 who underwent surgeries relatively later formed the validation cohort to validate the model's performance. Univariate and multivariate logistic regression analyses were conducted using the data of the two respective cohorts\, as well as the data of the combined cohort. The relevant preoperative potential risk factors include demographic characteristics\, medical history information\, thyroid function test\, ultrasound characteristics and BRAF V600E gene detection. A nomogram model was subsequently developed. The performance\, discrimination and calibration of the nomogram model were assessed in the training and validation cohorts and in the combined cohort.,The central LN metastasis rate of PTC with HT was 49.7% (301/606) and 48.7% (193/388) in the training and validation cohorts\, respectively. The univariate and multivariate logistic regression analyses indicated that younger age\, normal body mass index\, BRAF V600E mutation\, larger maximum diameter\, left lobe tumour\, aspect ratio >1\, capsular invasion and calcification were significant risk factors for central LN metastasis in PTC patients with HT. The preoperative nomogram showed good calibration and discrimination for the training and validation cohorts\, as well as for the combined data set.,The nomogram we developed and validated with a comprehensive set of preoperative factors is effective in predicting central LN metastasis in PTC patients with HT.",Clinical endocrinology,vol.94:2:310-321,2021,Journal Article,,,"https://orcid.org/0000-0001-7732-6517Department of Thyroid Surgery\, West China Hospital\, Sichuan University\, Chengdu\, China.,Department of Thyroid Surgery\, West China Hospital\, Sichuan University\, Chengdu\, China.,Department of Thyroid Surgery\, West China Hospital\, Sichuan University\, Chengdu\, China.,Department of Thyroid Surgery\, West China Hospital\, Sichuan University\, Chengdu\, China.",,"General Project pf Science and Technology Department of Sichuan Province,West China Hospital\, Sichuan University,Sichuan University,Sichuan University",",,,","2019JDKKP0071,18HXBH074,18HXBH074,2019JDKKP0071","Central lymph node metastasis,Hashimoto's thyroiditis,Nomogram,Papillary thyroid carcinoma"
33423919,"Solomon D,Leigh N,Bekhor E,Feferman Y,Dhorajiya P,Feingold D,Hofstedt M,Aycart SN,Golas BJ,Sarpel U,Labow DM,Magge DR",The role of molecular biomarkers in outcomes and patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases of colorectal origin.,"Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is effective in select patients with peritoneal metastases of colorectal (CRC) origin. The impact of different biomarkers in predicting recurrence after CRS/HIPEC is unclear.,Retrospective review of patients who underwent CRS/HIPEC for PC of CRC origin from 03/2007-08/2017. Molecular profile of the primary tumor was obtained from pathology reports\, whenever available.,Overall\, 100 patients underwent CRS/HIPEC for peritoneal metastases of CRC origin. Most patients presented high grade tumor histology (G2/G3\, n = 97\, 97%)\, and a majority showed mucinous features (n = 61\, 61%). At a median follow-up of 18 months\, median DFS for the overall population was 13 months (95% CI 9.6\, 16.4). Data reporting at least one mutational analysis was available in 64 patients. Microsatellite stability was detected in 42/50 (84%) patients\, mKRAS in 25/51 (49%)\, and mBRAF in 5/35 (14.3%). On Kaplan-Meier analysis\, BRAF was the only mutation associated with poor DFS (16 months\, CI 95% 11.7-43.3 vs. 7 months\, CI 95% 2.1-11.9\, p = .008). On multivariate analysis\, mBRAF independently predicted earlier recurrence (p = .032).,In this analysis\, mBRAF was independently associated with earlier recurrence in patients undergoing CRS/HIPEC for CRC\, leading to dismal median DFS (7 months). Strict patient selection is advisable in these patients.",The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland,vol.::,2021,Journal Article,,,"Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Pathology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA.,Department of Surgery\, Division of Surgical Oncology\, Icahn School of Medicine at Mount Sinai\, New York\, NY\, USA. Electronic address: Deepa.magge@mountsinai.org.",,,,,"CRS/HIPEC,Colorectal cancer,Mutational status,Peritoneal carcinomatosis"
33426601,"Kunnackal John G,Das Villgran V,Caufield-Noll C,Giardiello FM",Comparison of universal screening in major lynch-associated tumors: a systematic review of literature.,"Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p < 0.001). The pooled screening yield was highest in ST [52.5% (355/676), 95% CI 48.74-56.26%] followed by EC [22.65% (1142/5041), 95% CI 21.54-23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61-12.19%], OC [11.29% (320/2833), 95% CI 10.13-12.47%] and UT [11.2% (31/276), 95% CI 7.48-14.92%]. ST also had the highest pooled germline positivity for mismatch repair gene mutation [18.8%, 33/176, 95%CI 13.03-24.57], followed by EC [2.6% (97/3765), 95% CI 2.09-3.11], CRC [1.8% (682/37,220), 95% CI 1.66-1.94%], UT [1.8%(3/164), 95% CI - 0.24-3.83%] and OC [0.83%(25/2983), 95% CI 0.48-1.12%]. LS screening in EC yielded significantly higher somatic mutations compared to CRC [pooled percentage 16.94% [(538/3176), 95%CI 15.60-18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93-5.47%], Mann Whitney test, p < 0.0001. Universal LS testing should be routinely performed in OC, UT and STs in addition to CRC and EC. Our findings also support consideration for IHC and somatic mutation testing before germline testing in EC due to higher prevalence of somatic mutations as well as germline testing in all patients with ST. Our results have implications for future design of LS screening programs and further studies are needed to assess the cost effectiveness and burden on genetic counselling services with expanded universal testing for LS.",Familial cancer,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0002-0595-5434Clinical Assistant Professor\, Division of Gastroenterology and Hepatology\, University of Maryland School of Medicine\, 511 Idlewild Ave\, Easton\, MD\, 21601\, USA. george.john@umm.edu.,Pulmonary and Critical Care Fellow\, Allegheny Health Network\, Pittsburgh\, PA\, 15212\, USA.,Medical Librarian\, Johns Hopkins Bayview Medical Center\, Baltimore\, MD\, 21224\, USA.,Division of Gastroenterology and Hepatology\, Johns Hopkins University School of Medicine\, Baltimore\, MD\, 21205\, USA.",,NIH HHS,United States,P50CA062924,"Lynch syndrome,Universal screening"
33428122,"Shi X,Qu M,Jin X,Liu L,Meng F,Shen H","Relationship between TSHR, BRAF and PIK3CA gene copy number variations and thyroid nodules.","This study aims to investigate the relationship between the TSHR\, BRAF\, and PIK3CA gene copy number variations (CNVs) and thyroid nodules by analyzing gene CNVs\, and to explore the interaction between iodine status and the above genes CNVs in the occurrence of thyroid nodules.,Three hundred and ninety-five subjects were selected from 3 regions with different iodine status in Shanxi Province of China\, including 192 patients with thyroid nodules and 203 healthy controls. The basic information about subjects had been obtained through a questionnaire. B ultrasound was utilized to check thyroid nodules. Blood and urine samples were harvested to detect the thyroid function and urinary iodine concentration. Real-time quantitative polymerase chains reaction (RT-PCR) served to detect CNVs in DNA from human blood.,There was an association between TSHR gene CNV and thyroid nodules (χ2 = 8.403\, P = 0.004). The prevalence of BRAF and PIK3CA gene CNVs was not statistically significant between the case group and the control group. Differences in the TSHR gene CNV rates for cases of the 3 areas were statistically significant (χ2 = 10.072\, P = 0.007). No statistical difference in the prevalence rates of the 3 genes CNVs between diverse characteristics of thyroid nodules was observed. UIC > 300 μg/L (OR = 1.74\, 95% CI: 1.02-2.96\, P = 0.041) and TSHR gene CNV (OR = 3.53\, 95% CI: 1.40-8.92\, P = 0.008) were risk factors for thyroid nodules. There was no significant interaction between the UIC and the examined genes CNVs.,TSHR gene CNV and high urinary iodine levels can increase the risk of thyroid nodules. But the interactions between the 3 above genes CNVs and iodine nutrition were not found in the occurrence of thyroid nodules.",Endocrine,vol.::,2021,Journal Article,,,"Centre for Endemic Disease Control\, Chinese Centre for Disease Control and Prevention\, Harbin Medical University\, Harbin\, Heilongjiang\, China.,Centre for Endemic Disease Control\, Chinese Centre for Disease Control and Prevention\, Harbin Medical University\, Harbin\, Heilongjiang\, China.,Centre for Endemic Disease Control\, Chinese Centre for Disease Control and Prevention\, Harbin Medical University\, Harbin\, Heilongjiang\, China.,Centre for Endemic Disease Control\, Chinese Centre for Disease Control and Prevention\, Harbin Medical University\, Harbin\, Heilongjiang\, China.,Centre for Endemic Disease Control\, Chinese Centre for Disease Control and Prevention\, Harbin Medical University\, Harbin\, Heilongjiang\, China.,http://orcid.org/0000-0002-8807-9897Centre for Endemic Disease Control\, Chinese Centre for Disease Control and Prevention\, Harbin Medical University\, Harbin\, Heilongjiang\, China. shenhm119@hrbmu.edu.cn.",,National Natural Science Foundation of China,,81573098,"BRAF,Copy number variation,PIK3CA,TSHR,Thyroid nodules,Urinary iodine"
33442661,"Wang L,He X,Ugai T,Haruki K,Lo CH,Hang D,Akimoto N,Fujiyoshi K,Wang M,Fuchs CS,Meyerhardt JA,Zhang X,Wu K,Chan AT,Giovannucci EL,Ogino S,Song M",Risk Factors and Incidence of Colorectal Cancer According to Major Molecular Subtypes.,"Colorectal cancer (CRC) is a heterogeneous disease that can develop via 3 major pathways: conventional\, serrated\, and alternate. We aimed to examine whether the risk factor profiles differ according to pathway-related molecular subtypes.,We examined the association of 24 risk factors with 4 CRC molecular subtypes based on a combinatorial status of microsatellite instability (MSI)\, CpG island methylator phenotype (CIMP)\, and BRAF and KRAS mutations by collecting data from 2 large US cohorts. We used inverse probability weighted duplication-method Cox proportional hazards regression to evaluate differential associations across subtypes.,We documented 1175 CRC patients with molecular subtype data: subtype 1 (n = 498; conventional pathway; non-MSI-high\, CIMP-low or negative\, BRAF-wild-type\, KRAS-wild-type)\, subtype 2 (n = 138; serrated pathway; any MSI status\, CIMP-high\, BRAF-mutated\, KRAS-wild-type)\, subtype 3 (n = 367; alternate pathway; non-MSI-high\, CIMP-low or negative\, BRAF-wild-type\, KRAS-mutated)\, and subtype 4 (n = 172; other marker combinations). Statistically significant heterogeneity in associations with CRC subtypes was found for age\, sex\, and smoking\, with a higher hazard ratio (HR) observed for the subtype 2 (HR per 10 years of age = 2.64\, 95% CI = 2.13 to 3.26; HR for female = 2.65\, 95% CI = 1.60 to 4.39; HR per 20-pack-year of smoking = 1.29\, 95% CI = 1.14 to 1.45) than other CRC subtypes (all P heterogeneity < .005). A stronger association was found for adiposity measures with subtype 1 CRC in men and subtype 3 CRC in women and for several dietary factors with subtype 1 CRC\, although these differences did not achieve statistical significance at α  level of .005.,Risk factor profiles may differ for CRC arising from different molecular pathways.",JNCI cancer spectrum,vol.5:1:pkaa089,2021,Journal Article,,,"Center of Gastrointestinal Surgery\, the First Affiliated Hospital\, Sun Yat-Sen University\, Guangzhou\, P.R. China.,Department of Colorectal Surgery\, the Six Affiliated Hospital\, Sun Yat-sen University\, Guangzhou\, P.R. China.,Department of Epidemiology\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.,0000-0002-1686-3228Department of Pathology\, Brigham and Women's Hospital and Harvard Medical School\, Program in MPE Molecular Pathological Epidemiology\, Boston\, MA\, USA.,0000-0001-8202-4513Department of Epidemiology\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.,Department of Epidemiology and Biostatistics\, Jiangsu Key Lab of Cancer Biomarkers\, Prevention and Treatment\, Collaborative Innovation Center for Cancer Personalized Medicine\, School of Public Health\, Nanjing Medical University\, Nanjing\, P.R. China.,0000-0001-9880-4143Department of Pathology\, Brigham and Women's Hospital and Harvard Medical School\, Program in MPE Molecular Pathological Epidemiology\, Boston\, MA\, USA.,0000-0002-0310-5807Department of Pathology\, Brigham and Women's Hospital and Harvard Medical School\, Program in MPE Molecular Pathological Epidemiology\, Boston\, MA\, USA.,Department of Epidemiology\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.,0000-0003-1582-9842Department of Medicine\, Yale Cancer Center\, New Haven\, CT\, USA.,0000-0002-1120-0898Department of Medical Oncology\, Dana-Farber Cancer Institute and Harvard Medical School\, Boston\, MA\, USA.,Channing Division of Network Medicine\, Department of Medicine\, Brigham and Women's Hospital and Harvard Medical School\, Boston\, MA\, USA.,Department of Nutrition\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.,Division of Gastroenterology\, Massachusetts General Hospital and Harvard Medical School\, Boston\, MA\, USA.,Department of Epidemiology\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.,0000-0002-3909-2323Department of Epidemiology\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.,0000-0002-1324-0316Department of Epidemiology\, Harvard T. H. Chan School of Public Health\, Boston\, MA\, USA.",,,,,
33448717,"Morales E,Viskochil D,Hofmann J,Hagedorn C,Linscott L,Cheshier S,Bruggers CS",Multiple Intraspinal Gangliogliomas in a Child With Neurofibromatosis Type 1: Case Report and Literature Review.,"Neurofibromatosis type 1 (NF1)-associated primary intramedullary spinal cord ganglioglioma has only rarely been reported. Because of frequent nonresectability, they pose significant management challenges despite clinical indolence. This report describes a 4-year-old girl with NF1 who was found to have multiple discrete, infiltrative intramedullary cord masses, and biopsy demonstrated World Health Organization grade I ganglioglioma. Panel-based next-generation sequencing showed her previously identified germline NF1 mutation and a second somatic NF1 mutation. This represents the first report of multiple primary intramedullary gangliogliomas in a child with NF1 and demonstrates how biopsy with panel-based next-generation sequencing provides potential targets for MAPK/MEK/BRAF pathway inhibitor therapy.",Journal of pediatric hematology/oncology,vol.::,2021,Journal Article,,,"Division of Hematology-Oncology Department of Pediatrics\, Division of Medical Genetics Department of Pediatric Neurosurgery\, University of Utah Department of Medical Imaging\, Primary Children's Hospital\, Salt Lake City\, UT Department of Neuropathology\, University of California San Francisco\, San Francisco\, CA.,,,,,,",,,,,
32826083,"Prasanna T,Wong R,Price T,Shapiro J,Tie J,Wong HL,Nott L,Roder D,Lee M,Kosmider S,Jalali A,Burge M,Padbury R,Maddern G,Carruthers S,Moore J,Sorich M,Karapetis CS,Gibbs P,Yip D",Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer.,"Resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether the benefit is consistent for BRAF V600E mutant (MT) and wild type (WT) mCRC. This retrospective analysis explores the influence of BRAF MT on survival after metastasectomy.,Overall survival (OS) and recurrence-free survival (RFS) for BRAF MT and WT mCRC were evaluated. Survival was also analyzed in the cohort of BRAF MT with or without metastasectomy.,Five hundred and thirteen patients who had undergone metastasectomy were identified\, 6% were BRAF-MT. Median age 63. Median OS in BRAF MT vs WT: 25.7 vs 48.5 months (hazard ratio [HR] 1.95; 1.18-3.22). However\, difference was not significant in a multivariate model. Right primary tumor\, intact primary\, >1 metastatic site\, non-R0 resection\, peritoneal metastasis\, and synchronous metastasis were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 vs 19 months\, p=0.09). In another cohort of 158 BRAF-MT patients\, OS was significantly better after metastasectomy compared to ""no metastasectomy"" (HR 0.34; 0.18-0.65\, P= 0.001). Proficient mismatch repair status showed a trend toward worse survival after metastasectomy in BRAF MT (HR 1.71\, P = 0.08).,OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Median OS was >2 years in this study after metastasectomy among BRAFV600E MT patients suggesting a survival benefit of metastasectomy in this group where systemic therapeutic options are limited. Metastasectomy may be considered in carefully selected BRAF-MT patients.",Current problems in cancer,vol.45:1:100637,2021,Review,,,"Department of Medical Oncology\, The Canberra Hospital\, Garran\, ACT\, Australia; ANU Medical School\, Australian National University\, Australia; University of Canberra\, ACT\, Australia. Electronic address: Thiru.prasanna@act.gov.au.,Walter and Eliza Hall Institute of Medical Research\, Melbourne\, Australia; Department of Medical Oncology\, Eastern Health\, Melbourne\, Australia; Monash University\, Faculty of Medicine\, Nursing and Health Sciences\, Melbourne\, Australia.,The Queen Elizabeth Hospital and University of Adelaide\, Adelaide\, Australia.,Cabrini Haematology and Oncology Centre\, Melbourne\, Australia.,Walter and Eliza Hall Institute of Medical Research\, Melbourne\, Australia; Department of Medical Oncology\, Western Hospital\, Melbourne\, Australia; Department of Medical Oncology\, Peter MacCallum Cancer Centre\, Melbourne\, Australia.,Walter and Eliza Hall Institute of Medical Research\, Melbourne\, Australia.,Department of Medical Oncology\, Royal Hobart Hospital\, Hobart\, Tasmania\, Australia; Menzies Research institute\, Hobart\, Australia.,South Australian Health & Medical Research Institute (SAHMRI)\, Australia; University of South Australia\, Adelaide\, Australia.,Walter and Eliza Hall Institute of Medical Research\, Melbourne\, Australia; Department of Medical Oncology\, Eastern Health\, Melbourne\, Australia.,Department of Medical Oncology\, Western Hospital\, Melbourne\, Australia.,Walter and Eliza Hall Institute of Medical Research\, Melbourne\, Australia; Department of Medical Oncology\, Western Hospital\, Melbourne\, Australia.,Department of Medical Oncology\, Royal Brisbane Hospital\, Brisbane\, Australia.,Flinders University\, Bedford Park\, Australia; Department of Surgery\, Flinders Medical Centre\, Australia.,University of Adelaide Discipline of Surgery\, The Queen Elizabeth Hospital\, Adelaide\, Australia.,Department of Radiation Oncology\, Royal Adelaide Hospital\, Adelaide\, Australia.,Department of Surgery\, Royal Adelaide Hospital\, Adelaide\, Australia.,College of Medicine and Public Health\, Flinders University\, Adelaide\, Australia.,Flinders University\, Bedford Park\, Australia; Department of Medical Oncology\, Flinders Medical Centre\, Australia.,Walter and Eliza Hall Institute of Medical Research\, Melbourne\, Australia; Department of Medical Oncology\, Western Hospital\, Melbourne\, Australia.,Department of Medical Oncology\, The Canberra Hospital\, Garran\, ACT\, Australia; ANU Medical School\, Australian National University\, Australia.",,,,,"BRAF V600E mutation,Metastasectomy,Metastatic colorectal cancer,Survival"
33547983,"Dennison L,Mohan AA,Yarchoan M",Tumor and Systemic Immunomodulatory Effects of MEK Inhibition.,"Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS signaling pathway\, one of the most frequently mutated pathways in cancer biology. MEK inhibitors were initially developed to directly target oncogenic signaling\, but are recognized to have pleiotropic effects on both tumor cells and lymphocytes. Here\, we review the preclinical and clinical evidence that MEK inhibition is immunomodulatory and discuss the potential rationale for combining MEK inhibitors with systemic immunotherapies.,MEK inhibition may modulate the tumor microenvironment (TME) through direct effects on both tumor cells and immune cells. Despite encouraging evidence that MEK inhibition can reprogram the tumor microenvironment (TME) and augment anti-tumor immunity regardless of KRAS/BRAF status\, recent clinical outcome studies combining MEK inhibition with systemic immunotherapy have yielded mixed results. The combination of MEK inhibitors plus systemic immunotherapies has been tolerable\, but has thus far failed to demonstrate clear evidence of synergistic clinical activity. These results underscore the need to understand the appropriate therapeutic context for this combination. MEK inhibitors have the potential to inhibit oncogenic signaling and reprogram the tumor immune microenvironment\, representing an attractive therapy to combine with systemic immunotherapies. Ongoing preclinical and clinical studies will further clarify the immunomodulatory effects of MEK inhibitors to inform the design of rational therapeutic combinations.",Current oncology reports,vol.23:2:23,2021,Review,,,"The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins\, Baltimore\, MD\, 21231\, USA.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins\, Baltimore\, MD\, 21231\, USA.,http://orcid.org/0000-0003-4401-0748The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins\, Baltimore\, MD\, 21231\, USA. mark.yarchoan@jhmi.edu.",,,,,"Immunotherapy,MAPK,MEK,PD-1,PD-L1,RAS"
33551379,"Yeom H,Hwang SH,Han BI,Lee M",Differential Sensitivity of Wild-Type and BRAF-Mutated Cells to Combined BRAF and Autophagy Inhibition.,"BRAF inhibitors are insufficient monotherapies for BRAF-mutated cancer; therefore, we investigated which inhibitory pathway would yield the most effective therapeutic approach when targeted in combination with BRAF inhibition. The oncogenic BRAF inhibitor, PLX4720, increased basal autophagic flux in BRAF-mutated cells compared to wild-type (WT) BRAF cells. Interestingly, early autophagy inhibition improved the effectiveness of PLX4720 regardless of BRAF mutation, whereas late autophagy inhibition did not. Although ATG5 knockout led to PLX4720 resistance in both WT and BRAF-mutated cells, the MEK inhibitor trametinib exhibited a synergistic effect on PLX4720 sensitivity in WT BRAF cells but not in BRAF-mutated cells. Conversely, the prolonged inhibition of endoplasmic reticulum (ER) stress reduced basal autophagy in BRAF-mutated cells, thereby increasing PLX4720 sensitivity. Taken together, our results suggest that the combined inhibition of ER stress and BRAF may simultaneously suppress both pro-survival ER stress and autophagy, and may therefore be suitable for treatment of BRAF-mutated tumors whose autophagy is increased by chronic ER stress. Similarly, for WT BRAF tumors, therapies targeting MEK signaling may be a more effective treatment strategy. Together, this study presents a rational combination treatment strategy to improve the efficacy of BRAF inhibitors depending on BRAF mutation status.",Biomolecules & therapeutics,vol.::,2021,Journal Article,,,"Division of Life Sciences\, College of Life Sciences and Bioengineering\, Incheon National University\, Incheon 22012\, Republic of Korea.,Division of Life Sciences\, College of Life Sciences and Bioengineering\, Incheon National University\, Incheon 22012\, Republic of Korea.,Institute for New Drug Development\, Incheon National University\, Incheon 22012\, Republic of Korea.,Division of Life Sciences\, College of Life Sciences and Bioengineering\, Incheon National University\, Incheon 22012\, Republic of Korea.",,,,,"Autophagy,BRAF,Cancer,Melanoma,Mutation,TFEB"
33552685,"Dudnik E,Moskovitz M,Rottenberg Y,Lobachov A,Mandelboim R,Shochat T,Urban D,Wollner M,Nechushtan H,Rotem O,Zer A,Daher S,Bar J",Pembrolizumab as a monotherapy or in combination with platinum-based chemotherapy in advanced non-small cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50%: real-world data.,"Both pembrolizumab (P) and combination of pembrolizumab with platinum-based chemotherapy (PCT) represent standard 1st-line options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS) ≥50%. The two strategies have never been compared in a randomized trial. 256 consecutive patients with EGFR/ALK/ROS1-wild-type PD-L1 TPS ≥50% aNSCLC receiving P (group P, n = 203) or PCT (group PCT, n = 53) as a 1st-line treatment were identified in the electronic databases of 4 Israeli cancer centers. Time-to-treatment discontinuation (TTD) and overall survival (OS) were assessed. Baseline characteristics were well balanced, except for age and ECOG PS differences in favor of group PCT. Median (m)TTD was 4.9 months (mo) (95% CI, 3.1-7.6) vs 8.0mo (95% CI, 4.7-15.6) (p-0.09), mOS was 12.5mo (95% CI, 9.8-16.4) vs 20.4mo (95% CI, 10.8-NR) (p-0.08), with P and PCT, respectively. In the propensity score matching analysis (n = 106; 53 patients in each group matched for age, sex and ECOG PS), mTTD was 7.9mo (95% CI, 2.8-12.7) vs 8.0mo (95% CI, 4.7-15.6) (p-0.41), and mOS was 13.3mo (95% CI, 6.8-20.3) vs 20.4mo (95% CI, 10.8-NR) (p-0.18), with P and PCT, respectively. Among various subgroups of patients examined, only in females (n = 86) mOS differed significantly between treatments (10.2mo (95% CI, 6.8-17.2) with P vs NR (95% CI, 11.4-NR) with PCT; p-0.02). In the real-world setting, no statistically significant differences in long-term outcomes with P vs PCT were observed; a prospective randomized trial addressing the comparative efficacy of P and PCT in different patient subgroups is highly anticipated.List of abbreviations: AE - adverse events; ALK - anaplastic lymphoma kinase gene; ALT - alanine aminotransferase; (a)NSCLC - (advanced) non-small cell lung cancer; AST - aspartate aminotransferase; BRAF - v-Raf murine sarcoma viral oncogene homolog B; BRCA2 - BReast CAncer gene 2; c-Met - tyrosine-protein kinase Met; CTCAE, v. 4.03 - Common Terminology Criteria for Adverse Events, version 4.03; CTLA-4 - cytotoxic T-lymphocyte-associated protein 4; ECOG PS - Eastern Cooperative Oncology Group performance status; EGFR - epidermal growth factor receptor gene; FISH - fluorescent in situ hybridization; HER2 - human epidermal growth factor receptor 2; IC - tumor-infiltrating immune cells; ICI - immune check-point inhibitors; IHC - immunohistochemistry; IQR - interquartile range; irAE - immune related adverse events; ISCORT - Israeli Society for Clinical Oncology and Radiotherapy; KRAS - Kirsten rat sarcoma viral oncogene homolog; (m)TTD -(median) time-to-treatment discontinuation; mo - months; (m)OS - (median) overall survival; (m)PFS - (median) progression-free survival; muts/Mb - mutations per megabase; NA - not specified/not available; NOS - not otherwise specified; NR - not reported/not reached; ORR - objective response rate; P - pembrolizumab; PCR - polymerase chain reaction; PCT - combination of pembrolizumab with platinum-based chemotherapy; PD - progression of disease; PD-1 - programmed cell death-1; PD-L1 - programmed cell death ligand-1; pts - patients; RET - proto-oncogene RET; ROS1 - proto-oncogene tyrosine-protein kinase ROS1; SD - standard deviation; STK11 - serine/threonine kinase 11; TC - tumor cells; TMB - Tumor mutation burden; TPS - tumor proportion score.",Oncoimmunology,vol.10:1:1865653,2021,Journal Article,,,"https://orcid.org/0000-0001-6971-3576Thoracic Cancer Service\, Davidoff Cancer Center\, Rabin Medical Center\, Beilinson Campus\, Petah Tikva\, Israel.,Oncology Department\, Thoracic Cancer Service\, Rambam Health Care Campus\, Haifa\, Israel.,Oncology Department\, Hadassah Medical Center\, Jerusalem\, Israel.,Thoracic Cancer Service\, Institute of Oncology\, Sheba Medical Center\, Ramat Gan\, Israel.,Thoracic Cancer Service\, Davidoff Cancer Center\, Rabin Medical Center\, Beilinson Campus\, Petah Tikva\, Israel.,Statistical Consulting Unit\, Rabin Medical Center\, Beilinson Campus\, Petah Tikva\, Israel.,Sackler Faculty of Medicine\, Tel Aviv University\, Tel Aviv\, Israel.,Oncology Department\, Thoracic Cancer Service\, Rambam Health Care Campus\, Haifa\, Israel.,Oncology Department\, Hadassah Medical Center\, Jerusalem\, Israel.,Thoracic Cancer Service\, Davidoff Cancer Center\, Rabin Medical Center\, Beilinson Campus\, Petah Tikva\, Israel.,Thoracic Cancer Service\, Davidoff Cancer Center\, Rabin Medical Center\, Beilinson Campus\, Petah Tikva\, Israel.,Thoracic Cancer Service\, Institute of Oncology\, Sheba Medical Center\, Ramat Gan\, Israel.,Sackler Faculty of Medicine\, Tel Aviv University\, Tel Aviv\, Israel.",,,,,"PD-L1,Pembrolizumab,lung cancer,pembrolizumab chemotherapy,real world"
32621051,"Samà MT,Grosso E,Mele C,Laurora S,Monzeglio O,Marzullo P,Boldorini R,Aluffi Valletti P,Aimaretti G,Scatolini M,Pagano L",Molecular characterisation and clinical correlation of papillary thyroid microcarcinoma.,"Papillary thyroid microcarcinoma (mPTC) is defined as a papillary thyroid cancer sized 10 mm or less. Despite their generally indolent clinical course and good prognosis\, a subset of mPTCs shows potentially aggressive behaviour.,To search for predictors of clinical outcome of mPTCs\, we retrospectively evaluated the genetic tumour profile of 100 patients (23 M/77 F\, mean age ± SD 53.8 ± 13.4 years) with histologically confirmed mPTCs through analysis of BRAF\, NRAS and TERT promoter mutations as well as RET/PTC translocations.,Mean follow-up period was 8.4 ± 3.6 years. In 55 cases\, mPTC were detected incidentally after surgery. Capsular invasion\, bilateralism and multifocality were found in 11/100\, 17/100 and 24/100 cases\, respectively\, while lymph-nodes metastases were present at diagnosis in 9/100 cases. After 3.5 ± 2.0 years\, tumour relapse occurred in 6/100 cases and was locoregional in five (two in the thyroid bed\, three in laterocervical lymph-nodes)\, while lung metastasis occurred in one case. Biochemical persistence of disease was seen in 1/100 case. Mutations occurred in 55/100 cases; BRAFV600E was the most frequently detected (49/100) and was associated with higher tumour size\, bilateralism and follicular variant but not with capsular invasion. RET/PTC rearrangements were found in 2/100 cases\, NRASQ61R in 4/100\, while no mutations of TERT promoter gene were detected. Despite the observed association between BRAFV600E mutation and unfavourable histopathological features\, we found no direct association with tumour recurrence\, distant metastases and mortality.,In our study\, the search for the most frequent genetic alterations as prognostic markers in mPTCs would not have changed the therapeutic strategy.",Endocrine,vol.71:1:149-157,2021,Journal Article,,,"Endocrinology\, Department of Translational Medicine\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy. mariateresa.sama@maggioreosp.novara.it.,Laboratory of Molecular Oncology\, Fondazione Edo ed Elvo Tempia\, Ponderano\, Biella\, Italy.,Endocrinology\, Department of Translational Medicine\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy.,Laboratory of Molecular Oncology\, Fondazione Edo ed Elvo Tempia\, Ponderano\, Biella\, Italy.,Endocrinology\, Department of Translational Medicine\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy.,Endocrinology\, Department of Translational Medicine\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy.,Pathology Department\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy.,ENT Division\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy.,Endocrinology\, Department of Translational Medicine\, University Hospital ""Maggiore della Carità""\, University of Eastern Piedmont\, Novara\, Italy.,Laboratory of Molecular Oncology\, Fondazione Edo ed Elvo Tempia\, Ponderano\, Biella\, Italy.,Endocrinology\, Diabetes and Metabolism\, Department of Medical Sciences\, University of Turin\, Città della Salute e della Scienza\, Torino\, Italy.",,,,,"BRAFV600E mutation,Clinical behaviour,Genetic analysis,Papillary thyroid microcarcinoma,TNM"
33408093,"Hao X,Falo Iii LD,Chen G,Zhang J,Carey CD,Storkus WJ,Falo LD,You Z",Skin immunization for effective treatment of multifocal melanoma refractory to PD1 blockade and Braf inhibitors.,"Despite the remarkable benefits associated with the interventional treatment of melanomas (and other solid cancers) with immune checkpoint and Braf inhibitors (Brafi)\, most patients ultimately progress on therapy. The presence of multifocal/disseminated disease in patients increases their mortality risk. Hence\, the development of novel strategies to effectively treat patients with melanomas that are resistant to anti-PD1 mAb (αPD1) and/or Brafi\, particularly those with multifocal/disseminated disease remains a major unmet clinical need.,Mice developing induced/spontaneous BrafV600E/Pten-/- melanomas were treated by cutaneous immunization with a DNA vaccine encoding the melanoma-associated antigen TRP2\, with Brafi or αPD1 alone\, or with a combination of these treatments. Tumor progression\, tumor-infiltration by CD4+ and CD8+ T cells\, and the development of TRP2-specific CD8+ T cells were then monitored over time.,Vaccination led to durable antitumor immunity against PD1/Brafi-resistant melanomas in both single lesion and multifocal disease models\, and it sensitized PD1-resistant melanomas to salvage therapy with αPD1. The therapeutic efficacy of the vaccine was associated with host skin-resident cells\, the induction of a systemic\, broadly reactive IFNγ+CD8+ T cell repertoire\, increased frequencies of CD8+ TIL and reduced levels of PD1hi/intCD8+ T cells. Extended survival was associated with improved TIL functionality\, exemplified by the presence of enhanced levels of IFNγ+CD8+ TIL and IL2+CD4+ TIL.,These data support the use of a novel genetic vaccine for the effective treatment of localized or multifocal melanoma refractory to conventional αPD1-based and/or Brafi-based (immune)therapy.",Journal for immunotherapy of cancer,vol.9:1:,2021,Journal Article,,,"Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,http://orcid.org/0000-0001-8961-4444Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA.,http://orcid.org/0000-0002-6160-0769Department of Dermatology\, University of Pittsburgh School of Medicine\, Pittsburgh\, Pennsylvania\, USA youz@upmc.edu.",,"NCI NIH HHS,NCI NIH HHS,NCI NIH HHS","United States,United States,United States","P50 CA121973,R01 CA204419,R21 CA191522","immunotherapy,melanoma,vaccination"
33452216,"Evans DG,Lalloo F,Ryan NA,Bowers N,Green K,Woodward ER,Clancy T,Bolton J,McVey RJ,Wallace AJ,Newton K,Hill J,McMahon R,Crosbie EJ",Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers.,"Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine\, which serves a population of 5.6 million.,Tumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate.,In total\, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs)\, 739 endometrial cancers (ECs) and 761 other)\, of which 672/3694 (18.2%) had protein loss\, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%\, p<0.0001). Overall\, 65/134 (48.5%) patients with MLH1 loss and no MLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6\, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant\, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss.,Reflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.",Journal of medical genetics,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0002-8482-5784Division of Evolution and Genomic Medicine\, The University of Manchester\, Manchester\, UK.,Clinical Genetics Service\, Manchester Centre for Genomic Medicine\, North-West Genomics Laboratory Hub\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Division of Cancer Sciences\, The University of Manchester\, Manchester\, UK.,Clinical Genetics Service\, Manchester Centre for Genomic Medicine\, North-West Genomics Laboratory Hub\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Clinical Genetics Service\, Manchester Centre for Genomic Medicine\, North-West Genomics Laboratory Hub\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,http://orcid.org/0000-0002-6297-2855Division of Evolution and Genomic Medicine\, The University of Manchester\, Manchester\, UK.,Clinical Genetics Service\, Manchester Centre for Genomic Medicine\, North-West Genomics Laboratory Hub\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Department of Pathology\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Department of Pathology\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Clinical Genetics Service\, Manchester Centre for Genomic Medicine\, North-West Genomics Laboratory Hub\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Department of Surgery\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Department of Surgery\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,Department of Pathology\, Manchester University NHS Foundation Trust\, Manchester\, Greater Manchester\, UK.,http://orcid.org/0000-0003-0284-8630Division of Cancer Sciences\, The University of Manchester\, Manchester\, UK emma.crosbie@manchester.ac.uk.",,,,,"genetic predisposition to disease,genetic testing,surgical oncology"
33452985,"Kutilin DS,Tsandekova MR,Porkhanova NV",Features of the Copy Number Variation of Certain Genes in Tumor Cells in Patients with Serous Ovarian Adenocarcinoma.,"We analyzed the peculiarities of the copy number variation of genes that regulate apoptosis, DNA repair, cell proliferation, metabolism, and estrogen reception in tumor and normal cells of high-grade and low-grade serous adenocarcinoma of the ovaries. Using real-time qPCR method, the relative copy number of 34 genes (BAX, BCL2, TP53, MDM2, CASP9, CASP3, CASP7, CASP8, PRKCI, SOX2, OCT4, PIK3, PTEN, C-MYC, SOX18, AKT1, NOTCH1, BRCA1, BRCA2, EXO1, SCNN1A, KRAS, EGFR, BRAF, CYP1A1, CYP1A2, CYP1B1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A, and SULT1E1) was determined in normal and tumor cells of the ovaries extracted by contactless capture laser microsection from FFPE-blocks of 200 patients. The most typical molecular markers of ovarian serous adenocarcinoma cells were identified: copy number of PIK3CA, BCL2, BAX, CASP3, and CASP8 genes. Based on the differences in the gene copy number variation, two molecular subtypes of serous adenocarcinoma were identified, corresponding to two histological subtypes: high-grade (MDM2, SOX2, ESR1, CYP1B1, SULT1E1, TP53, BRCA2) and low-grade (PIK3CA, PTEN, BCL2, BAX, and CASP3). Each of these subtypes was also characterized by molecular heterogeneity and can be subdivided into several subgroups: 3 subgroups for high-grade and 4 subgroups for low-grade serous adenocarcinoma. These findings extend our understanding of the molecular mechanisms of carcinogenesis in the ovarian tissue, confirm molecular difference between the two histological subtypes of serous adenocarcinoma probably underlying their different clinical course.",Bulletin of experimental biology and medicine,vol.::,2021,Journal Article,,,"National Medical Research Oncology Center\, Ministry of Health of the Russian Federation\, Rostov-on-Don\, Russia. k.denees@yandex.ru.,National Medical Research Oncology Center\, Ministry of Health of the Russian Federation\, Rostov-on-Don\, Russia.,National Medical Research Oncology Center\, Ministry of Health of the Russian Federation\, Rostov-on-Don\, Russia.",,,,,"apoptosis,cell proliferation,gene copy number variation,laser microdissection,serous ovarian adenocarcinoma"
33467521,"Tabolacci C,Cordella M,Mariotti S,Rossi S,Senatore C,Lintas C,Levati L,D'Arcangelo D,Facchiano A,D'Atri S,Nisini R,Facchiano F",Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals.,"The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines-that potentially facilitate melanoma growth-than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance.",Biomedicines,vol.9:1:,2021,Journal Article,,,"0000-0001-5001-285XDepartment of Oncology and Molecular Medicine\, Istituto Superiore di Sanità\, Viale Regina Elena 299\, 00161 Rome\, Italy.,Department of Oncology and Molecular Medicine\, Istituto Superiore di Sanità\, Viale Regina Elena 299\, 00161 Rome\, Italy.,Department of Infectious Diseases\, Istituto Superiore di Sanità\, 00161 Rome\, Italy.,0000-0002-8854-7072Department of Oncology and Molecular Medicine\, Istituto Superiore di Sanità\, Viale Regina Elena 299\, 00161 Rome\, Italy.,Department of Oncology and Molecular Medicine\, Istituto Superiore di Sanità\, Viale Regina Elena 299\, 00161 Rome\, Italy.,0000-0003-1209-8554Department of Experimental Medicine\, University Campus Bio-Medico\, 00128 Rome\, Italy.,Laboratory of Molecular Oncology\, IDI-IRCCS\, 00167 Rome\, Italy.,Laboratory of Molecular Oncology\, IDI-IRCCS\, 00167 Rome\, Italy.,0000-0002-4243-2392Laboratory of Molecular Oncology\, IDI-IRCCS\, 00167 Rome\, Italy.,Laboratory of Molecular Oncology\, IDI-IRCCS\, 00167 Rome\, Italy.,Department of Infectious Diseases\, Istituto Superiore di Sanità\, 00161 Rome\, Italy.,Department of Oncology and Molecular Medicine\, Istituto Superiore di Sanità\, Viale Regina Elena 299\, 00161 Rome\, Italy.",,"Italian Ministry of Health,Italian Ministry of Health,Italian Ministry of Health,Telethon-Italy",",,,","Italy-USA Oncoproteomic Program,Oncotechnology Program,Ricerca Corrente,GTF08002","BRAF inhibitors resistance,basigin,inflammation,melanoma,secretory signals"
32654197,"Tsuyama S,Kohsaka S,Hayashi T,Suehara Y,Hashimoto T,Kajiyama Y,Tsurumaru M,Ueno T,Mano H,Yao T,Saito T",Comprehensive clinicopathological and molecular analysis of primary malignant melanoma of the oesophagus.,"This study was performed to elucidate the clinicopathological characteristics\, genetic alterations and therapeutic targets of primary malignant melanoma of the oesophagus (PMME).,The clinicopathology and molecular pathology of 13 PMME cases and 10 skin malignant melanoma (SKMM) cases were analysed with next-generation sequencing (NGS) and immunohistochemistry. The 3-year overall survival rate and the median survival time for PMME patients were 23.1% and 11.9 months\, respectively. Three (23.1%) and eight (61.5%) PMME cases showed a papillary structure and lymph node metastasis\, respectively. DNA and RNA hybridization capture-based NGS analysis revealed that NF1 was the most frequently mutated gene (30%) in 10 of the PMME cases. Other mutations detected in PMME included SF3B1 (20%)\, KRAS (10%)\, BRCA2 (10%)\, KIT (10%) and TP53 (10%) mutations. Commonly detected BRAF mutations in SKMM were not detected in PMME. Immunohistochemistry and mutation status were concordant between p53/c-Kit and TP53/KIT\, respectively. Focal expression of programmed death-ligand 1 was observed in one PMME sample. The tumour mutation burden in PMME was significantly lower than that in SKMM (P = 0.030). No PMME case showed high microsatellite instability. RNA sequencing revealed a distinctive pattern with respect to RNA expression. T-cell co-stimulation differed between PMME and SKMM.,The RAS-mitogen-activated protein kinase pathway is one of the main pathways involved in PMME. The genetic profile of PMME was similar to that of mucosal/acral melanoma\, but differed from the SKMM profile. A subset of PMMEs may contain actionable mutations. Immunotherapy seemed to be less effective for most PMMEs in this series.",Histopathology,vol.78:2:240-251,2021,Review,,,"Department of Human Pathology\, Juntendo University\, Graduate School of Medicine\, Tokyo\, 113-8421\, Japan.,Division of Cellular Signaling\, National Cancer Center Research Institute\, Tokyo\, 104-0045\, Japan.,https://orcid.org/0000-0002-8544-9370Department of Human Pathology\, Juntendo University\, Graduate School of Medicine\, Tokyo\, 113-8421\, Japan.,Intractable Disease Research Center\, Juntendo University\, Graduate School of Medicine\, Tokyo\, 113-8421\, Japan.,Department of Esophageal and Gastroenterological Surgery\, Juntendo University School of Medicine\, Tokyo\, 113-8421\, Japan.,Department of Esophageal and Gastroenterological Surgery\, Juntendo University School of Medicine\, Tokyo\, 113-8421\, Japan.,Department of Esophageal and Gastroenterological Surgery\, Juntendo University School of Medicine\, Tokyo\, 113-8421\, Japan.,Division of Cellular Signaling\, National Cancer Center Research Institute\, Tokyo\, 104-0045\, Japan.,Division of Cellular Signaling\, National Cancer Center Research Institute\, Tokyo\, 104-0045\, Japan.,Department of Human Pathology\, Juntendo University\, Graduate School of Medicine\, Tokyo\, 113-8421\, Japan.,https://orcid.org/0000-0001-9690-8440Department of Human Pathology\, Juntendo University\, Graduate School of Medicine\, Tokyo\, 113-8421\, Japan.",,"General Scientific Research from the Ministry of Education\, Science\, Sports\, and Culture,General Scientific Research from the Ministry of Education\, Science\, Sports\, and Culture,the Japan Agency for Medical Research and Development,the Project for Cancer Research And Therapeutic Evolution (P-CREATE),the Program for Integrated Database of Clinical and Genomic Information,the Practical Research for Innovative Cancer Control",",,,,,","#17K08704,#17K08730,JP17am0001009.,JP18cm0106502,JP18kk0205003,JP18ck0106252","immunotherapy,molecular pathogenesis,next-generation sequencing (NGS),primary malignant melanoma of the oesophagus (PMME),tumour mutation burden (TMB)"
32977343,Ringel MD,New Horizons: Emerging Therapies and Targets in Thyroid Cancer.,"The treatment of patients with progressive metastatic follicular cell-derived and medullary thyroid cancers that do not respond to standard therapeutic modalities presents a therapeutic challenge. As a deeper understanding of the molecular drivers for these tumors has occurred and more potent and specific compounds are developed, the number of Food and Drug Administration (FDA)-approved treatments for thyroid cancer has expanded. In addition, with the advent of disease-agnostic target-directed FDA approvals an ever-broadening number of therapeutic options are available for clinicians and patients. However, to date, complete remissions are rare, the average durations of response are relatively modest, and toxicities are common. These factors accentuate the need for further understanding of the mechanisms of resistance that result in treatment failures, the development of biomarkers that can improve patient selection for treatment earlier in the disease process, and the continued need for new therapeutic strategies. In this article, recent approvals relevant to thyroid cancer will be discussed along with selected new potential avenues that might be exploited for future therapies.",The Journal of clinical endocrinology and metabolism,vol.106:1:e382-e388,2021,Journal Article,,,"Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.",,,,,"BRAF,RAS,immunotherapy,metastatic thyroid cancer,radioactive iodine"
33279248,"Mohassab AM,Hassan HA,Abdelhamid D,Gouda AM,Youssif BGM,Tateishi H,Fujita M,Otsuka M,Abdel-Aziz M","Design and synthesis of novel quinoline/chalcone/1,2,4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAF kinases.","New quinoline / chalcone hybrids containing 1,2,4-triazole moiety have been designed, synthesized and their structures elucidated and confirmed by various spectroscopic techniques. The designed compounds showed moderate to good activity on different NCI 60 cell lines in a single-dose assay with a growth inhibition rate ranging from 50% to 94%. Compounds 7b, 7d, 9b, and 9d were the most active compounds in most cancer cell lines with a growth inhibition percent between 77% and 94%. Newly synthesized hybrids were evaluated for their anti-proliferative activity against a panel of four human cancer cell lines. Compounds 7a, 7b, 9a, 9b, and 9d showed promising antiproliferative activities. These compounds were further tested for their inhibitory potency against EGFR and BRAFV600E kinases with erlotinib as a reference drug. The molecular docking study of compounds 7a, 7b, 9a, 9b, and 9d revealed nice fitting into the active site of EGFR and BRAFV600E kinases. Compounds 7b, 9b, and 9d displayed the highest binding affinities and similar binding pattern to those of erlotinib.",Bioorganic chemistry,vol.106::104510,2021,Journal Article,,,"Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia 61519\, Egypt.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia 61519\, Egypt. Electronic address: heba.hasan@mu.edu.eg.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia 61519\, Egypt.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Beni-Suef University\, Beni-Suef 62514\, Egypt.,Pharmaceutical Organic Chemistry Department\, Faculty of Pharmacy\, Assiut University\, Assiut 71526\, Egypt. Electronic address: bgyoussif@ju.edu.sa.,Medicinal and Biological Chemistry Science Farm Joint Research Laboratory\, Faculty of Life Sciences\, Kumamoto University\, 5-1 Oe-honmachi\, Chuo-ku\, Kumamoto 862-0973\, Japan.,Medicinal and Biological Chemistry Science Farm Joint Research Laboratory\, Faculty of Life Sciences\, Kumamoto University\, 5-1 Oe-honmachi\, Chuo-ku\, Kumamoto 862-0973\, Japan.,Medicinal and Biological Chemistry Science Farm Joint Research Laboratory\, Faculty of Life Sciences\, Kumamoto University\, 5-1 Oe-honmachi\, Chuo-ku\, Kumamoto 862-0973\, Japan; Department of Drug Discovery\, Science Farm Ltd.\, 1-7-30 Kuhonji\, Chuo-ku\, Kumamoto 862-0976\, Japan.,Department of Medicinal Chemistry\, Faculty of Pharmacy\, Minia University\, Minia 61519\, Egypt. Electronic address: Abulnil@hotmail.com.",,,,,"Apoptosis,BRAF(V600E),Chalcone,Docking,EGFR,Quinoline,Triazole"
33280830,"Ali EMH,Abdel-Maksoud MS,Ammar UM,Mersal KI,Ho Yoo K,Jooryeong P,Oh CH","Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFinhibitors.","BRAFV600E mutation has been detected in various malignant tumours. Developing of potent BRAFV600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC50 values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC50 values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAFV600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAFV600E with IC50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.",Bioorganic chemistry,vol.106::104508,2021,Journal Article,,,"Center for Biomaterials\, Korea Institute of Science & Technology (KIST School)\, Seongbuk-gu\, Seoul 02792\, Republic of Korea; University of Science & Technology (UST)\, Yuseong-gu\, Daejeon 34113\, Republic of Korea; Pharmaceutical Chemistry Department\, Faculty of Pharmacy\, Modern University of Technology and Information (MTI)\, Cairo 12055\, Egypt.,Medicinal & Pharmaceutical Chemistry Department\, Pharmaceutical and Drug Industries Research Division\, National Research Centre NRC (ID: 60014618)\, Dokki\, Giza 12622\, Egypt.,Center for Biomaterials\, Korea Institute of Science & Technology (KIST School)\, Seongbuk-gu\, Seoul 02792\, Republic of Korea; University of Science & Technology (UST)\, Yuseong-gu\, Daejeon 34113\, Republic of Korea; Pharmaceutical Chemistry Department\, Faculty of Pharmacy\, Ahram Canadian University\, Giza 12566\, Egypt.,Center for Biomaterials\, Korea Institute of Science & Technology (KIST School)\, Seongbuk-gu\, Seoul 02792\, Republic of Korea; University of Science & Technology (UST)\, Yuseong-gu\, Daejeon 34113\, Republic of Korea.,Chemical Kinomics Research Center\, Korea Institute of Science and Technology\, Seoul\, Republic of Korea.,Department of Beauty Science\, Hanseo University\, Seosan 31962\, Republic of Korea.,Center for Biomaterials\, Korea Institute of Science & Technology (KIST School)\, Seongbuk-gu\, Seoul 02792\, Republic of Korea; University of Science & Technology (UST)\, Yuseong-gu\, Daejeon 34113\, Republic of Korea. Electronic address: choh@kist.re.kr.",,,,,"Anticancer,BRAF(V600E) inhibitors,Imidazole,Protein kinase inhibitors,SAR"
32978897,"Kuchel A,Ahern E,Collins S,Whitehall V,Okano S,Pelecanos A,Wyld D,Eastgate M,Burge M","Trends in epidemiology, treatment and molecular testing of metastatic colorectal cancer in a real-world multi-institution cohort study.","Colorectal cancer (CRC) is the third most common cancer in Australia\, and survival after diagnosis of metastatic disease is improving. Our aim was to assess trends in epidemiology\, treatment\, molecular testing and survival in patients with metastatic CRC (mCRC).,Clinical data from February 2013 to December 2018 was recorded in a prospective\, observational\, multicenter cohort study conducted in Queensland\, Australia\, examining clinical and molecular biomarkers in cases of mCRC.,A total of 159 patients who had metastasis diagnosed after February 2013 were included in survival analysis. Median age at diagnosis was 63.9 years\, but 29% had early-onset disease (diagnosis aged <50 years). Median overall survival was 2.5 years (95% confidence interval [CI]\, 2.2-3.0) for the 159 patients included in survival analysis. Independent factors correlated with poor prognosis included right-sided primary tumor\, neutrophil-lymphocyte ratio >5\, increased alkaline phosphatase level (ALP) and an increasing number of sites of metastatic disease. In contrast\, metastasectomy was associated with improved overall survival (adjusted HR = 0.29' 95% CI\, 0.16-0.54)\, with similar survival between patients who had liver and non-liver metastasectomy sites. Half (10/20) of the BRAF mutant CRC were also microsatellite unstable. The proportion of detected mutations amongst tested samples increased over time for Kirsten Rat Sarcoma (KRAS; OR [per year] = 1.19; 95% CI\, 1.01-1.39). Concurrently\, the methods of molecular genetics testing employed in routine clinical practice changed towards the adoption of next-generation sequencing.,Metastasectomy in mCRC may be beneficial regardless of the anatomical site of metastasis. The adoption of next-generation sequencing techniques for molecular genetics testing coincided with a slightly increased rate of detection of KRAS and BRAF mutations\, potentially reflecting greater test sensitivity. Further translational research is required in mCRC to define novel targets for treatment.",Asia-Pacific journal of clinical oncology,vol.17:1:84-93,2021,Observational Study,"|Colorectal Neoplasms|epidemiology|pathology|therapy|,|Female|,|Humans|,|Male|,|Metastasectomy|,|Middle Aged|,|Molecular Diagnostic Techniques|,|Prognosis|,|Prospective Studies|,|Queensland|epidemiology|,|Survival Analysis|",,"Department of Medical Oncology\, Cancer Care Services\, The Royal Brisbane and Women's Hospital\, Herston\, Australia.,https://orcid.org/0000-0002-2062-5695Department of Medical Oncology\, Cancer Care Services\, The Royal Brisbane and Women's Hospital\, Herston\, Australia.,Department of Medical Oncology\, Cancer Care Services\, The Royal Brisbane and Women's Hospital\, Herston\, Australia.,School of Medicine\, University of Queensland\, Herston\, Australia.,Statistics Unit\, Queensland Institute of Medical Research Berghofer\, Herston\, Australia.,Statistics Unit\, Queensland Institute of Medical Research Berghofer\, Herston\, Australia.,Department of Medical Oncology\, Cancer Care Services\, The Royal Brisbane and Women's Hospital\, Herston\, Australia.,Department of Medical Oncology\, Cancer Care Services\, The Royal Brisbane and Women's Hospital\, Herston\, Australia.,Department of Medical Oncology\, Cancer Care Services\, The Royal Brisbane and Women's Hospital\, Herston\, Australia.",,,,,"cancer epidemiology,cancer genetics,colorectal,medical oncology,registry"
33303574,"Lelliott EJ,Mangiola S,Ramsbottom KM,Zethoven M,Lim L,Lau PKH,Oliver AJ,Martelotto LG,Kirby L,Martin C,Patel RP,Slater A,Cullinane C,Papenfuss AT,Haynes NM,McArthur GA,Oliaro J,Sheppard KE","Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma.","Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a-/-Pten-/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103+ dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.",Cancer immunology research,vol.9:2:136-146,2021,Journal Article,,,"https://orcid.org/0000-0002-5028-6938Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0001-7474-836XThe Walter and Eliza Hall Institute of Medical Research\, Parkville\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0002-6528-891XCancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0003-1071-7956Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Single Cell Innovation Laboratory\, The University of Melbourne\, Parkville\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0001-8916-0307Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0002-1102-8506Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0001-8908-6071Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0002-2097-6428Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia.,https://orcid.org/0000-0002-2798-4703Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne\, Victoria\, Australia. karen.sheppard@petermac.org.",,,,,
33537843,"Butt SU,Mejias A,Morelli C,Torga G,Happe M,Patrikidou A,Arkenau HT",BRAF/MEK inhibitors for BRAF V600E-mutant cancers in non-approved setting: a case series.,"The management of cancer has been traditionally dependent on the primary tumour type and specific histologic subtypes. Recently, the introduction of molecular profiling tools and its increasing use in clinical practice has facilitated the emergence of novel genomically driven treatment options within the standard of care landscape as well as in the clinical trial setting. One such aberration is mutation in v-Raf murine sarcoma viral oncogene homolog B (BRAF), which results in hyperactivation of RAS-RAF-MEK-ERK signaling in the Mitogen-activated protein kinases (MAPK) pathway. BRAF and Mitogen-activated protein kinase, extracellular signal-regulated kinase kinase (MEK) inhibitors, although being currently approved for melanoma, non-small cell lung cancer (NSCLC) and colon cancer, have reported activity across other various cancers harbouring BRAF aberrations. It has been proposed that combined MEK and BRAF inhibition could overcome the acquired resistance commonly developed among patients receiving BRAF or MEK inhibitors as monotherapy. We report five cases of BRAF V600E (substitution of glutamic acid for valine in codon 600) aberrant refractory metastatic cancers treated with dual BRAF/MEK combination inhibitor therapy leading to an excellent clinical and radiological response and protracted duration of disease control.",Cancer chemotherapy and pharmacology,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0002-3827-7481Drug Development Unit\, Sarah Cannon Research Institute\, 93 Harley Street\, London\, W1G 6AD\, UK. dr.s.butt01@gmail.com.,Hospital Universitario Virgen del Rocio\, Seville\, Spain.,Tor Vergata University of Rome\, Viale Oxford 81\, 00133\, Rome\, RM\, Italy.,Drug Development Unit\, Sarah Cannon Research Institute\, 93 Harley Street\, London\, W1G 6AD\, UK.,School of Medicine\, University of Cologne\, Joseph-Stelzmann-Straße 20\, 50931\, Cologne\, Germany.,Drug Development Unit\, Sarah Cannon Research Institute\, 93 Harley Street\, London\, W1G 6AD\, UK.,Drug Development Unit\, Sarah Cannon Research Institute\, 93 Harley Street\, London\, W1G 6AD\, UK.",,,,,"BRAF,Cholangiocarcinoma,Craniopharyngioma,Endometrial,Pancreatic,V600E"
31985580,"Robinson H,Karpe M,Edidi I,Fisher A,Drew Y,Ralte A,O'Donnell RL",Enteric Type Bartholin Gland Adenocarcinoma: An Unusual Variant of a Rare Neoplasm.,"Vulval cancer is rare. With Bartholin gland carcinomas representing <5% of all vulval carcinomas they present both diagnostic and management challenges. There are a small number of cases in the literature describing Bartholin gland carcinomas with unusual histology which necessitates the need to explore the possibility of metastases from elsewhere. We present a case of a 55-yr-old woman presenting with a vulval lesion within the Bartholin gland. Morphology demonstrated enteric type adenocarcinoma and the immunohistochemistry profile was positive for CK7, CK20, CDX2, CEA, and CA19-9. There was no evidence of an alternative primary cancer and the tumor was excised with negative regional sentinel node assessment. Genotyping showed no detectable mutations in KRAS, BRAF or NRAS suggesting a possible future role for anti-EGFR therapy.",International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists,vol.40:2:190-195,2021,Journal Article,,,",,,,,,",,,,,
32803788,"Ravella L,Lopez J,Descotes F,Giai J,Lapras V,Denier ML,Borson-Chazot F,Lifante JC,Decaussin-Petrucci M",Cytological features and nuclear scores: Diagnostic tools in preoperative fine needle aspiration of indeterminate thyroid nodules with RAS or BRAF K601E mutations?,"The cytological diagnosis of follicular-patterned thyroid lesions is challenging\, especially since the World Health Organisation classification has recognised non-invasive follicular thyroid neoplasm with papillary-like features. These entities are often classified as indeterminate on cytology. Molecular testing has been proposed to help classify indeterminate nodules. RAS and K601E BRAF mutations are mostly encountered in follicular-patterned lesions\, but their diagnostic value is not well established. Nuclear scores have also been proposed to help classify indeterminate lesions.,To investigate the correlation between cytological features and histology and to assess nuclear scores in a series of indeterminate RAS or BRAF K601E positive thyroid nodules.,The cytological parameters of 69 indeterminate RAS or BRAF K601E-positive thyroid nodules were evaluated. The Strickland and Maletta scores and a new nuclear score were assessed. Diagnosis of malignant\, benign or indolent neoplasms was confirmed in each case by histology. Malignant and indolent nodules were considered surgical nodules\, and adenomas non-surgical nodule.,Surgical nodules were associated with the presence of ground glass nuclei (P = .001)\, grooves (P < .001) or irregular nuclear membranes (P = .01) on cytology. Nuclear scores were more often ≥2 in surgical nodules compared to benign ones (P < .001)\, with high sensitivity\, but a low negative predictive value.,Analysis of nuclear features is useful to distinguish non-surgical from surgical nodules in indeterminate FNAs. Although nuclear scores are not ideal rule-out tests for indeterminate RAS or BRAF K601E positive nodules\, they seem useful to screen non-molecular tested or non-mutated indeterminate FNAs. This work shows that meticulous analysis of nuclear features on cytological specimens can be useful to distinguish non-surgical nodules (adenoma) from surgical nodules in indeterminate FNAs. Although nuclear scores are not rule-out tests for indeterminate RAS or BRAF K601E positive nodules\, they are useful in screening non-molecular tested or non-mutated indeterminate FNAs for surgery.",Cytopathology : official journal of the British Society for Clinical Cytology,vol.32:1:37-44,2021,Journal Article,,,"0000-0002-7651-0889Centre de Biologie et Pathologie Sud\, Centre Hospitalier Lyon Sud\, Pierre Bénite\, France.,Biochemistry and Molecular Biology Department\, Centre Hospitalier Lyon Sud\, Pierre Bénite\, France.,Biochemistry and Molecular Biology Department\, Centre Hospitalier Lyon Sud\, Pierre Bénite\, France.,CNRS\, UMR 5558\, Laboratoire de Biométrie et Biologie Evolutive\, Equipe Biostatistique-Santé\, Villeurbanne\, France.,Radiology Department\, Centre Hospitalier Lyon Sud\, Pierre Bénite\, France.,Radiology Department\, Centre Hospitalier Lyon Sud\, Pierre Bénite\, France.,Endocrinology Department\, Groupement Hospitalier Est\, Bron\, France.,Endocrine Surgery Department\, Centre Hospitalier Lyon Sud\, France.,Centre de Biologie et Pathologie Sud\, Centre Hospitalier Lyon Sud\, Pierre Bénite\, France.",,,,,"\nRAS\n,BRAF K601E,Bethesda,non-invasive follicular thyroid neoplasm with papillary-like nuclear features,thyroid cytology,thyroid nodules"
33498757,"Weber DD,Thapa M,Aminzadeh-Gohari S,Redtenbacher AS,Catalano L,Feichtinger RG,Koelblinger P,Dallmann G,Emberger M,Kofler B,Lang R",Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts.,"Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, p-cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.",Cancers,vol.13:3:,2021,Journal Article,,,"Research Program for Receptor Biochemistry and Tumor Metabolism\, Department of Pediatrics\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,BIOCRATES Life Sciences AG\, 6020 Innsbruck\, Austria.,Research Program for Receptor Biochemistry and Tumor Metabolism\, Department of Pediatrics\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,Research Program for Receptor Biochemistry and Tumor Metabolism\, Department of Pediatrics\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,Research Program for Receptor Biochemistry and Tumor Metabolism\, Department of Pediatrics\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,0000-0002-4215-8258Research Program for Receptor Biochemistry and Tumor Metabolism\, Department of Pediatrics\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,Department of Dermatology and Allergology\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,BIOCRATES Life Sciences AG\, 6020 Innsbruck\, Austria.,Patholab Salzburg\, 5020 Salzburg\, Austria.,0000-0002-1198-4776Research Program for Receptor Biochemistry and Tumor Metabolism\, Department of Pediatrics\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.,0000-0002-9750-0188Department of Dermatology and Allergology\, University Hospital of the Paracelsus Medical University\, 5020 Salzburg\, Austria.",,"Horizon 2020 Framework Programme,Paracelsus Medizinische Privatuniversität,Roche,Les Laboratories Pierre Fabre",",,,","EU H2020-MSCA-ITN-2016-722605,E-17/25/132-LKK,restricted,restricted","Warburg effect,beta-alanine metabolism,cancer metabolism,lipid metabolism,melanoma,metabolic biomarker,targeted metabolomics"
33530327,"Schmidt D,Scharf MM,Sydow D,Aßmann E,Martí-Solano M,Keul M,Volkamer A,Kolb P",Analyzing Kinase Similarity in Small Molecule and Protein Structural Space to Explore the Limits of Multi-Target Screening.,"While selective inhibition is one of the key assets for a small molecule drug, many diseases can only be tackled by simultaneous inhibition of several proteins. An example where achieving selectivity is especially challenging are ligands targeting human kinases. This difficulty arises from the high structural conservation of the kinase ATP binding sites, the area targeted by most inhibitors. We investigated the possibility to identify novel small molecule ligands with pre-defined binding profiles for a series of kinase targets and anti-targets by in silico docking. The candidate ligands originating from these calculations were assayed to determine their experimental binding profiles. Compared to previous studies, the acquired hit rates were low in this specific setup, which aimed at not only selecting multi-target kinase ligands, but also designing out binding to anti-targets. Specifically, only a single profiled substance could be verified as a sub-micromolar, dual-specific EGFR/ErbB2 ligand that indeed avoided its selected anti-target BRAF. We subsequently re-analyzed our target choice and in silico strategy based on these findings, with a particular emphasis on the hit rates that can be expected from a given target combination. To that end, we supplemented the structure-based docking calculations with bioinformatic considerations of binding pocket sequence and structure similarity as well as ligand-centric comparisons of kinases. Taken together, our results provide a multi-faceted picture of how pocket space can determine the success of docking in multi-target drug discovery efforts.","Molecules (Basel, Switzerland)",vol.26:3:,2021,Journal Article,,,"0000-0001-7319-3462Institut für Pharmazeutische und Medizinische Chemie\, Heinrich-Heine-Universität Düsseldorf\, 40225 Düsseldorf\, Germany.,0000-0002-3305-3956Pharmaceutical Chemistry\, Philipps-University Marburg\, Marbacher Weg 6\, 35037 Marburg\, Germany.,0000-0003-4205-8705In Silico Toxicology and Structural Bioinformatics\, Institute of Physiology\, Charité-Universitätsmedizin Berlin\, Charitéplatz 1\, 10117 Berlin\, Germany.,0000-0002-7249-069XIn Silico Toxicology and Structural Bioinformatics\, Institute of Physiology\, Charité-Universitätsmedizin Berlin\, Charitéplatz 1\, 10117 Berlin\, Germany.,Pharmaceutical Chemistry\, Philipps-University Marburg\, Marbacher Weg 6\, 35037 Marburg\, Germany.,Chemical Biology\, Technical University Dortmund\, Otto-Hahn-Str. 4a\, 44227 Dortmund\, Germany.,0000-0002-3760-580XIn Silico Toxicology and Structural Bioinformatics\, Institute of Physiology\, Charité-Universitätsmedizin Berlin\, Charitéplatz 1\, 10117 Berlin\, Germany.,0000-0003-4089-614XPharmaceutical Chemistry\, Philipps-University Marburg\, Marbacher Weg 6\, 35037 Marburg\, Germany.",,"Deutsche Forschungsgemeinschaft,Deutsche Forschungsgemeinschaft",",","KO4095/1-1,VO2353/1-1","anti-target,binding site comparison,bioinformatics,chemoinformatics,docking,kinases,multi-target ligands"
33530449,"Leclerc J,Vermaut C,Buisine MP",Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors.,"Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management.",Cancers,vol.13:3:,2021,Review,,,"0000-0003-1130-7211Molecular Oncogenetics\, Department of Biochemistry and Molecular Biology\, CHU Lille\, F-59000 Lille\, France.,Molecular Oncogenetics\, Department of Biochemistry and Molecular Biology\, CHU Lille\, F-59000 Lille\, France.,0000-0002-3255-5380Molecular Oncogenetics\, Department of Biochemistry and Molecular Biology\, CHU Lille\, F-59000 Lille\, France.",,,,,"BRAF mutation,Lynch syndrome,MLH1 promoter methylation,microsatellite instability,mismatch repair genes"
33530579,"Guida M,Bartolomeo N,Quaglino P,Madonna G,Pigozzo J,Di Giacomo AM,Minisini AM,Tucci M,Spagnolo F,Occelli M,Ridolfi L,Queirolo P,De Risi I,Quaresmini D,Gambale E,Chiaron Sileni V,Ascierto PA,Stigliano L,Strippoli S",No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study.,"It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7-18) versus 9 months (95% CI, 6-16) and 32 (95% CI, 23-49) versus 27 months (95% CI, 16-35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.",Cancers,vol.13:3:,2021,Journal Article,,,"Rare Tumors and Melanoma Unit\, IRCCS Istituto Tumori ""Giovanni Paolo II""\, 70124 Bari\, Italy.,0000-0002-8540-4615Department of Biomedical Sciences and Human Oncology\, University of Bari\, 70124 Bari\, Italy.,Department of Medical Sciences\, Dermatologic Clinic\, University of Turin\, 10126 Turin\, Italy.,0000-0001-9395-3190Department of Melanoma\, Cancer Immunotherapy and Development Therapeutics\, Istituto Nazionale Tumori IRCCS Fondazione ""G. Pascale""\, 80131 Napoli\, Italy.,Melanoma Oncology Unit\, Veneto Institute of Oncology IOV-IRCCS\, 31033 Padova\, Italy.,Center for Immuno-Oncology\, Medical Oncology and Immunotherapy\, Department of Oncology\, University Hospital of Siena\, 53100 Siena\, Italy.,Department of Oncology\, ASUFC University Hospital\, 33100 Udine\, Italy.,0000-0003-4008-4897Medical Oncology Unit\, IRCCS Istituto Tumori ""Giovanni Paolo II""\, University of Bari Aldo Moro\, 70124 Bari\, Italy.,Skin Cancer Unit\, IRCCS Ospedale Policlinico San Martino\, 16132 Genova\, Italy.,Azienda Ospedaliera Santa Croce e Carle di Cuneo SC Oncologia\, 12100 Cuneo\, Italy.,0000-0003-1870-3380Department of Oncology\, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ""Dino Amadori""\, 47014 Meldola\, Italy.,Division of Melanoma Sarcoma and Rare Tumors\, IEO European Institute of Oncology IRCCS\, 20141 Milan\, Italy.,Rare Tumors and Melanoma Unit\, IRCCS Istituto Tumori ""Giovanni Paolo II""\, 70124 Bari\, Italy.,Rare Tumors and Melanoma Unit\, IRCCS Istituto Tumori ""Giovanni Paolo II""\, 70124 Bari\, Italy.,Center for Immuno-Oncology\, Medical Oncology and Immunotherapy\, Department of Oncology\, University Hospital of Siena\, 53100 Siena\, Italy.,0000-0001-9191-9124Melanoma Oncology Unit\, Veneto Institute of Oncology IOV-IRCCS\, 31033 Padova\, Italy.,0000-0002-8322-475XDepartment of Melanoma\, Cancer Immunotherapy and Development Therapeutics\, Istituto Nazionale Tumori IRCCS Fondazione ""G. Pascale""\, 80131 Napoli\, Italy.,Department of Medical Sciences\, Dermatologic Clinic\, University of Turin\, 10126 Turin\, Italy.,0000-0001-7982-7788Rare Tumors and Melanoma Unit\, IRCCS Istituto Tumori ""Giovanni Paolo II""\, 70124 Bari\, Italy.",,"Istituto Nazionale Tumori IRCCS ""Fondazione G. Pascale""",,M2/2,"NRAS mutation,checkpoint inhibitors,immunotherapy,melanoma"
33535416,"Binder H,Schmidt M,Loeffler-Wirth H,Mortensen LS,Kunz M",Melanoma Single-Cell Biology in Experimental and Clinical Settings.,"Cellular heterogeneity is regarded as a major factor for treatment response and resistance in a variety of malignant tumors, including malignant melanoma. More recent developments of single-cell sequencing technology provided deeper insights into this phenomenon. Single-cell data were used to identify prognostic subtypes of melanoma tumors, with a special emphasis on immune cells and fibroblasts in the tumor microenvironment. Moreover, treatment resistance to checkpoint inhibitor therapy has been shown to be associated with a set of differentially expressed immune cell signatures unraveling new targetable intracellular signaling pathways. Characterization of T cell states under checkpoint inhibitor treatment showed that exhausted CD8+ T cell types in melanoma lesions still have a high proliferative index. Other studies identified treatment resistance mechanisms to targeted treatment against the mutated BRAF serine/threonine protein kinase including repression of the melanoma differentiation gene microphthalmia-associated transcription factor (MITF) and induction of AXL receptor tyrosine kinase. Interestingly, treatment resistance mechanisms not only included selection processes of pre-existing subclones but also transition between different states of gene expression. Taken together, single-cell technology has provided deeper insights into melanoma biology and has put forward our understanding of the role of tumor heterogeneity and transcriptional plasticity, which may impact on innovative clinical trial designs and experimental approaches.",Journal of clinical medicine,vol.10:3:,2021,Review,,,"0000-0002-2242-4678Interdisciplinary Center for Bioinformatics\, University of Leipzig\, 04107 Leipzig\, Germany.,0000-0002-5317-3920Interdisciplinary Center for Bioinformatics\, University of Leipzig\, 04107 Leipzig\, Germany.,Interdisciplinary Center for Bioinformatics\, University of Leipzig\, 04107 Leipzig\, Germany.,Interdisciplinary Center for Bioinformatics\, University of Leipzig\, 04107 Leipzig\, Germany.,Department of Dermatology\, Venereology and Allergology\, University of Leipzig Medical Center\, Philipp-Rosenthal-Str. 23-25\, 04103 Leipzig\, Germany.",,,,,"melanoma,pseudotime analysis,single-cell transcriptome sequencing,treatment response"
33535609,"Siraj AK,Parvathareddy SK,Pratheeshkumar P,Divya SP,Al-Sobhi SS,Al-Dayel F,Al-Kuraya KS",PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by Mutation.,"PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines. PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with aggressive clinico-pathological parameters. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF-mutated PTC cell lines compared to a BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF-mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF-mutated cell lines significantly decreased the cell growth and induced apoptosis. Our data suggest that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, BRAF mutation-positive patients that are unresponsive to standard treatment.",Cancers,vol.13:3:,2021,Journal Article,,,"Human Cancer Genomic Research\, Research Center\, King Faisal Specialist Hospital and Research Center\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.,Human Cancer Genomic Research\, Research Center\, King Faisal Specialist Hospital and Research Center\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.,Human Cancer Genomic Research\, Research Center\, King Faisal Specialist Hospital and Research Center\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.,Human Cancer Genomic Research\, Research Center\, King Faisal Specialist Hospital and Research Center\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.,Department of Surgery\, King Faisal Specialist Hospital and Research Center\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.,Department of Pathology\, King Faisal Specialist Hospital and Research Centre\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.,0000-0002-4126-3419Human Cancer Genomic Research\, Research Center\, King Faisal Specialist Hospital and Research Center\, P.O. Box 3354\, Riyadh 11211\, Saudi Arabia.",,,,,"BRAFV600E mutation,PD-L1,cell growth,papillary thyroid cancer,recurrence-free survival,vemurafenib"
32743766,"Poli R,Scatolini M,Grosso E,Maletta F,Gallo M,Liscia D,Nelva A,Cesario F,Forte G,Metovic J,Volante M,Arvat E,Papotti M","Malignant struma ovarii: next-generation sequencing of six cases revealed Nras, Braf, and Jak3 mutations.","Struma ovarii (SO) is a highly specialized ovarian teratoma\, consisting of thyroid tissue. Rarely\, carcinomas histologically identical to their thyroid counterparts may occur\, and are comprehensively defined as malignant struma ovarii (MSO). Their optimal management is controversial\, and the molecular profile of the malignant counterpart in the ovary is incompletely known. In this study\, the clinicopathological and molecular features of six MSO from different Italian Institutions were analysed\, to explore genetic profiles of potential therapeutic interest.,The histopathological features and immunoprofile (according to the known markers Galectin-3\, HBME1\, cytokeratin 19 and CD56) were reviewed. In addition\, all cases underwent genetic analysis with a next-generation sequencing (NGS) hot spot cancer panel detecting mutations in 50 genes involved in cancerogenesis. RET/PTC rearrangements and TERT promoter alterations were also evaluated.,Papillary carcinoma in all similar to its thyroid counterpart was found in five of six cases\, including classical (two tumors) and follicular variant (three tumors) types. The last case was a poorly differentiated carcinoma. An activating gene mutation\, was detected in five of six cases\, including two NRAS\, two BRAF\, and one JAK3 oncogene mutations. No alterations were found in the other panel genes\, nor in TERT promoter\, or in RET chromosomal regions.,MSO is a rare condition. Papillary carcinoma is the predominant malignant type\, sharing both histomorphological and molecular features of its thyroid counterpart. Interestingly\, the single case of poorly differentiated carcinoma displayed a JAK3 mutation. The presence of such driving mutation could be of potential interest in guiding postoperative treatment.",Endocrine,vol.71:1:216-224,2021,Journal Article,,,"http://orcid.org/0000-0003-3413-9054Division of Internal Medicine\, Ospedale degli Infermi\, via dei Ponderanesi 2 Ponderano\, 13875\, Biella\, Italy. rob.poli1979@libero.it.,http://orcid.org/0000-0003-1616-1151Molecular Oncology Laboratory\, Fondazione ""Edo ed Elvo Tempia Valenta""\, via dei Ponderanesi 2\, Ponderano\, 13875\, Biella\, Italy.,Molecular Oncology Laboratory\, Fondazione ""Edo ed Elvo Tempia Valenta""\, via dei Ponderanesi 2\, Ponderano\, 13875\, Biella\, Italy.,Pathology Unit\, AOU Città della Salute e della Scienza Hospital\, via Santena 7\, 10126\, Turin\, Italy.,Oncological Endocrinology\, AOU Città della Salute e della Scienza di Torino Hospital\, via Genova 3\, 10126\, Turin\, Italy.,Pathology Unit\, Ospedale degli Infermi\, via dei Ponderanesi 2 Ponderano\, 13875\, Biella\, Italy.,Endocrinology and Diabetology Unit\, Ospedale degli Infermi\, via dei Ponderanesi 2 Ponderano\, 13875\, Biella\, Italy.,Division of Endocrinology\, Diabetes and Metabolism\, Santa Croce e Carle Hospital\, Cuneo\, Italy.,Pathology Unit\, Santa Croce e Carle Hospital\, via M Coppino 26\, 12100\, Cuneo\, Italy.,Pathology Unit\, Department of Oncology\, University of Turin\, via Santena 7\, 10126\, Turin\, Italy.,Pathology Unit\, Department of Oncology\, University of Turin\, via Santena 7\, 10126\, Turin\, Italy.,Oncological Endocrinology\, Department of Medical Sciences\, University of Turin\, via Genova 3\, 10126\, Turin\, Italy.,Pathology Unit\, Department of Oncology\, University of Turin\, via Santena 7\, 10126\, Turin\, Italy.",,,,,"BRAF mutation,JAK3,Next-generation sequencing,RAS mutation,Struma ovarii,Thyroid cancer"
33635116,"Jain E,Kumar A,Jain R,Sharma S",Primary Mucinous Cystadenocarcinoma of the Breast: A Rare Case Report With Review of Literature.,"Primary mucinous cystadenocarcinoma (MCA) of the breast is a rare variant of breast carcinoma known to have a favorable prognosis despite showing a basal-like phenotype. We describe a case of MCA breast in a 45-year-old female with a palpable mass in the breast. On the basis of the histopathological and immunohistochemical evaluation of a lumpectomy specimen with the absence of mass anywhere else on whole-body imaging, a diagnosis of primary MCA was rendered. Mismatch repair protein evaluation showed this tumor to be microsatellite stable. Molecular testing revealed the absence of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations. To date only 27 cases of MCA breast have been reported. To the best of our knowledge, ours is the first case documenting diffuse Cytokeratin 20 (CK20) positivity, microsatellite stability, and the absence of KRAS, NRAS, and BRAF mutations in these tumors. The rarity of this tumor further evokes an interest in this case. A better understanding of the disease warrants a review of more cases with longer follow-ups.",International journal of surgical pathology,vol.::1066896921991650,2021,Journal Article,,,"https://orcid.org/0000-0002-2688-9827Core Diagnostics Private Limited\, Gurgaon\, Haryana\, India.,Core Diagnostics Private Limited\, Gurgaon\, Haryana\, India.,Dr Lal Path Lab\, New Delhi\, India.,Core Diagnostics Private Limited\, Gurgaon\, Haryana\, India.",,,,,"breast,favorable,mismatch repair protein,mucinous cystadenocarcinoma,rare"
33644840,"Emaus MN,Anderson JL","Selective extraction of low-abundance BRAF V600E mutation from plasma, urine, and sputum using ion-tagged oligonucleotides and magnetic ionic liquids.","Sequence-specific DNA extractions have the potential to improve the detection of low-abundance mutations from complex matrices, making them ideal for circulating tumor DNA analysis during the early stages of cancer. Ion-tagged oligonucleotides (ITOs) are oligonucleotides modified with an allylimidazolium salt via thiolene click chemistry. The allylimidazolium-based tag allows the ITO-DNA duplex to be selectively captured by a hydrophobic magnetic ionic liquid (MIL). In this study, the selectivity of the ITO-MIL method was examined by extracting low abundance of the BRAF V600E mutation-a common single-nucleotide polymorphism associated with several different cancers-from diluted human plasma, artificial urine, and diluted artificial sputum. Quantitative polymerase chain reaction (qPCR) was not able to distinguish a 9% BRAF V600E standard (50 fg·μL-1 BRAF V600E, 500 fg·μL-1 wild-type BRAF) from the 100% wild-type BRAF (50 fg·μL-1) standard. However, introducing the ITO-MIL extraction prior to qPCR allowed for samples consisting of 0.1% BRAF V600E (50 fg·μL-1 V600E BRAF, 50,000 fg·μL-1 wild-type BRAF) to be distinguished from the 100% wild-type BRAF standard. Ion-tagged oligonucleotides (ITOs) are combined with magnetic ionic liquids (MILs) to extract low-abundance BRAF V600E mutation from diluted human plasma, artificial urine, and diluted artificial sputum. The ITO-MIL extraction prior to qPCR allowed for samples consisting of 0.1% BRAF V600E to be distinguished from the 100% wild-type BRAF standard.",Analytical and bioanalytical chemistry,vol.::,2021,Journal Article,,,"Department of Chemistry\, Iowa State University\, 1605 Gilman Hall\, Ames\, IA\, 50011\, USA.,Department of Chemistry\, Iowa State University\, 1605 Gilman Hall\, Ames\, IA\, 50011\, USA. andersoj@iastate.edu.",,Division of Chemistry,,CHE-1709372,"BRAF mutation,DNA extraction,Plasma,Single-nucleotide polymorphism,Urine"
33646525,"Lim-Fat MJ,Song KW,Iorgulescu JB,Andersen BM,Forst DA,Jordan JT,Gerstner ER,Reardon DA,Wen PY,Arrillaga-Romany I","Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma.","Although uncommon\, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors.,We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics\, molecular genomics\, and preoperative MRI were analyzed.,Nineteen glioblastoma patients were included\, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13\, 76.9%)\, polysomy 7 (8/12\, 66.7%)\, monosomy 10 (5/12\, 41.7%)\, PTEN biallelic loss/loss-of-function (5/13\, 38.5%) and TERT promoter mutations (5/15\, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy\, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients\, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9).,Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.",Journal of neuro-oncology,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0002-4317-5770Division of Neurology\, Department of Medicine\, Sunnybrook Health Sciences Centre\, University of Toronto\, Toronto\, ON\, M4N 3M5\, Canada. maryjane.limfat@sunnybrook.ca.,Department of Neurology\, Massachusetts General Hospital\, Boston\, MA\, 02114\, USA.,Department of Pathology\, Brigham and Women's Hospital\, Boston\, MA\, 02115\, USA.,Center for Neuro-Oncology\, Dana-Farber Cancer Institute\, Boston\, MA\, 02115\, USA.,Department of Neurology\, Massachusetts General Hospital\, Boston\, MA\, 02114\, USA.,Department of Neurology\, Massachusetts General Hospital\, Boston\, MA\, 02114\, USA.,Department of Neurology\, Massachusetts General Hospital\, Boston\, MA\, 02114\, USA.,Center for Neuro-Oncology\, Dana-Farber Cancer Institute\, Boston\, MA\, 02115\, USA.,Center for Neuro-Oncology\, Dana-Farber Cancer Institute\, Boston\, MA\, 02115\, USA.,Department of Neurology\, Massachusetts General Hospital\, Boston\, MA\, 02114\, USA. iarrillaga@mgh.harvard.edu.",,,,,"BRAF,BRAF inhibitor,Glioblastoma,MEK inhibitor,Molecular targeted therapy"
32552254,"Savvateeva E,Smoldovskaya O,Feyzkhanova G,Rubina A",Multiple biomarker approach for the diagnosis and therapy of rheumatoid arthritis.,"The lack of specific clinical symptoms for patients in the early stage of rheumatoid arthritis (RA) has created strong interest in the laboratory diagnosis of RA. The main laboratory markers of RA, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), can be found in patients with other pathologies and in healthy donors. Even today, there is no single laboratory test that can diagnosis RA with high sensitivity and specificity. To improve the diagnosis and treatment of RA, alternative biomarkers, including 14-3-3η protein, connective tissue growth factor (CTGF), antibodies against PAD4, antibodies against BRAF, and anti-acetylated and anti-carbamylated protein antibodies have been studied extensively. The use of a multiple biomarker approach, the simultaneous measurement of a set of biomarkers, is an alternative strategy for the diagnosis of RA and for predicting the therapeutic effect of biological disease-modifying antirheumatic drugs (DMARDs). However, despite the large number of studies, only a few biomarker combinations have been validated and can be applied in clinical practice. In this article, results of studies focused on the multiple biomarker approach (both multiplex and combined single-analyte assays) to diagnose RA and to predict response to biological drug therapy are reviewed. Additionally, general factors limiting the use of multiplex analysis in RA diagnostics and therapy are discussed.",Critical reviews in clinical laboratory sciences,vol.58:1:17-28,2021,Journal Article,,,"Laboratory of Biological Microchips\, Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, Moscow\, Russia.,Laboratory of Biological Microchips\, Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, Moscow\, Russia.,Laboratory of Biological Microchips\, Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, Moscow\, Russia.,https://orcid.org/0000-0002-6120-7780Laboratory of Biological Microchips\, Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, Moscow\, Russia.",,,,,"Rheumatoid arthritis,autoantibodies,biological DMARD,multiplex immunoassay,protein array"
33191640,"Brunhara BB,Becker AP,Neder L,Gonçalves PG,de Oliveira C,Clara CA,Reis RM,Bidinotto LT",Evaluation of the prognostic potential of EGFL7 in pilocytic astrocytomas.,"Pilocytic astrocytoma (PA) is the most frequent solid neoplasm in childhood. It has a good 5-year overall survival (90% in childhood and 52% in adults). However, up to 20% of patients experience residual tumor growth, recurrence, and death. Although the main genetic alteration of PAs, including KIAA1549:BRAF fusion, involves chromosome 7q34, we previously found frequent loss in chr9q34.3 locus in a small subset of these tumors. Among the genes present in this locus, EGFL7 is related to poor prognosis in several tumor types. In this study, we aimed to assess EGFL7 expression through immunohistochemistry, and to evaluate its prognostic value in a series of 64 clinically and molecularly well-characterized pilocytic astrocytomas. We found high expression of EGFL7 in 71.9% of patients. Low EGFL7 expression was associated with older patients, the mean age mainly older than 11 years (P = 0.027). EGFL7 expression was not associated with presence of KIAA1549:BRAF fusion, BRAF mutation, FGFR1 mutation, nor FGFR1 duplication. Moreover, high EGFL7 expression was associated with high FGFR1 (P = 0.037) and 5'-deoxy-5'-methyltioadenosine phosphorylase (MTAP) (P = 0.005) expression, and with unfavorable outcome of patients (P = 0.047). Multivariate analysis revealed low EGFL7 expression related to older patients and high EGFL7 expression related to retained expression of MTAP. In addition, we found a borderline significance of unfavorable outcome and high EGFL7 expression. Finally, EGFL7 expression was not associated with overall or event-free survival of PA patients. Our findings point to EGFL7 expression as a novel candidate prognostic marker in PA, which should be further investigated.",Neuropathology : official journal of the Japanese Society of Neuropathology,vol.41:1:21-28,2021,Journal Article,,,"Molecular Oncology Research Center\, Barretos Cancer Hospital\, Barretos\, Brazil.,Department of Radiation Oncology\, The Ohio State University\, Columbus\, Ohio\, USA.,Molecular Oncology Research Center\, Barretos Cancer Hospital\, Barretos\, Brazil.,Molecular Oncology Research Center\, Barretos Cancer Hospital\, Barretos\, Brazil.,Molecular Oncology Research Center\, Barretos Cancer Hospital\, Barretos\, Brazil.,Department of Neurosurgery\, Barretos Cancer Hospital\, Barretos\, Brazil.,https://orcid.org/0000-0002-9639-7940Molecular Oncology Research Center\, Barretos Cancer Hospital\, Barretos\, Brazil.,https://orcid.org/0000-0002-6909-8347Molecular Oncology Research Center\, Barretos Cancer Hospital\, Barretos\, Brazil.",,"Conselho Nacional de Desenvolvimento Científico e Tecnológico,Fundação de Amparo à Pesquisa do Estado de São Paulo,Fundação de Amparo à Pesquisa do Estado de São Paulo,Fundação de Amparo à Pesquisa do Estado de São Paulo,Fundação de Amparo à Pesquisa do Estado de São Paulo",",,,,","472447/2013-0,2012/19590-0,2016/21727-4,2016/23919-8,2017/09749-5","EGFL7,FGFR1,MTAP,immunohistochemistry,pilocytic astrocytoma"
33443622,"Inoue C,Saito R,Kishikawa S,Hayashi T,Kumasaka T,Yamada T,Oishi H,Yamazaki Y,Fujishima F,Watanabe M,Sasano H",Novel genetic characteristics of multifocal micronodular pneumocyte hyperplasia (MMPH): a case report with frequent BRAF mutations analyzed by next-generation sequencing supporting benign behaviors of MMPH.,"A woman in her 30s, who was clinically diagnosed with tuberous sclerosis complex, underwent lung transplantation due to lymphangioleiomyomatosis with concomitant multifocal micronodular pneumocyte hyperplasia (MMPH). Histologically, MMPH lesions demonstrated variety in histology; some showed homogenous cells with mild nuclear atypia and elastic fibers proliferation, and the others showed enlarged nuclei without elastic fibers. Because the natural history of MMPH is not well characterized, we used next-generation sequencing to perform a comprehensive genetic analysis for the MMPH lesions to explore their malignant potential. Regardless of their histological variety, three of four lesions had BRAF missense mutations, especially the types frequently detected in atypical adenomatous hyperplasia that is considered to be benign rather than a precursor of adenocarcinoma. None of them had major driver mutations of lung adenocarcinoma, except for BRAF mutations. In conclusion, our study of the lesions from this patient indicated the benign characteristic of MMPH.",Virchows Archiv : an international journal of pathology,vol.::,2021,Journal Article,,,"Department of Anatomic Pathology\, Tohoku University School of Medicine\, 2-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan.,http://orcid.org/0000-0003-3627-1788Department of Anatomic Pathology\, Tohoku University School of Medicine\, 2-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan. saitoarlu@patholo2.med.tohoku.ac.jp.,Department of Human Pathology\, Juntendo University School of Medicine\, Tokyo\, Japan.,Department of Human Pathology\, Juntendo University School of Medicine\, Tokyo\, Japan.,Department of Pathology\, Japanese Red Cross Medical Center\, Tokyo\, Japan.,Department of Thoracic Surgery\, Institute of Development\, Aging and Cancer\, Tohoku University\, Sendai\, Miyagi\, Japan.,Department of Thoracic Surgery\, Institute of Development\, Aging and Cancer\, Tohoku University\, Sendai\, Miyagi\, Japan.,Department of Anatomic Pathology\, Tohoku University School of Medicine\, 2-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan.,Department of Pathology\, Tohoku University Hospital\, Sendai\, Miyagi\, Japan.,Department of Pathology\, Tohoku University Hospital\, Sendai\, Miyagi\, Japan.,Department of Anatomic Pathology\, Tohoku University School of Medicine\, 2-1 Seiryo-machi\, Aoba-ku\, Sendai\, Miyagi\, 980-8575\, Japan.",,,,,"BRAF mutation,Lymphangioleiomyomatosis,Multifocal micronodular pneumocyte hyperplasia,Tuberous sclerosis complex"
33478186,"Li T,Li J",[Efficacy of Immune Checkpoint Inhibitors for Non-small Cell Lung Cancer 
with Rare Mutation].,"Over the past several decades, advances in driven targeted therapy has revolutionized the management of oncogene-driven non-small cell lung cancer (NSCLC). However, there are only a few targeted drugs available for patients with rare mutations, such as BRAF, HER2, MET, RET, etc. In recent years, immune checkpoint inhibitors (ICIs) have demonstrated promising benefit in NSCLC. Till now, efficacy of ICIs for NSCLC with rare mutation is largely unknown. It is fairly difficult to conduct a large formal prospective controlled trials because of the rarity of these mutation. In this article, currently available real world studies based on convincing clinical evidence will be reviewed, which will ultimately facilitate our rational use of ICIs for NSCLC with rare mutation.
.",Zhongguo fei ai za zhi = Chinese journal of lung cancer,vol.24:1:19-24,2021,Journal Article,,,"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences ,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\, Chinese Academy of Medical Sciences ",,,,,"Immune check point inhibitors,Lung neoplasms,Rare mutation"
32666385,"Run L,Wang L,Nong X,Li N,Huang X,Xiao Y",Involvement of HMGB1 in vemurafenib resistance in thyroid cancer cells harboring BRAF (V600E) mutation by regulating excessive autophagy.,"Thyroid carcinoma is the most frequent endocrine malignancy with high occurrence of BRAFV600E mutations. Though targeted therapy by vemurafenib\, a specific inhibitor for BRAFV600E\, has achieved great advance in therapeutic landscape\, resistance occurrence is still a clinical challenge. Here\, we sought to elucidate the function of high mobility group box 1 (HMGB1) in vemurafenib resistance in thyroid cancer harboring BRAF mutation.,The expression of HMGB1 in BRAF-mutant BCPAP and BRAF-wild CAL-62 cells were determined by qRT-PCR and western. Then\, BCPAP cells were transfected with recombinant HMGB1 plasmids\, and vemurafenib-resistant BCPAP-R cells were treated with si-HMGB1. The efficacy of HMGB1 on vemurafenib resistance was evaluated by detecting cell viability\, apoptosis\, and caspase-3 activity. In addition\, the involvement of autophagy pathway was investigated.,Lower expression of HMGB1 was observed in BRAF-mutant BCPAP cells that had high sensitivity to vemurafenib. Overexpression of HMGB1 attenuated BCPAP cell sensitivity to vemurafenib by increasing cell viability and decreasing cell apoptosis and caspase-3 activity. Intriguingly\, higher expression of HMGB1 was confirmed in vemurafenib-resistant BCPAP-R cells. Moreover\, knockdown of HMGB1 sensitized BCPAP-R cells to vemurafenib resistance. Mechanistically\, vemurafenib exposure induced autophagy by enhancing LC3II\, Beclin-1 expression\, and reducing autophagy substrate p62 expression. Importantly\, targeting HMGB1 suppressed vemurafenib-induced autophagy. Blocking autophagy pathway with its inhibitor 3-MA offset BCPAP-R cell resistance to vemurafenib.,These findings highlight that HMGB1-mediated autophagy may account for vemurafenib resistance in thyroid cancer harboring BRAF mutation\, implying a promising approach to overcome vemurafenib resistance in vemurafenib-mutant thyroid carcinomas.",Endocrine,vol.71:2:418-426,2021,Journal Article,,,"Department of Endocrinology\, Xi'an Central Hospital\, Xi'an JiaoTong University\, Xi'an\, 710003\, Shannxi\, PR China.,Department of Endocrinology\, Xi'an Central Hospital\, Xi'an JiaoTong University\, Xi'an\, 710003\, Shannxi\, PR China.,Department of Endocrinology\, Xi'an Central Hospital\, Xi'an JiaoTong University\, Xi'an\, 710003\, Shannxi\, PR China.,Department of Endocrinology\, Xi'an Central Hospital\, Xi'an JiaoTong University\, Xi'an\, 710003\, Shannxi\, PR China.,Department of General Surgery\, Xi'an Central Hospital\, Xi'an JiaoTong University\, Xi'an\, 710003\, Shannxi\, PR China. huangxincenter@126.com.,Department of Endocrinology\, Shaanxi Traditional Chinese Medicine Hospital\, Xi'an\, 710003\, Shannxi\, PR China. xiaoyangsxzy@yeah.net.",,,,,"Autophagy,BRAF mutation,HMGB1,Thyroid cancer,Vemurafenib"
33574842,"Wang X,Montoyo-Pujol YG,Bermudez S,Corpas G,Martin A,Almazan F,Cabrera T,López-Nevot MA",Serum Cytokine Profiles of Melanoma Patients and Their Association with Tumor Progression and Metastasis.,"Previous studies have shown that melanoma cells produce excessive levels of cytokines\, which have various biological roles during melanoma development. The aim of this study was to expand the profile of serum cytokines\, chemokines\, growth factors\, and angiogenic factors that are associated with melanoma\, to find more cytokines with abnormal concentrations in melanoma patients\, to identify whether the level of cytokines correlated with prognostic variants\, such as Breslow thickness and BRAF mutation\, and\, finally\, to find out the cytokines that play important roles during melanoma development.,Multiplex immunobead assay technology and 45-plex immunoassays ProcartaPlex™ kits were used to simultaneously compare the levels of cytokines\, growth factors\, angiogenic factors\, and chemokines between the serum of healthy patients (n = 30) and those with melanoma (n = 72). Data were analyzed according to the clinical characteristics of the designated patient subgroups.,Compared to the control group\, melanoma patients had higher levels of VEGF-A\, PDGF-BB\, IL-1RA\, PIGF-1\, IFN-γ\, TNF-α\, MIP-1α\, and SCF\, but lower levels of BDNF\, SDF-1α\, MCP-1\, Eotaxin\, EGF\, and IL-7. Furthermore\, the levels of TNF-α (P=0.320\, r = 0.019)\, IFN-γ (P=0.311\, r = 0.023)\, VEGF-A (P=0.014\, r = 0.337)\, and BDNF (0.004\, r = -0.391) showed a significant correlation with Breslow thickness. IL-7 was of lower levels in patients harboring BRAF mutants. Melanoma patients with high levels of MIP-1α and MCP-1 showed the poorest overall survival.,We found that the levels of VEGF-A and PDGF-BB in the serum of both primary and metastatic melanoma patients are elevated. TNF-α\, IFN-γ\, and VEGF-A presented a positive correlation with Breslow thickness\, whereas BDNF showed a negative association. MIP-1α and MCP-1 correlated negatively with survival. In addition\, lower levels of IL-7 were found in patients harboring BRAF mutants. These findings indicate that these cytokines may play critical roles in the progression of melanoma.",Journal of oncology,vol.2021::6610769,2021,Journal Article,,,"https://orcid.org/0000-0003-4964-9460Servicio de Análisis Clínicos e Inmunología\, Hospital Universitario Virgen de Las Nieves\, Avda. Fuerzas Armadas s/n\, Granada 18014\, Spain.,https://orcid.org/0000-0003-3169-0924Servicio de Análisis Clínicos e Inmunología\, Hospital Universitario Virgen de Las Nieves\, Avda. Fuerzas Armadas s/n\, Granada 18014\, Spain.,https://orcid.org/0000-0001-5758-2572Servicio de Análisis Clínicos e Inmunología\, Hospital Universitario Virgen de Las Nieves\, Avda. Fuerzas Armadas s/n\, Granada 18014\, Spain.,Servicio de Análisis Clínicos e Inmunología\, Hospital Universitario Virgen de Las Nieves\, Avda. Fuerzas Armadas s/n\, Granada 18014\, Spain.,Servicio de Anatomía Patológica\, Hospital Universitario Virgen de Las Nieves\, Avda. Fuerzas Armadas s/n\, Granada 18014\, Spain.,https://orcid.org/0000-0002-0000-1885Servicio de Dermatología\, Hospital Universitario Clinico San Cecilio (PTS)\, Avenida de la Investigación s/n\, Granada 18014\, Spain.,https://orcid.org/0000-0002-9871-1374Departamento Bioquímica\, Biología Molecular e Inmunología III\, Universidad de Granada\, Granada\, Spain.,https://orcid.org/0000-0002-3465-6062Servicio de Análisis Clínicos e Inmunología\, Hospital Universitario Virgen de Las Nieves\, Avda. Fuerzas Armadas s/n\, Granada 18014\, Spain.",,,,,
33574927,"Dong Y,Wang D,Luo Y,Chen L,Bai H,Shen Y,Zhang Y,Chen X,Su X,Zhao J,Liu H,Lu J,Yao Z,Zhao Y,He C,Li X",Comprehensive evaluation of risk factors for lymph node metastasis in patients with papillary thyroid carcinoma.,"With the increasing incidence of papillary thyroid cancer (PTC), it is important to risk-stratify patients who may have a more aggressive tumor biology. The present study aimed to evaluate the risk factors for lymph node metastasis (LNM) in patients with PTC, which may provide a significant reference for clinical diagnosis and treatment. In total, 1,045 patients with PTC [313 with PT microcarcinoma (PTMC) and 732 with non-PTMC] between August 2016 and August 2019 were investigated. The B-type Raf kinase (BRAF) V600E mutation was tested in all samples. The clinical data (sex, age, tumor location, sample type and pathological features) were retrospectively analyzed. Logistic regression analysis was performed to evaluate independent risk factors for LNM. A total of 181/313 (57.8%) PTMC cases and 145/732 (19.8%) non-PTMC cases had a BRAF V600E mutation. In the PTMC cases, significant differences in sex and sample type were identified (BRAF V600E mutation vs. wild-type). In the non-PTMC cases, significant differences in sex and age were identified (BRAF V600E mutation vs. wild-type). Female sex and tumor diameter ≤1 cm were significant independent predictors of LNM in PTC. In PTMC, female sex was a significant independent predictor of LNM. A bilateral tumor was an independent protective factor for LNM in PTC, PTMC and non-PTMC. The BRAF V600E mutation rate of ultrasound-guided fine-needle aspiration cytology was higher compared with FFPE in PTMC (P=0.018). In contrast to previous studies, the results of the present study suggested that being female and having a tumor of diameter ≤1 cm were risk factors for LNM, and that the BRAF wild-type of PTMC may be more aggressive than other types. Notably, the position of the tumor in the bilateral thyroid was also an independent protective factor for LNM. Therefore, ultrasound-guided fine-needle aspiration should be recommended for gene analysis (BRAF V600E) in PTMC. In addition, clinicians should consider an individualized treatment according to gene mutations, sex, age, tumor size and the location of the tumor, in order to achieve an improved therapeutic efficacy.",Oncology letters,vol.21:3:188,2021,Journal Article,,,"Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Department of Clinical Laboratory\, People's Hospital of Rongchang District\, Rongchang\, Chongqing 402460\, P.R. China.,Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Key Laboratory of Molecular Biology of Infectious Diseases\, Ministry of Education\, Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Department of Endocrine Surgery\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Department of Infectious Diseases\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Department of Neurosurgery\, People's Hospital of Tibet Autonomous Region\, Lhasa\, Tibet 850000\, P.R. China.,Department of Clinical Laboratory\, The Third Affiliated Hospital of Guizhou Medical University\, Duyun\, Guizhou 558000\, P.R. China.,Department of General Surgery\, The Chengdu Fifth People's Hospital\, Chengdu\, Sichuan 611130\, P.R. China.,Department of Ultrasound\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Key Laboratory of Molecular Biology of Infectious Diseases\, Ministry of Education\, Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.,Clinical Molecular Medicine Testing Center\, The First Affiliated Hospital of Chongqing Medical University\, Yuzhong\, Chongqing 400016\, P.R. China.",,,,,"BRAF mutation,genetic testing,non-papillary thyroid microcarcinoma,papillary thyroid carcinoma,papillary thyroid microcarcinoma"
33574947,"Hu C,Huang Y,Luo P,Yang Y",Effect of antioxidants coenzyme Q10 and β-carotene on the cytotoxicity of vemurafenib against human malignant melanoma.,"Melanoma is a type of highly invasive skin cancer derived from melanocytes with poor prognosis. Vemurafenib (PLX4032) is a clinically approved targeted therapeutic for BRAF mutant melanoma that has a high therapeutic response rate and significantly prolongs the overall survival time of patients with melanoma. Antioxidants have been widely used as supplements for cancer prevention and for decreasing the side effects of cancer therapy. However, antioxidants can also protect cancer cells from oxidative stress and promote cancer growth and progression. The present study aimed to examine the effect of the antioxidants coenzyme Q10 (CoQ10) and β-carotene on melanoma cell growth and invasiveness and on the cytotoxicity of vemurafenib against both vemurafenib-sensitive (SK-MEL-28) and vemurafenib-resistant (A2058) human malignant melanoma cell lines. MTS assay and wound-healing assay demonstrated that CoQ10 alone significantly reduced the viability and migration of melanoma cells, respectively, and synergistically worked with vemurafenib to decrease the viability and migration of human melanoma cells. In contrast, MTS assay and flow cytometry revealed that β-carotene alone did not affect the viability and apoptosis induction of melanoma cells; however, it inhibited cell migration and invasiveness. Wound-healing and Transwell assay demonstrated that β-carotene alleviated the cytotoxicity of vemurafenib and mitigated the inhibitory effect of vemurafenib on cell migration and invasion. Both CoQ10 and β-carotene protected melanoma cells from undergoing apoptosis induced by vemurafenib. Immunoblotting demonstrated that β-carotene at physiological concentration worked synergistically with vemurafenib to suppress the Ras-Raf-Mek-Erk intracellular signaling pathway. The present study aimed to add to the evidence of the in vitro effects of CoQ10 and β-carotene on the antimelanoma effects of vemurafenib.",Oncology letters,vol.21:3:208,2021,Journal Article,,,"Division of Biology\, Kansas State University\, Manhattan\, KS 66506\, USA.,Department of Hematopathology\, Anqing Municipal Hospital\, Anqing\, Anhui 246004\, P.R. China.,School of Natural Sciences\, College of Science and Technology\, Wenzhou Kean University\, Wenzhou\, Zhejiang 325035\, P.R. China.,School of Natural Sciences\, College of Science and Technology\, Wenzhou Kean University\, Wenzhou\, Zhejiang 325035\, P.R. China.",,,,,"Ras-Raf-Mek-Erk intracellular signaling pathway,apoptosis,coenzyme Q10,invasion,melanoma,vemurafenib,β-carotene"
33464748,"Paton DJW,Wong D,Amanuel B,Cheah K,Ardakani NM",S100/CD34-Positive Spindle Cell Mesenchymal Neoplasm Harboring KIAA1549-BRAF Fusion.,"Mesenchymal neoplasms with oncogenic kinase activity due to genomic alterations in receptor tyrosine kinase genes are a morphologically heterogeneous group with a variable biologic potential. A subset of these neoplasms are characterized by immunophenotypic property of dual S100 protein/CD34 expression, histopathological resemblance to lipofibromatosis or peripheral nerve sheath tumors, and often alterations in neurotrophic tropomyosin-related kinase genes. In this article, we present a case of an S100 protein/CD34-positive spindle cell neoplasm harboring a rare BRAF gene rearrangement (KIAA1549-BRAF fusion) and discuss the clinical, histopathological, and molecular variations associated with such neoplasms.",The American Journal of dermatopathology,vol.43:3:217-220,2021,Journal Article,,,"Western Diagnostic Pathology\, Perth\, Australia.,The University of Western Australia\, School of Pathology and Laboratory Medicine\, Crawley\, Australia.,The University of Western Australia\, School of Pathology and Laboratory Medicine\, Crawley\, Australia.,Dorevich Pathology\, Albury\, Australia; and.,The University of Western Australia\, School of Pathology and Laboratory Medicine\, Crawley\, Australia.",,,,,
33249369,"Emelyanova MA,Telysheva EN,Orlova KV,Ryabaya OO,Snigiryova GP,Abramov IS,Mikhailovich VM",Microarray-based analysis of the BRAF V600 mutations in circulating tumor DNA in melanoma patients.,"Circulating tumor DNA (ctDNA) holds great potential for cancer therapy and can provide diagnostic and prognostic information before and during treatment.,Plasma DNA samples from 97 melanoma patients\, 20 healthy donors and 3 patients with benign skin tumors were analyzed by microarray analysis and droplet digital PCR (ddPCR).,A microarray for simultaneous detection of six BRAF V600 mutations in ctDNA has been developed. The method allows the detection of 0.05% mutated DNA from WT DNA background. For paired samples (pre-surgery plasma and tumor tissue) isolated from 74 patients\, the concordance of genotypes between tumor DNA and ctDNA was 65% (48/74). BRAF mutations in ctDNA were detected in 27/50 patients with BRAF-positive tumors and in 3/24 patients with BRAF wild-type tumors. The presence of ctDNA BRAF mutations in 23 plasma samples from melanoma patients undergoing therapy correlated significantly with tumor progression (P=0.005). The increase in cell-free DNA levels measured by ddPCR also correlated with disease progression (P=0.02). The concordance of results obtained by microarray identification of BRAF mutations and those obtained by ddPCR was 91%.,The novel microarray-based approach can be a useful non-invasive tool for accurate identification of ctDNA BRAF mutations to monitor disease progression.",Cancer genetics,vol.250-251::25-35,2021,Journal Article,,,"Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, 119991 Moscow\, 32 Vavilova St.\, Russian Federation.,Russian Scientific Center of Roentgen Radiology\, Ministry of Healthcare of the Russian Federation\, 117997 Moscow\, Profsoyuznaya St. 86\, Russian Federation.,N.N. Blokhin National Medical Research Center for Oncology\, Ministry of Health of the Russian Federation\, 115478 Moscow\, Kashirskoye shosse 24\, Russian Federation.,N.N. Blokhin National Medical Research Center for Oncology\, Ministry of Health of the Russian Federation\, 115478 Moscow\, Kashirskoye shosse 24\, Russian Federation.,Russian Scientific Center of Roentgen Radiology\, Ministry of Healthcare of the Russian Federation\, 117997 Moscow\, Profsoyuznaya St. 86\, Russian Federation.,Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, 119991 Moscow\, 32 Vavilova St.\, Russian Federation.,Engelhardt Institute of Molecular Biology\, Russian Academy of Sciences\, 119991 Moscow\, 32 Vavilova St.\, Russian Federation. Electronic address: vmikh@eimb.ru.",,,,,"BRAF mutations,Circulating tumor DNA,Genotyping,Melanoma,Microarray"
33441391,"Mosnier JF,Airaud F,Métairie S,Volteau C,Bezieau S,Denis M",Mapping of colorectal carcinoma diseases with activation of Wnt/beta-catenin signalling pathway using hierarchical clustering approach.,"To map the colorectal carcinoma (CRC) diseases with significant Wnt signalling pathway activation for delineating their clinicopathological and molecular profiles.,Mapping is based on hierarchical clustering analyses of a series of 283 CRCs. Data tabulated were histopathological patterns\, immunophenotypic differentiation\, RAS\, RAF\, CTNNB1 mutations and microsatellite instability status\, tumour-infiltrating lymphocytes (TILs) and genetic setting. Beta-catenin expression in more than 10% of cell nuclei in the centre of tumour serves as a surrogate marker of significant activation of Wnt signalling pathway.,Nuclei beta-catenin expression was present in 95% of CRCs; 56% of them met the criteria of high level of nuclei beta-catenin expression (≥10%). Proportion of beta-catenin positive nuclei was significantly higher in younger patients\, rectal and left-sided colonic carcinomas. CRCs with high level of nuclei beta-catenin expression were regrouped into three clusters: (1) microsatellite stability (MSS) CRCs with no constitutive MAPK pathway activation including 90% of low-grade adenocarcinoma\, NOS\, with intestinal differentiation without TILs; (2) RAS-mutated MSS CRCs including low-grade adenocarcinoma\, NOS\, with intestinal differentiation and mucinous adenocarcinoma without TILs; (3) MSI-H CRCs including both BRAF-mutated CRCs evolving from serrated pathway and CTNNB1-mutated CRCs associated with Lynch syndrome.,MSS low-grade adenocarcinoma\, NOS\, with intestinal differentiation without TILs ('crypt-like adenocarcinoma') might be the morphological pending of canonical molecular subtype of CRC defined as displayed molecular epithelial differentiation and upregulation of WNT in consensus molecular classification of CRC.",Journal of clinical pathology,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0003-2637-3641Pathology\, CHU Nantes\, Nantes\, France jfmosnier@live.fr.,Department of Genetics\, Centre Hospitalier Universitaire de Nantes\, Nantes\, France.,Department of Digestive and Endocrinology Surgeries\, Centre Hospitalier Universitaire de Nantes\, Nantes\, France.,Biostatistics Department\, Centre Hospitalier Universitaire de Nantes\, Nantes\, France.,Department of Genetics\, Centre Hospitalier Universitaire de Nantes\, Nantes\, France.,Department of Biochemistry and Oncogenomics\, Centre Hospitalier Universitaire\, Nantes\, France.",,,,,"biomarkers,cell differentiation,colorectal neoplasms,immunohistochemistry,tumor"
32666260,"Kamakura D,Asano R,Kawai H,Yasunaga M",Mechanism of action of a T cell-dependent bispecific antibody as a breakthrough immunotherapy against refractory colorectal cancer with an oncogenic mutation.,"T cell-dependent bispecific antibody (TDB)-induced T cell activation, which can eliminate tumor cells independent of MHC engagement, is expected to be a novel breakthrough immunotherapy against refractory cancer. However, the mechanism of action of TDBs has not been fully elucidated thus far. We focused on TDB-induced T cell-tumor cell contact as an important initial step in direct T cell-mediated tumor cell killing via transport of cytotoxic cell proteases (e.g., granzymes) with or without immunological synapse formation. Using an anti-EGFR/CD3 TDB, hEx3, we visualized and quantified T cell-tumor cell contact and demonstrated a correlation between the degree of cell contact and TDB efficacy. We also found that cytokines, including interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) secreted by activated T cells, damaged tumor cells in a cell contact-independent manner. Moreover, therapeutic experiences clearly indicated that hEx3, unlike conventional anti-EGFR antibodies, was effective against colorectal cancer (CRC) cells with mutant KRAS, BRAF, or PIK3CA. In a pharmacokinetic analysis, T cells spread gradually in accordance with the hEx3 distribution within tumor tissue. Accordingly, we propose that TDBs should have four action steps: 1st, passive targeting via size-dependent tumor accumulation; 2nd, active targeting via specific binding to tumor cells; 3rd, T cell redirection toward tumor cells; and 4th, TDB-induced cell contact-dependent (direct) or -independent (indirect) tumor cell killing. Finally, our TDB hEx3 may be a promising reagent against refractory CRC with an oncogenic mutation associated with a poor prognosis.","Cancer immunology, immunotherapy : CII",vol.70:1:177-188,2021,Journal Article,,,"Division of Developmental Therapeutics\, Exploratory Oncology Research and Clinical Trial Center\, National Cancer Center\, 6-5-1 Kashiwanoha\, Kashiwa\, Chiba\, 277-8577\, Japan.,Department of Biotechnology and Life Science\, Graduate School of Engineering\, Tokyo University of Agriculture and Technology\, Tokyo\, 184-8588\, Japan.,Research and Development Department\, LPIXEL Inc.\, Tokyo\, 100-0004\, Japan.,http://orcid.org/0000-0003-3356-0197Division of Developmental Therapeutics\, Exploratory Oncology Research and Clinical Trial Center\, National Cancer Center\, 6-5-1 Kashiwanoha\, Kashiwa\, Chiba\, 277-8577\, Japan. mayasuna@east.ncc.go.jp.",,"National Cancer Center Research and Development Fund,Japan Society for the Promotion of Science (JP),Project for Development of Innovative Research on Cancer Therapeutics",",,","30-S-4 and 2020-S-2,18H02702,18cm0106240","Antibody therapeutics,Bispecific antibody (BsAb),Colorectal cancer,Immunological synapse,Immunotherapy,T cell-dependent bispecific antibody (TDB)"
32810930,"Lee Y,Lee S,Sung JS,Chung HJ,Lim AR,Kim JW,Choi YJ,Park KH,Kim YH",Clinical Application of Targeted Deep Sequencing in Metastatic Colorectal Cancer Patients: Actionable Genomic Alteration in K-MASTER Project.,"Next-generation sequencing (NGS) can facilitate precision medicine approaches in metastatic colorectal cancer (mCRC) patients. We investigated the molecular profiling of Korean mCRC patients under the K-MASTER project which was initiated in June 2017 as a nationwide precision medicine oncology clinical trial platform which used NGS assay to screen actionable mutations.,As of 22 January 2020\, total of 994 mCRC patients were registered in K-MASTER project. Targeted sequencing was performed using three platforms which were composed of the K-MASTER cancer panel v1.1 and the SNUH FIRST Cancer Panel v3.01. If tumor tissue was not available\, cell-free DNA was extracted and the targeted sequencing was performed by Axen Cancer Panel as a liquid biopsy.,In 994 mCRC patients\, we found 1\,564 clinically meaningful pathogenic variants which mutated in 71 genes. Anti-EGFR therapy candidates were 467 patients (47.0%) and BRAF V600E mutation (n=47\, 4.7%)\, deficient mismatch repair/microsatellite instability-high (n=15\, 1.5%)\, HER2 amplifications (n=10\, 1.0%) could be incorporated with recently approved drugs. The patients with high tumor mutation burden (n=101\, 12.7%) and DNA damaging response and repair defect pathway alteration (n=42\, 4.2%) could be enrolled clinical trials with immune checkpoint inhibitors. There were more colorectal cancer molecular alterations such as PIK3CA\, KRAS G12C\, atypical BRAF\, and HER2 mutations and even rarer but actionable genes that approved or ongoing clinical trials in other solid tumors.,K-MASTER project provides an intriguing background to investigate new clinical trials with biomarkers and give therapeutic opportunity for mCRC patients.",Cancer research and treatment : official journal of Korean Cancer Association,vol.53:1:123-130,2021,Journal Article,,,"Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.,Department of Internal Medicine\, Korea University Anam Hospital\, Korea University College of Medicine\, Seoul\, Korea.",,"Korea Health Industry Development Institute,Ministry of Health and Welfare",",",HI17C2206,"Colorectal neoplasms,Genomics,High-throughput nucleotide sequencing"
32868527,"Sasaki E,Masago K,Fujita S,Iwakoshi A,Kuroda H,Hosoda W",AKT1 Mutations in Peripheral Bronchiolar Papilloma: Glandular Papilloma and Mixed Squamous Cell and Glandular Papilloma Is Distinct From Bronchiolar Adenoma.,"Glandular papilloma (GP) and mixed squamous cell and glandular papilloma (MP) are rare benign pulmonary tumors occurring in the bronchi. Bronchiolar adenoma (BA) was recently characterized as a pulmonary tumor exhibiting alveolar spread. Both GP/MP and BA are composed of a mixture of glandular, ciliated, squamous, and basal cells. We aimed to clarify whether GP/MP and BA represent the same tumor. We evaluated the detailed histologic characteristics of 11 cases involving pulmonary peripheral tumors that exhibited histologic features of GP/MP or BA, and performed genetic analyses using targeted panel sequencing, allele-specific polymerase chain reaction, and digital polymerase chain reaction. Histologically, 4 and 7 tumors were classified as GP/MP and BA, respectively. GP/MP showed endobronchiolar papillary growth with a pseudostratified or stratified epithelium. In contrast, 5 BAs showed a predominant flat structure with a bilayered or pseudostratified epithelium, whereas 2 BAs showed a GP/MP-like papillary architecture. The mean epithelial thickness in each tumor was significantly larger in GP/MPs and BAs with a GP/MP-like morphology (103 to 242 μm) than in flat-predominant BA (23 to 47 μm, P=0.0010). AKT1 E17K mutations were detected in all GP/MPs and BAs with GP/MP-like morphology but were absent in the 5 flat-predominant BAs. AKT1 mutations were always concurrent with BRAF or HRAS mutations, and the variant allele frequency or percentage of mutant copies of AKT1 mutations was equal to those of BRAF or HRAS mutations. GP/MPs are characterized by AKT1 mutations concurrent with BRAF or HRAS mutations. Peribronchiolar papillary tumors with AKT1 mutations may also be classified as GP/MP.",The American journal of surgical pathology,vol.45:1:119-126,2021,"Research Support, Non-U.S. Gov't",,,"Departments of Pathology and Molecular Diagnostics.,Departments of Pathology and Molecular Diagnostics.,Departments of Pathology and Molecular Diagnostics.,Departments of Pathology and Molecular Diagnostics.Department of Pathology\, Nagoya Medical Center\, Nagoya\, Aichi Prefecture\, Japan.,Thoracic Surgery\, Aichi Cancer Center Hospital.,Departments of Pathology and Molecular Diagnostics.",,,,,
33478111,"Tanaka Y,Murata M,Shen CH,Furue M,Ito T",NECTIN4: A Novel Therapeutic Target for Melanoma.,"Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK inhibitors. Alternative treatments for BRAFi-resistant melanoma are highly anticipated. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tumors. We aimed to investigate the role of NECTIN4 in melanoma and its potency as a therapeutic target using 126 melanoma samples and BRAFi-resistant cells. Immunohistochemically, most of the clinical samples expressed NECTIN4, at least in part. NECTIN4 was highly expressed in BRAF-mutated melanoma and its high expression was associated with disease-free survival. In BRAFi-resistant melanoma cells, NECTIN4 and the PI3K/Akt pathway were upregulated, along with the acquisition of BRAFi resistance. Monomethyl auristatin E, a cytotoxic part of NECTIN4-targeted antibody-drug conjugate, was effective for BRAF-mutated or BRAFi-resistant melanoma cells. NECTIN4 inhibition increased the sensitivity of BRAFi-resistant cells to BRAFi and induced apoptosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted therapies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance.",International journal of molecular sciences,vol.22:2:,2021,Journal Article,,,"0000-0001-8433-6035Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,0000-0002-1068-6873Department 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.,0000-0002-2967-1073Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.,0000-0002-2679-8546Department of Dermatology\, Graduate School of Medical Sciences\, Kyushu University\, Fukuoka 812-8582\, Japan.",,"Japan Society for the Promotion of Science,Takeda Science Foundation",",","19K16867,Takeda Science Foundation Grant","BRAF,BRAFi resistance,NECTIN4,antibody–drug conjugate,malignant melanoma"
33500258,"Pokorny R,McPherson JP,Haaland B,Grossmann KF,Luckett C,Voorhies BN,Sageser DS,Wallentine J,Tolman Z,Hu-Lieskovan S,Swami U",Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma.,"Randomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data\, and shorter therapies may be effective.,Data of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1\, 2015\, to December 31\, 2018\, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (>6 months and <18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy\, had prior exposure to PD-1 therapy\, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation\, progression-free survival (PFS)\, and retreatment characteristics was analyzed.,Of 480 patients who received PD-1 inhibitors\, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%)\, partial response in 28 (53.8%)\, and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3-49.2) from treatment discontinuation\, 39 (75%) patients remained without disease progression\, while 13 (25%) had progression (median PFS 3.9 months; range 0.7-30.9). On multivariable analysis\, younger age\, history of brain metastasis\, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment\, anti-PD-1 therapies\, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.,In this large real-world\, observational cohort study\, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation\, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.",Journal for immunotherapy of cancer,vol.9:1:,2021,Journal Article,,,"Department of Pharmacy\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Department of Pharmacy\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Division of Oncology and Department of Population Health Sciences\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Department of Oncology\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Department of Oncology\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Division of Oncology\, Department of Medicine\, Intermountain Healthcare\, Salt Lake City\, Utah\, USA.,Department of Pharmacy\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Department of Oncology\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Department of Pharmacy\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,Department of Oncology\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA.,http://orcid.org/0000-0003-3518-0411Department of Oncology\, Huntsman Cancer Institute\, University of Utah\, Salt Lake City\, Utah\, USA umang.swami@hci.utah.edu.",,,,,"immunotherapy,melanoma"
32820496,"Uecker M,Lehmann U,Braubach P,Schukfeh N,Madadi-Sanjani O,Ure BM,Petersen C,Kuebler JF",Choledochal Cysts Resected during Childhood Show No Mutations of KRAS and BRAF as Early Markers of Malignancy in Cholangiocytes.," In patients with choledochal cysts (CDC)\, a hyperplasia-dysplasia-carcinoma sequence can lead to biliary tract malignancy. The limited data available suggest that the risk decreases considerably after excision in childhood. We analyzed samples of resected CDC from pediatric patients histologically and performed mutational analysis of the proto-oncogenes KRAS and BRAF as early markers of malignant alteration in cholangiocytes., After institutional review board approval\, patients undergoing resection for CDC in our center from 2011 to 2019 were retrospectively identified. Histopathological reports were searched for inflammation and endothelial alteration. Cases with sufficient tissue specimen were tested for KRAS codon 12/13 and BRAF codon 600 mutations by pyrosequencing., In total\, 42 patients underwent resection for choledochal cyst in the study period. Median age at surgery was 2.4 years (range = 18 days-18 years). Histopathological analysis showed no malignancy\, but various degrees of inflammation or fibrosis in approximately 50% of the patients and in all age groups. Sufficient tissue for mutation analysis was available for 22 cases\, all of which tested negative for KRAS or BRAF mutation., In our series\, chronic inflammatory changes were frequently present in CDC of infants and children. However\, the lack of KRAS and BRAF mutations suggests that no malignant changes have been initiated in this group of European patients undergoing early resection.",European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie,vol.31:1:20-24,2021,Journal Article,,,"Department of Pediatric Surgery\, Hannover Medical School\, Hannover\, Germany.,Department of Pathology\, Hannover Medical School\, Hannover\, Germany.,Department of Pathology\, Hannover Medical School\, Hannover\, Germany.,Department of Pediatric Surgery\, Hannover Medical School\, Hannover\, Germany.,Department of Pediatric Surgery\, Hannover Medical School\, Hannover\, Germany.,Department of Pediatric Surgery\, Hannover Medical School\, Hannover\, Germany.,Department of Pediatric Surgery\, Hannover Medical School\, Hannover\, Germany.,Department of Pediatric Surgery\, Hannover Medical School\, Hannover\, Germany.",,,,,
33002893,"Wang S,Sun RZ,Han Q,Wang SY,Wang EH,Liu Y",Genomic Study of Chinese Quadruple-negative GISTs Using Next-generation Sequencing Technology.,"Approximately 10% of gastrointestinal stromal tumors (GISTs) are devoid of KIT\, PDGFRA (platelet-derived growth factor-alpha)\, BRAF\, and SDH alterations. The aim of this study was to characterize molecular drivers in Chinese patients with quadruple-negative GISTs.,In 1022 Chinese patients with GIST\, mutations of KIT and PDGFRA were analyzed by direct sequencing. Of these mutations\, 142 KIT/PDGFRA wild-type (WT) GISTs were detected\, and succinate dehydrogenase (SDH) deficiency was determined using immunohistochemistry analysis of succinate dehydrogenase B. In 78 KIT/PDGFRA/SDH cases\, we performed targeted 425 cancer-related gene analysis using next-generation sequencing. The correlation between molecular findings and clinicopathologic features was also analyzed.,We defined 72 quadruple-negative GISTs from enrollments. They featured nongastric localization with histologic characteristics of spindle cells and male predilection. An overall 27.78% (20/72) of quadruple-negative tumors carried TP53\, and 25.00% (18/72) carried RB1 mutations\, which were frequently associated with high mitotic index and large size. TP53 analyses demonstrated coexistence with mutational activation of other oncogenes in 12 of 20 cases. A total of 18 RB1-mutated cases were independent of TP53. Further\, no tumors carried NF1 and BRAF mutations.,We report the genomic analysis of Chinese quadruple-negative patients. These databases may help advance our understanding of quadruple-negative GISTs' progression. Next-generation sequencing from GISTs is feasible to provide relevant data for guiding individualized therapy.",Applied immunohistochemistry & molecular morphology : AIMM,vol.29:1:34-41,2021,"Research Support, Non-U.S. Gov't",,,"Department of Medical Microbiology and Human Parasitology\, the Basic Medicine College of China Medical University.,Department of Pathology\, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University\, Shenyang\, People's Republic of China.,Department of Pathology\, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University\, Shenyang\, People's Republic of China.,Department of Pathology\, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University\, Shenyang\, People's Republic of China.,Department of Pathology\, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University\, Shenyang\, People's Republic of China.,Department of Pathology\, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University\, Shenyang\, People's Republic of China.",,,,,
33572972,"Santiappillai NT,Abuhammad S,Slater A,Kirby L,McArthur GA,Sheppard KE,Smith LK",CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAF Melanoma via a p53 Dependent Pathway.,"Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors.",Cancers,vol.13:3:,2021,Journal Article,,,"Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.,0000-0001-9138-270XCancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.,0000-0002-2798-4703Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.,Cancer Research Division\, Peter MacCallum Cancer Centre\, Melbourne 3052\, Australia.",,"National Health and Medical Research Council,Cancer Council Victoria",",","1175894,1108149","BRAF,CDK4,melanoma,metabolism,targeted therapy"
33579557,"Funck-Brentano E,Malissen N,Roger A,Lebbé C,Deilhes F,Frénard C,Dréno B,Meyer N,Grob JJ,Tétu P,Saiag P",Which adjuvant treatment for patients with BRAF-mutant cutaneous melanoma?,"Treatment of patients with melanoma has considerably improved over the past decade and more recently with adjuvant therapies for patients with American Joint Committee on Cancer (AJCC) stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma, in order to prevent recurrence. In the adjuvant setting, two options are available to patients with BRAFV600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib). In the absence of comparative studies, it is difficult to determine which of these options is best. Our aim was to review published studies focusing on the management of patients with BRAFV600-mutant melanoma in the adjuvant setting. We also reviewed the main clinical trials of BRAF plus MEK inhibitors and immunotherapy in advanced (i.e. unresectable metastatic) BRAF-mutant melanoma in an attempt to identify results potentially affecting the management of patients on adjuvants. More adverse events are observed with targeted therapy, but all resolve rapidly upon drug discontinuation, whereas with immune checkpoint blockers some adverse events may persist. New therapeutic strategies are emerging, notably neoadjuvant therapies for stage III patients and adjuvant therapies for stage II patients; the place of the adjuvant strategy amidst all these options will soon be re-evaluated. The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings. This review will lead clinicians to a better understanding of the different adjuvant treatments available for patients with totally resected AJCC stage III and IV BRAFV600-mutant melanoma before considering subsequent treatment strategies.",Annales de dermatologie et de venereologie,vol.::,2021,Review,,,"Department of General and Oncologic Dermatology\, Ambroise-Paré hospital\, AP-HP\, Boulogne-Billancourt\, France; Research unit EA4340 ""Biomarkers and clinical trials in oncology and onco-hematology""\, Versailles-Saint-Quentin-en-Yvelines University\, Paris-Saclay University\, France. Electronic address: elisa.funck-brentano@aphp.fr.,Department of Dermatology and Skin Cancer\, Aix-Marseille University\, AP-HM\, Hôpital Timone\, Marseille\, France.,Department of General and Oncologic Dermatology\, Ambroise-Paré hospital\, AP-HP\, Boulogne-Billancourt\, France; Research unit EA4340 ""Biomarkers and clinical trials in oncology and onco-hematology""\, Versailles-Saint-Quentin-en-Yvelines University\, Paris-Saclay University\, France.,Inserm U976\, Department of Dermatology\, Dermatology\, Paris University\, Hôpital Saint-Louis\, AP-HP\, Paris\, France.,Dermatology Department\, CHU de Toulouse\, Toulouse\, France.,Department of Dermatology\, CRCINA\, CIC1413\, CHU de Nantes\, université de Nantes\, Nantes\, France.,Department of Dermatology\, CRCINA\, CIC1413\, CHU de Nantes\, université de Nantes\, Nantes\, France.,Dermatology Department\, CHU de Toulouse\, Toulouse\, France.,Department of Dermatology and Skin Cancer\, Aix-Marseille University\, AP-HM\, Hôpital Timone\, Marseille\, France.,Department of Dermatology\, CRCINA\, CIC1413\, CHU de Nantes\, université de Nantes\, Nantes\, France.,Department of General and Oncologic Dermatology\, Ambroise-Paré hospital\, AP-HP\, Boulogne-Billancourt\, France; Research unit EA4340 ""Biomarkers and clinical trials in oncology and onco-hematology""\, Versailles-Saint-Quentin-en-Yvelines University\, Paris-Saclay University\, France.",,,,,"Adjuvant therapy,BRAF(V600)-mutant melanoma,Immunotherapy,Targeted therapy"
33580193,"Ribeiro MFSA,Knebel FH,Bettoni F,Saddi R,Sacardo KP,Canedo FSNA,Alessi JVM,Shimada AK,Marin JFG,Camargo AA,Katz A","Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient.","The survival outcomes of the FLAURA trial support osimertinib as the new standard of care for untreated patients harboring activating mutations in the epidermal growth factor receptor (EGFR). Despite the initial response, disease progression invariably occurs. Although uncommon, BRAF V600E mutation arises as a unique mechanism of resistance, and thus far, no prospective studies are available to support concurrent EGFR/BRAF blockade. We report a case of impressive radiological and ctDNA response under dabrafenib, trametinib, and osimertinib in an advanced EGFR-mutant lung adenocarcinoma patient who developed BRAF V600E as one of the acquired resistance mechanisms to second-line osimertinib. Moreover, the patient experienced remarkable clinical improvement and good tolerance to combination therapy. The present case suggests the importance of prospective studies evaluating both efficacy and safety of the combination in later line settings and points towards the potential of ctDNA to monitor resistance mechanisms and treatment benefit in clinical practice.",NPJ precision oncology,vol.5:1:5,2021,Journal Article,,,"http://orcid.org/0000-0002-5602-164XOncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil. mauricio.fsaribeiro@hsl.org.br.,Molecular Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Molecular Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Nuclear Medicine Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,Molecular Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.,http://orcid.org/0000-0002-1811-1169Oncology Center\, Hospital Sírio-Libanês\, Rua Dona Adma Jafet\, 91\, 01308-050\, São Paulo\, SP\, Brazil.",,,,,
33580200,"Else M,Blakemore SJ,Strefford JC,Catovsky D","The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial.","Causes of death, in particular deaths due to infection, have not been widely studied in randomised trials in chronic lymphocytic leukaemia. With long-term follow-up (median 13 years) we examined the cause of death in 600/777 patients in the LRF CLL4 trial. Blood samples, taken at randomisation from 499 patients, were available for identifying gene mutations. Infection was a cause of death in 258 patients (43%). Patients dying of infection were more likely than those who died of other causes to have received ≥2 lines of treatment (194/258 [75%] versus 231/342 [68%], P = 0.04) and to have died in the winter months (149/258 [58%] versus 166/342 [49%], P = 0.03), respectively. In patients with mutation data, the factors significantly associated with death from infection versus all other deaths were 11q deletion (47/162 [29%] versus 40/209 [19%], P = 0.03) and mutations of the BRAF, FBXW7, NRAS and XPO1 genes. Death was caused by an infection in 46/67 assessable patients (69%) who had a mutation of one or more of these four genes versus only 129/333 patients (39%) without any of these mutations (odds ratio: 3.46 [95% CI 1.98-6.07] P < 0.0001). Careful management of infection risk, including prophylaxis against infection, may be important in patients who carry these mutations.",Leukemia,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0001-8578-4796Division of Molecular Pathology\, The Institute of Cancer Research\, London\, UK.,Cancer Genomics\, School of Cancer Sciences\, Faculty of Medicine\, University of Southampton\, Southampton\, UK.,http://orcid.org/0000-0002-0972-2881Cancer Genomics\, School of Cancer Sciences\, Faculty of Medicine\, University of Southampton\, Southampton\, UK.,http://orcid.org/0000-0001-6421-1075Division of Molecular Pathology\, The Institute of Cancer Research\, London\, UK. daniel.catovsky@icr.ac.uk.",,,,,
33476492,"de Azevedo SJ,de Melo AC,Roberts L,Caro I,Xue C,Wainstein A",First-line atezolizumab monotherapy in patients with advanced BRAF wild-type melanoma.,"Anti-programmed death-1 agents are an established option for advanced melanoma, but the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab, an agent approved for the treatment of multiple solid tumors, was not previously evaluated. This phase 1b study cohort (NCT03178851; cohort C) evaluated first-line atezolizumab 1,200 mg every 3 weeks in adults with BRAFV600 wild-type, histologically confirmed, advanced or metastatic melanoma. The co-primary end points were confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1 and disease control rate (DCR = complete response [CR] +partial response [PR] +stable disease [SD] at 16 weeks). Of 52 enrolled patients, most had lactate dehydrogenase levels lower than the upper limit of normal (77%) and PD-L1-positive tumors (55%). Investigator-assessed confirmed ORR was 35% (95% CI, 22%-49%) and included three CRs (6%) and 15 PRs (29%); DCR was 46%. Median investigator-assessed progression-free survival was 3.7 months (95% CI, 2.1-7.3). The most common any-grade adverse events were anemia (27%), headache (19%), hypertension (19%), constipation (17%), diarrhea (17%), hypothyroidism (17%), asthenia (15%), and pain in extremity (15%). First-line atezolizumab monotherapy is safe and tolerable and has antitumor activity in patients with BRAFV600 wild-type advanced or metastatic melanoma.",Pigment cell & melanoma research,vol.::,2021,Journal Article,,,"https://orcid.org/0000-0002-9230-4284Hospital de Clínicas de Porto Alegre\, Unidade de Pesquisa Clinica em Oncologia\, Porto Alegre\, Brazil.,Instituto Nacional de Câncer\, Rio de Janeiro\, Brazil.,Genentech/Roche\, South San Francisco\, CA\, USA.,Genentech/Roche\, South San Francisco\, CA\, USA.,Hoffmann-La Roche Limited\, Mississauga\, ON\, Canada.,Cenantron Centro Avançado de Tratamento Oncológico\, Ltda.\, Belo Horizonte\, Brazil.",,F. Hoffmann-La Roche Ltd,,No grant/award number,"antibodies,atezolizumab,immunomodulation,melanoma,monoclonal antibody"
33491923,"Reschke R,Jäger I,Mehnert-Theuerkauf A,Ziemer M",Therapy understanding and health related quality of life in stage III/IV melanoma patients treated with novel adjuvant therapies.,"Our aims were to investigate the motivation for therapy\, the understanding and valuation of potential treatment toxicities in melanoma patients offered adjuvant therapies.,Between September 2018 and September 2019 49 adjuvant patients with stage III and IV melanoma received a self-created\, pre-treatment questionnaire. Furthermore\, the patients were handed out the REPERES-G\, EQ-5D-3L and EORTC QLQ C-30 questionnaires.,Eight patients (18.3 %) decided against adjuvant therapy (mean age 71.6 years). Four of these had stage IIIA melanoma. The majority of patients (73.4 %) decided for adjuvant treatment with PD1-inhibitors despite their potential high grade\, persistent\, irreversible or even fatal toxicities. About a third of patients with BRAF V600 mutated melanoma who decided for therapy chose targeted therapy (31.3 %). These patients were younger (mean age 49 years)\, still working and had families with children. The REPERES-G questionnaire showed that our patients were generally satisfied with medical care. The average scores in the EQ-5D-3L and EORTC QLQ C-30 questionnaires indicated good subjective general health.,Despite the associated toxicities as well as the required time and effort for a one-year treatment the majority of patients decided for adjuvant treatments.",Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG,vol.19:2:215-221,2021,Journal Article,,,"Department of Dermatology\, University Medical Center Leipzig\, Leipzig\, Germany.,Department of Dermatology\, University Medical Center Leipzig\, Leipzig\, Germany.,Department of Medical Psychology and Medical Sociology\, University Medical Center Leipzig\, Leipzig\, Germany.,Department of Dermatology\, University Medical Center Leipzig\, Leipzig\, Germany.",,,,,
33582915,"Chang XN,Shang FM,Jiang HY,Chen C,Zhao ZY,Deng SH,Fan J,Dong XC,Yang M,Li Y,Cai KL,Liu L,Liu HL,Nie X",Clinicopathological Features and Prognostic Value of KRAS/NRAS/BRAF Mutations in Colorectal Cancer Patients of Central China.,"The incidence of colorectal cancer (CRC) is increasing in China, with high mortality. Here, we aimed to evaluate the latest clinicopathological features and prognostic value of the KRAS/NRAS/BRAF mutation status in CRC patients in Central China. The clinical data of 1549 CRC patients with stage I-IV disease diagnosed at Union Hospital, Tongji Medical College of Huazhong University of Science and Technology from 2015 to 2017 were collected and analyzed retrospectively. KRAS/NRAS/BRAF mutations were detected by real-time quantitative polymerase chain reaction (q-PCR) in 410 CRC patients, with mutation frequencies of KRAS, NRAS and BRAF of 47.56%, 2.93% and 4.15%, respectively. The gene mutation status and clinicopathological characteristics of 410 patients with CRC who underwent qPCR were analyzed. The KRAS and BRAF gene mutations were related to the pathological differentiation and number of metastatic lymph nodes. The BRAF gene mutation was also associated with cancer thrombosis in blood vessels. Cox regression analysis showed that there was no statistically significant difference in the overall survival (OS) between patients with KRAS, NRAS mutants and wild-type CRC patients, while the BRAF gene mutation was negatively correlated with the OS rate of CRC patients. It is suggested that the BRAF gene mutation may be an independent risk factor for the prognosis of CRC.",Current medical science,vol.41:1:118-126,2021,Journal Article,,,"Department of Pathology\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Cancer Center\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Epidemiology and Biostatistics\, the Ministry of Education Key Lab of Environment and Health\, School of Public Health\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430030\, China.,Cancer Center\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Cancer Center\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Gastrointestinal Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Pathology\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Pathology\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Pathology\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Pathology\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Gastrointestinal Surgery\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China.,Department of Epidemiology and Biostatistics\, the Ministry of Education Key Lab of Environment and Health\, School of Public Health\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430030\, China.,Cancer Center\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China. hongli_liu@hust.edu.cn.,Department of Pathology\, Union Hospital\, Tongji Medical College\, Huazhong University of Science and Technology\, Wuhan\, 430022\, China. niexiuyishi@126.com.",,,,,"BRAF mutation,KRAS mutation,NRAS mutation,colorectal cancer,prognosis"
33630242,"González Astorga B,Salvà Ballabrera F,Aranda Aguilar E,Élez Fernández E,García-Alfonso P,González Flores E,Vera García R,Fernández Montes A,López Muñoz AM,Salud Salvia A",Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept.,"Colorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient's profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.",Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico,vol.::,2021,Review,,,"Hospital Universitario Clínico San Cecilio\, Granada\, Spain.,Hospital Universitari Vall d'Hebron\, Barcelona\, Spain.,Hospital Universitario Reina Sofía\, Córdoba\, Spain.,Hospital Universitari Vall d'Hebron\, Barcelona\, Spain.,Hospital General Universitario Gregorio Marañón\, Madrid\, Spain.,Hospital Universitario Virgen de Las Nieves\, Granada\, Spain.,http://orcid.org/0000-0003-1524-3147Complejo Hospitalario de Navarra\, Navarra\, Spain. ruth.vera.garcia@navarra.es.,Complexo Hospitalario de Ourense\, Ourense\, Spain.,Hospital Universitario de Burgos\, Burgos\, Spain.,Hospital Universitari Arnau de Vilanova\, Lleida\, Spain.",,,,,"Aflibercept,BRAF,Colorectal cancer,Metastatic,Mutation,Patient profile,Patient selection,RAS,Treatment"
33087895,"Bhave P,Pallan L,Long GV,Menzies AM,Atkinson V,Cohen JV,Sullivan RJ,Chiarion-Sileni V,Nyakas M,Kahler K,Hauschild A,Plummer R,Trojaniello C,Ascierto PA,Zimmer L,Schadendorf D,Allayous C,Lebbe C,Maurichi A,Santinami M,Roy S,Robert C,Lesimple T,Patel S,Versluis JM,Blank CU,Khattak A,Van der Westhuizen A,Carlino MS,Shackleton M,Haydon A",Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.,"Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.,Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics\, adjuvant therapy\, recurrence\, treatment at relapse and outcomes were examined.,Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent)\, combination ipilimumab-nivolumab\, TT rechallenge and ipilimumab monotherapy was 63%\, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census\, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent)\, 92% for combination ipilimumab and nivolumab\, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028).,Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.",British journal of cancer,vol.124:3:574-580,2021,Journal Article,,,"http://orcid.org/0000-0001-9084-8467Department of Medical Oncology\, Alfred Hospital\, Melbourne\, VIC\, Australia. Prachi_Bhave@yahoo.com.,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.,Department of Medical Oncology\, Princess Alexandra Hospital\, Greenslopes Private Hospital and University of Queensland\, Brisbane\, QLD\, Australia.,Department of Medical Oncology\, Massachusetts General Hospital\, Boston\, MA\, USA.,Department of Medical Oncology\, Massachusetts General Hospital\, Boston\, MA\, USA.,Melanoma Oncology Unit\, Veneto Institute of Oncology-IRCCS\, Padova\, Italy.,Department of Oncology\, Oslo University Hospital\, Oslo\, Norway.,Department of Dermatology\, University Hospital Schleswig-Holstein\, Campus Kiel\, Kiel\, Germany.,Department of Dermatology\, University Hospital Schleswig-Holstein\, Campus Kiel\, Kiel\, Germany.,Northern Centre for Cancer Care\, Freeman Hospital\, Newcastle upon Tyne\, UK.,Department of Melanoma and Cancer Immunotherapy\, Istituto Nazionale Tumori IRCCS Fondazione Pascale\, Napoli\, Italy.,Department of Melanoma and Cancer Immunotherapy\, Istituto Nazionale Tumori IRCCS Fondazione Pascale\, Napoli\, Italy.,Department of Dermatology\, University Hospital Essen\, Essen & German Cancer Consortium\, Heidelberg\, Germany.,Department of Dermatology\, University Hospital Essen\, Essen & German Cancer Consortium\, Heidelberg\, Germany.,AP-HP Dermatology Department\, Saint-Louis Hospital\, Paris\, France.,AP-HP Dermatology Department\, Saint-Louis Hospital\, Paris\, France.,Department of Surgery\, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano\, Milan\, Italy.,Department of Surgery\, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano\, Milan\, Italy.,Department of Dermatology\, Gustave Roussy and Paris-Saclay Institute\, Villejuif\, France.,Department of Dermatology\, Gustave Roussy and Paris-Saclay Institute\, Villejuif\, France.,Department of Medical Oncology\, Centre Eugène Marqui\, Rennes\, France.,Department of Melanoma Medical Oncology\, MD Anderson Cancer Centre\, Houston\, TX\, USA.,Department of Medical Oncology\, Netherlands Cancer Institute\, Amsterdam\, The Netherlands.,Department of Medical Oncology\, Netherlands Cancer Institute\, Amsterdam\, The Netherlands.,Department of Medical Oncology\, Fiona Stanley Hospital\, Perth\, WA\, Australia.,Department of Medical Oncology\, Calvary Mater Hospital\, Newcastle\, NSW\, Australia.,Melanoma Institute Australia\, The University of Sydney\, Sydney\, NSW\, Australia.,Department of Medical Oncology\, Alfred Hospital\, Melbourne\, VIC\, Australia.,http://orcid.org/0000-0002-4631-5855Department of Medical Oncology\, Alfred Hospital\, Melbourne\, VIC\, Australia.",,,,,
33560745,"Lai J,Garvey KY,Li P,Azevedo RA",Primary Ovarian Melanoma Arising From a Mature Teratoma With Melanoma In Situ Present in the Ciliated Columnar and Squamous Epithelium in a Patient With Synchronous Skin Basal Cell Carcinoma.,"Primary ovarian melanoma arising from ovarian teratomas are rarely reported and difficult to accurately diagnose. Cases in the literature rely on a diagnosis of exclusion, and cases of primary ovarian melanoma with pathologic evidence of melanoma in situ are exceedingly rare. We report a case of a 66-yr-old female who presented to emergency department with abdominal pain and bloating. Computed tomography scan showed a 21 cm complex pelvic mass. An urgent laparoscopic bilateral salpingo-oophorectomy was performed. Pathologically the mass was identified as a mature teratoma. Within the cystic teratoma, there was an area showing a sheet arrangement of atypical cells. Those atypical cells were positive for Melan A, Sox10, HMB45, and c-KIT, and negative for PD-L1. Melanoma in situ was present in both the squamous and ciliated columnar epithelium. The melanoma was negative for PD-L1, and no BRAF (codon 600, exons 11, 14, and 15) or c-KIT (exons 2, 9, 10, 11, 13, 14, 15, 17, 18) mutations were identified, thus supporting the so-called triple negative malignant melanoma. A thorough dermatologic exam was conducted and only a 3 mm skin basal cell carcinoma was confirmed on biopsy. At 11 mo of follow-up, the patient is disease free and doing well and no metastatic melanoma has been identified. To the best of our knowledge, this is the first documented case of a primary ovarian melanoma arising in a mature teratoma with evidence of melanoma in situ present in both ciliated columnar and squamous epithelium in a patient with synchronous skin basal cell carcinoma. Our case is positive for c-KIT protein (CD117) by immunohistochemistry, but negative for KIT mutation. More case reports are needed to further characterize the disease.",International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists,vol.::,2021,Journal Article,,,"Departments of Pathology and Laboratory Medicine (J.L.) Obstetrics and Gynecology (K.Y.G.\, R.A.A.)\, Kaiser Permanente Sacramento Medical Center\, Sacramento\, California Department of Pathology\, University of Utah\, ARUP laboratories Inc.\, Salt Lake City\, Utah (P.L.).,,,",,,,,
33560788,"Lobo-Martins S,Pais HL,Soares-de-Almeida L,Costa L,Mansinho A,Teixeira de Sousa R",BRAF L597K mutation: an opportunity to treat.,"The outcomes of patients with metastatic melanoma (MM) have significantly improved after the introduction of BRAF-specific inhibitors. Herein is reported a patient with MM and non-V600-BRAF mutation who responded to iBRAF/iMEK therapy. In July 2014, a 63-year-old man presented with a 4.1mm-thick V600E-BRAF wild type melanoma on the back. Metastases were identified in one sentinel node and two of 11 subsequently excised lymph nodes, with no signs of distant metastatic disease. In September 2017, lung metastasis was observed and pembrolizumab was started. Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab. After four cycles, an asymmetric response was observed. In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018. Seven days after treatment start, a remarkable clinical improvement was observed. In April 2018, the patient achieved partial response, which was sustained until October 2018. Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.",Dermatology online journal,vol.27:1:,2021,Journal Article,,,"Department of Medical Oncology\, Hospital de Santa Maria-Centro Hospitalar Universitário Lisboa Norte\, Lisbon Instituto de Medicina Molecular-João Lobo Antunes\, Faculty of Medicine\, University of Lisbon\, Lisbon. slmoncology@gmail.com.,,,,,",,,,,
33562809,"Park J,Lee S,Kim K,Park H,Ki CS,Oh YL,Shin JH,Kim JS,Kim SW,Chung JH,Kim TH"," Promoter Mutations and the 8th Edition TNM Classification in Predicting the Survival of Thyroid Cancer Patients.","Our research group has previously shown that the presence of TERT promoter mutations is an independent prognostic factor, by applying the TERT mutation status to the variables of the AJCC 7th edition. This study aimed to determine if TERT mutations could be independent predictors of thyroid cancer-specific mortality based on the AJCC TNM 8th edition, with long-term follow-up. This was a retrospective study of 393 patients with pathologically confirmed differentiated thyroid carcinoma (DTC) after thyroidectomy at a tertiary Korean hospital from 1994 to 2004. The thyroid cancer-specific mortality rate was 6.9% (5.2% for papillary and 15.2% for follicular cancers). TERT promoter mutations were identified in 10.9% (43/393) of DTC cases (9.8% of papillary and 16.7% of follicular cancer) and were associated with older age (p < 0.001), the presence of extrathyroidal invasion (p < 0.001), distant metastasis (p = 0.001), and advanced stage at diagnosis (p < 0.001). The 10-year survival rate in mutant TERT was 67.4% for DTC patients (vs. 98% for wild-type; adjusted hazard ratio (HR) of 9.93, (95% CI: 3.67-26.90)) and 75% for patients with papillary cancer (vs. 99%; 18.55 (4.83-71.18)). In addition, TERT promoter mutations were related to poor prognosis regardless of histologic type (p < 0.001 for both papillary and follicular cancer) or initial stage (p < 0.001, p = 0.004, and p = 0.086 for stages I, II, and III and IV, respectively). TERT promoter mutations comprise an independent poor prognostic factor after adjusting for the clinicopathological risk factors of the AJCC TNM 8th edition, histologic type, and each stage at diagnosis, which could increase prognostic predictability for patients with DTC.",Cancers,vol.13:4:,2021,Journal Article,,,"0000-0002-7873-1458Division of Endocrinology & Metabolism\, Department of Medicine\, Thyroid Center\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Department of Digital Health\, Samsung Advanced Institute for Health Sciences & Technology\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Department of Digital Health\, Samsung Advanced Institute for Health Sciences & Technology\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Division of Endocrinology & Metabolism\, Department of Medicine\, Thyroid Center\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Green Cross Genome\, Yongin 16924\, Korea.,0000-0002-9563-5046Department of Pathology\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Department of Radiology\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Department of Surgery\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Division of Endocrinology & Metabolism\, Department of Medicine\, Thyroid Center\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,Division of Endocrinology & Metabolism\, Department of Medicine\, Thyroid Center\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.,0000-0002-7975-2437Division of Endocrinology & Metabolism\, Department of Medicine\, Thyroid Center\, Samsung Medical Center\, School of Medicine\, Sungkyunkwan University\, Seoul 06351\, Korea.",,Samsung Medical Center,,OTA1810531,"BRAF,TERT promoter,differentiated thyroid cancer,mortality,prognosis"
33576854,"Schmitz-Dräger BJ,Skutetzki A,Rieker RJ,Schwab SA,Stöhr R,Bismarck E,Savov O,Ebert T,Benderska-Söder N,Hartmann A",Eosinophilic cystitis mimicking bladder cancer-considerations on the management based upon a case report and a review of the literature.,"The hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and infiltration of various organs with eosinophils. Eosinophilic cystitis (EC), mimicking bladder cancer clinically but also in ultrasound and in radiographic imaging, is one potential manifestation of the HES occurring in adults as well as in children. This case report describes the course of disease in a 57-year-old male presenting with severe gait disorders and symptoms of a low compliance bladder caused by a large retropubic tumor. After extensive urine and serologic examination and histologic confirmation of EC the patient was subjected to medical treatment with cetirizine and prednisolone for 5 weeks. While gait disorders rapidly resolved, micturition normalized only 10 months after initiation of therapy. Based upon this course the authors recommend patience and reluctance concerning radical surgical intervention in EC. Key Points • Eosinophilic cystitis is a rare condition with app. 200 cases reported, so far. • Etiology of eosinophilic cystitis is obscure, but allergies and parasitic infections may trigger the disease. • Genetic alterations (e.g., BRAF mutations) may predispose for the disease • Corticosteroids and antihistamines are the backbone of therapy and may be complemented by antibiotics and non-steroidal anti-inflammatory drugs in case of concomitant (underlying) infections. • As recovery can occur even after a long time, radical surgery should be restricted to highly selected cases.",Virchows Archiv : an international journal of pathology,vol.::,2021,Journal Article,,,"http://orcid.org/0000-0002-4004-1857St. Theresienkrankenhaus\, Nürnberg\, Urologie 24\, Nuremberg\, Germany. bernd_sd@yahoo.de.,Department of Trauma Surgery and Orthopedic Surgery\, Friedrich-Alexander University Erlangen-Nuremberg\, University Hospital Erlangen\, Erlangen\, Germany.,Department of Pathology\, St. Theresienkrankenhaus\, Nuremberg\, Germany.,Radiologis\, Dr. Meer und Kollegen\, Oberasbach-Nuremberg\, Zirndorf\, Germany.,Institute of Pathology\, Friedrich-Alexander University Erlangen-Nuremberg\, University Hospital Erlangen\, Erlangen\, Germany.,St. Theresienkrankenhaus\, Nürnberg\, Urologie 24\, Nuremberg\, Germany.,St. Theresienkrankenhaus\, Nürnberg\, Urologie 24\, Nuremberg\, Germany.,St. Theresienkrankenhaus\, Nürnberg\, Urologie 24\, Nuremberg\, Germany.,St. Theresienkrankenhaus\, Nürnberg\, Urologie 24\, Nuremberg\, Germany.,Institute of Pathology\, Friedrich-Alexander University Erlangen-Nuremberg\, University Hospital Erlangen\, Erlangen\, Germany.",,,,,"Bladder tumor,Eosinophilic cystitis,Hypereosinophilic syndrome,Inflammatory pseudotumor"
33617147,"Persa OD,Fromme JE,Mauch C",Sequencing of immunotherapy and targeted therapy for BRAF mutated melanoma: a retrospective study.,,Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG,vol.::,2021,Letter,,,"Department of Dermatology and Venereology\, Cologne University Hospital\, Germany.,Department of Dermatology and Venereology\, Cologne University Hospital\, Germany.,Department of Dermatology and Venereology\, Cologne University Hospital\, Germany.",,,,,
33461766,"Venkatesh A,Joshi A,Allinson K,Das T,Santarius T,Jefferies SJ,Harris FP,Jena R,Doherty GJ",Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: A Case Report and Literature Review.,"Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.",Current problems in cancer,vol.::100701,2021,Case Reports,,,"School of Clinical Medicine\, University of Cambridge\, Cambridge Biomedical Campus\, Cambridge\, UK.,School of Clinical Medicine\, University of Cambridge\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Histopathology and Cytology\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Radiology\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Neurosurgery\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Oncology\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Oncology\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Oncology\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK; Department of Oncology\, University of Cambridge\, Cambridge Biomedical Campus\, Cambridge\, UK.,Department of Oncology\, Addenbrooke's Hospital\, Cambridge University Hospitals NHS Foundation Trust\, Cambridge Biomedical Campus\, Cambridge\, UK. Electronic address: gary.doherty@addenbrookes.nhs.uk.",,,,,"BRAF V600E mutation,Epithelioid glioblastoma multiforme,dabrafenib,targeted therapies,trametinib"
33166576,"Gupta S,Cheville JC,Galeano BK,Sukov WR,Herrera-Hernandez L,Reed KA,Lohse CM,Thompson RH,Boorjian SA,Leibovich BC,Jimenez RE",Renal neoplasia with papillary architecture involving the pelvicalyceal system.,"Pelvicalyceal system (PS) involvement by renal cell carcinoma (RCC) is staged as pT3a disease (American Joint Committee on Cancer [AJCC], 8th edition). As papillary RCC (PRCC) has been infrequently represented in studies looking at the prognostic impact of PS involvement, we reviewed our institutional cohort of 8225 cases for PS involvement by PRCC. Nine such cases were subjected to histopathologic review and immunohistochemistry. Fluorescence in situ hybridization for TFE3/TFEB alterations was performed if indicated. One case each (1 of 9, 11%) was classified as TFE3-rearranged and FH-deficient RCC. The majority were high grade (World Health Organization/International Society of Urologic Pathology grade 3: 8 of 9, 89%) or had features of aggressive disease, including hilar fat (6 of 9, 67%) and regional lymph node involvement (5 of 7, 71%). One low-grade 3.3-cm tumor with isolated PS involvement with a germline heterozygous FH p.Lys477dup alteration with retained FH, lack of increased S-(2-succino)-cysteine expression, BRAF V600E immunohistochemistry positivity, and lack of trisomy 7/17 on chromosomal microarray was identified, arguing against an FH-deficient and conventional PRCC. Our study shows that PS involvement by renal neoplasia with papillary architecture is a rare event. Aside from PRCC, it is important to note that these may include other aggressive and nonaggressive subtypes of renal neoplasia with papillary architecture. One case of isolated PS involvement by a low-grade, noninvasive tumor that we refer to as nephrogenic papillary neoplasm was identified. At present, there are insufficient data to stage such tumors as pT3a (AJCC, 8th edition), and additional studies are needed to address this question.",Human pathology,vol.107::46-57,2021,Journal Article,,,"Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA. Electronic address: gupta.sounak@mayo.edu.,Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Health Sciences Research\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Urology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Urology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Urology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.,Department of Laboratory Medicine and Pathology\, Mayo Clinic\, Rochester\, 55905\, MN\, USA.",,,,,"BRAF p.V600E–mutated RCC,FH p.Lys477dup,Nephrogenic papillary renal neoplasia,Papillary renal cell carcinoma,Pelvicalyceal system,Staging"
33271567,"Kashihara T,Muguruma N,Fujimoto S,Miyamoto Y,Sato Y,Takayama T",Recent Advances in Molecular Imaging of Colorectal Tumors.,"Recent endoscopic studies have revealed that small colorectal tumors are often overlooked during colonoscopy\, indicating that more sensitive detection methods are needed.,Molecular imaging has received considerable attention as a new endoscopic technique with high sensitivity. It generally employs a fluorescence-labeled compound that specifically binds to a molecule on the tumor. Fluorescent probes for molecular imaging are largely classified as 2 types: a fluorescence-labeled antibody targeting a molecule specifically expressed on the tumor cell surface such as epidermal growth factor receptor or vascular endothelial growth factor (VEGF); and a fluorescence-labeled small molecule compound targeting a molecule specifically expressed in tumor cells including c-Met\, glutathione S-transferase\, γ-glutamyltranspeptidase\, cathepsin\, or endothelin A receptor. These probes successfully detected colorectal tumors in several animal studies. Moreover\, 3 recent human clinical trials evaluating endoscopic molecular imaging for colorectal tumors have been reported. In one study\, a Cy5-labeled synthetic peptide against c-Met was developed\, and fluorescent endoscopic observation with this probe detected a greater number of colorectal adenomas than with white light observation. Another trial used IR800-labeled anti-VEGF antibody\, which sensitively detected human colorectal adenomas by fluorescent endoscopy. Last\, a fluorescent probe with synthetic peptide against BRAF-positive cells was able to visualize sessile serrated lesions. The fluorescent probes accumulated at very high levels in colorectal tumor cells but at lower levels in surrounding nonneoplastic mucosa. Key Messages: We expect that molecular imaging techniques with fluorescent probes will soon lead to the establishment of a highly sensitive endoscopic method for colorectal tumor detection.",Digestion,vol.102:1:57-64,2021,Review,,,"Department of Gastroenterology and Oncology\, Institute of Biomedical Sciences\, Tokushima University Graduate School\, Tokushima\, Japan.,Department of Gastroenterology and Oncology\, Institute of Biomedical Sciences\, Tokushima University Graduate School\, Tokushima\, Japan.,Department of Gastroenterology and Oncology\, Institute of Biomedical Sciences\, Tokushima University Graduate School\, Tokushima\, Japan.,Department of Gastroenterology and Oncology\, Institute of Biomedical Sciences\, Tokushima University Graduate School\, Tokushima\, Japan.,Department of Gastroenterology and Oncology\, Institute of Biomedical Sciences\, Tokushima University Graduate School\, Tokushima\, Japan.,Department of Gastroenterology and Oncology\, Institute of Biomedical Sciences\, Tokushima University Graduate School\, Tokushima\, Japan\, takayama@tokushima-u.ac.jp.",,,,,"Colorectal cancer,Fluorescence endoscopy,Molecular imaging"
33476722,"Basolo A,Matrone A,Elisei R,Santini F",Effects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism.,"The increasing knowledge of the molecular mechanisms in the cell signaling pathways of malignant cells, has recently led to the discovery of several tyrosine kinases (TKs), mainly TK receptors (TKR), which play a major role in the pathogenesis of many types of cancer. These receptors, physiologically involved in cell growth and angiogenesis, may harbor mutations or be overexpressed in malignant cells, and represent a target for anticancer therapy. Indeed, several therapeutic agents targeting specific altered pathways such as RET, BRAF, RAS, EGFR and VEGFR, have been identified. Tyrosine kinase inhibitors (TKIs) affect TK dependent oncogenic pathways by competing with ATP binding sites of the TK domain, thus blocking the activity of the enzyme, and thereby inhibiting the growth and spread of several cancers. Although the therapeutic action may be very effective, these molecules, due to their mechanism of multitargeted inhibition, may produce adverse events involving several biological systems. Both hypothyroidism and thyrotoxicosis have been reported during treatment with TKI, as well as an effect on the activity of enzymes involved in thyroid hormone metabolism. The pathogenic mechanisms leading to thyroid dysfunction and changes in serum thyroid function tests occurring in patients on TKI are reviewed and discussed in this manuscript.",Seminars in cancer biology,vol.::,2021,Review,,,"Department of Clinical and Experimental Medicine\, Endocrinology Unit\, University Hospital of Pisa\, Via Paradisa 2\, 56124\, Pisa\, Italy. Electronic address: alessio.basolo@med.unipi.it.,Department of Clinical and Experimental Medicine\, Endocrinology Unit\, University Hospital of Pisa\, Via Paradisa 2\, 56124\, Pisa\, Italy. Electronic address: antonio.matrone@med.unipi.it.,Department of Clinical and Experimental Medicine\, Endocrinology Unit\, University Hospital of Pisa\, Via Paradisa 2\, 56124\, Pisa\, Italy. Electronic address: rossella.elisei@med.unipi.it.,Department of Clinical and Experimental Medicine\, Endocrinology Unit\, University Hospital of Pisa\, Via Paradisa 2\, 56124\, Pisa\, Italy. Electronic address: ferruccio.santini@med.unipi.it.",,,,,"Deiodinases,Hypothyroidism,Thyroid dysfunction,Thyroid hormone metabolism,Thyrotoxicosis,Tyrosine kinase inhibitors"
33522658,"Maeda Y,Tidyman WE,Ander BP,Pritchard CA,Rauen KA",Ras/MAPK Dysregulation in Development Causes a Skeletal Myopathy in an Activating Braf Mouse Model for Cardio-facio-cutaneous Syndrome.,"Cardio-facio-cutaneous syndrome (CFC) is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF\, MEK1 or MEK2\, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies\, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC\, a mouse model with an activating BrafL597V allele was utilized.,The activating BrafL597V allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which lead to a reduction in muscle size which are functionally weaker. MAPK pathway activation caused inhibition of myofiber differentiation during embryonic myogenesis and global transcriptional dysregulation of developmental pathways. Inhibition in differentiation can be rescued by MEK inhibition.,A skeletal myopathy was identified in the CFC BrafL597V mouse validating the use of models to study the effect of Ras/MAPK dysregulation on skeletal myogenesis. RASopathies present a novel opportunity to identify new paradigms of myogenesis and further our understanding of Ras in development. Rescue of the phenotype by inhibitors may help advance the development of therapeutic options for RASopathy patients. This article is protected by copyright. All rights reserved.",Developmental dynamics : an official publication of the American Association of Anatomists,vol.::,2021,Journal Article,,,"Department of Pediatrics\, University of California Davis\, Sacramento\, CA\, USA.,Department of Pediatrics\, University of California Davis\, Sacramento\, CA\, USA.,UC Davis MIND Institute\, Sacramento\, CA\, USA.,Leicester Cancer Research Centre\, University of Leicester\, UK.,https://orcid.org/0000-0003-1719-7228Department of Pediatrics\, University of California Davis\, Sacramento\, CA\, USA.",,,,,"Hypotonia,MEK inhibitor,RASopathies,Ras/MAPK,p38 MAPK"
33545343,"Banach K,Kowalska J,Rzepka Z,Beberok A,Rok J,Wrześniok D",The role of UVA radiation in ketoprofen-mediated BRAF-mutant amelanotic melanoma cells death - A study at the cellular and molecular level.,"Malignant melanoma is the cause of 80% of deaths in skin cancer patients. Treatment of melanoma in the 4th stage of clinical advancement, in which inoperable metastasis occur, does not provide sufficient effects. Ketoprofen has phototoxic properties and it can be used as a new treatment option for skin cancers as a part of photochemotherapy. The present study was designed to investigate whether ketoprofen in combination with UVA induces cytotoxic, anti-proliferative and pro-apoptotic effects on melanoma cells. It was stated that co-treatment with 1.0 mM ketoprofen and UVA irradiation disturbed homeostasis of C32 melanoma cells by lowering its vitality (decrease of GSH level). Contrary to C32 cells, melanocytes showed low sensitivity to ketoprofen and UVA radiation, pointing selectivity in the mode of action towards melanoma cells. Co-treatment with ketoprofen and UVA irradiation has cytotoxic and anti-proliferative and pro-apoptotic effect on C32. The co-treatment triggered the DNA fragmentation and changed the cell cycle in C32 cells. In conclusion, it could be stated that local application of ketoprofen in combination with UVA irradiation may be used to support the treatment of melanoma and creates the possibility of reducing the risk of cancer recurrence and metastasis.",Toxicology in vitro : an international journal published in association with BIBRA,vol.72::105108,2021,Journal Article,,,"Medical University of Silesia\, Faculty of Pharmaceutical Sciences in Sosnowiec\, Department of Pharmaceutical Chemistry\, Jagiellońska 4\, 41-200 Sosnowiec\, Poland.,Medical University of Silesia\, Faculty of Pharmaceutical Sciences in Sosnowiec\, Department of Pharmaceutical Chemistry\, Jagiellońska 4\, 41-200 Sosnowiec\, Poland.,Medical University of Silesia\, Faculty of Pharmaceutical Sciences in Sosnowiec\, Department of Pharmaceutical Chemistry\, Jagiellońska 4\, 41-200 Sosnowiec\, Poland.,Medical University of Silesia\, Faculty of Pharmaceutical Sciences in Sosnowiec\, Department of Pharmaceutical Chemistry\, Jagiellońska 4\, 41-200 Sosnowiec\, Poland.,Medical University of Silesia\, Faculty of Pharmaceutical Sciences in Sosnowiec\, Department of Pharmaceutical Chemistry\, Jagiellońska 4\, 41-200 Sosnowiec\, Poland.,Medical University of Silesia\, Faculty of Pharmaceutical Sciences in Sosnowiec\, Department of Pharmaceutical Chemistry\, Jagiellońska 4\, 41-200 Sosnowiec\, Poland. Electronic address: dwrzesniok@sum.edu.pl.",,,,,"GSH,Ketoprofen,Melanoma,UVA"
32340435,"Satorres C,García-Campos M,Bustamante-Balén M",Molecular Features of the Serrated Pathway to Colorectal Cancer: Current Knowledge and Future Directions.,"Serrated lesions are the precursor lesions of a new model of colorectal carcinogenesis. From a molecular standpoint, the serrated pathway is thought to be responsible for up to 30% of all colorectal cancer cases. The three major processes of this molecular mechanism are alterations in the mitogen-activated protein kinase pathway, production of the CpG island methylation phenotype, and generation of microsatellite instability. Other contributing processes are activation of WNT, alterations in the regulation of tumor suppressor genes, and alterations in microRNAs or in MUC5AC hypomethylation. Although alterations in the serrated pathway also contribute, their precise roles remain obscure because of the various methodologies and definitions used by different research groups. This knowledge gap affects clinical assessment of precursor lesions for their carcinogenic risk. The present review describes the current literature reporting the molecular mechanisms underlying each type of serrated lesion and each phenotype of serrated pathway colorectal cancer, identifying those areas that merit additional research. We also propose a unified serrated carcinogenesis pathway combining molecular alterations and types of serrated lesions, which ends in different serrated pathway colorectal cancer phenotypes depending on the route followed. Finally, we describe some key issues that need to be addressed in order to incorporate the newest technologies in serrated pathway research and to improve overall knowledge for developing specific prevention strategies and new therapeutic targets.",Gut and liver,vol.15:1:31-43,2021,Review,,,"https://orcid.org/0000-0002-1442-634XGastrointestinal Endoscopy Research Group\, La Fe Health Research Institute\, Valencia\, Spain.,https://orcid.org/0000-0002-9496-223XGastrointestinal Endoscopy Unit\, Digestive Diseases Department\, La Fe Polytechnic University Hospital\, Valencia\, Spain.,https://orcid.org/0000-0003-2019-0158Gastrointestinal Endoscopy Research Group\, La Fe Health Research Institute\, Valencia\, Spain.",,,,,"BRAF,Carcinogenesis,Colorectal,Molecular biology,Polyps"
32567790,"Tran KB,Gimenez G,Tsai P,Kolekar S,Rodger EJ,Chatterjee A,Jabed A,Shih JH,Joseph WR,Marshall ES,Wang Q,Print CG,Eccles MR,Baguley BC,Shepherd PR",Genomic and signalling pathway characterization of the NZM panel of melanoma cell lines: A valuable model for studying the impact of genetic diversity in melanoma.,"Melanoma is a disease associated with a very high mutation burden and thus the possibility of a diverse range of oncogenic mechanisms that allow it to evade therapeutic interventions and the immune system. Here, we describe the characterization of a panel of 102 cell lines from metastatic melanomas (the NZM lines), including using whole-exome and RNA sequencing to analyse genetic variants and gene expression changes in a subset of this panel. Lines possessing all major melanoma genotypes were identified, and hierarchical clustering of gene expression profiles revealed four broad subgroups of cell lines. Immunogenotyping identified a range of HLA haplotypes as well as expression of neoantigens and cancer-testis antigens in the lines. Together, these characteristics make the NZM panel a valuable resource for cell-based, immunological and xenograft studies to better understand the diversity of melanoma biology and the responses of melanoma to therapeutic interventions.",Pigment cell & melanoma research,vol.34:1:136-143,2021,Journal Article,,,"Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery\, Auckland\, New Zealand.,Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery\, Auckland\, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery\, Auckland\, New Zealand.,Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Auckland Cancer Society Research Centre\, University of Auckland\, Auckland\, New Zealand.,Auckland Cancer Society Research Centre\, University of Auckland\, Auckland\, New Zealand.,Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery\, Auckland\, New Zealand.,Auckland Cancer Society Research Centre\, University of Auckland\, Auckland\, New Zealand.,https://orcid.org/0000-0001-9742-5811Department of Molecular Medicine and Pathology\, University of Auckland\, Auckland\, New Zealand.",,"Auckland and Northland Branch of the Cancer Society of New Zealand,Health Research Council of New Zealand,Maurice Wilkins Centre for Molecular Biodiscovery",",,",,"BRAF,CTTNB1,KRAS,NF1,NRAS,PDGFRA,PIK3CA,cancer,immunotherapy,melanoma,molecular subtypes,neoantigen,testis antigen"
32881028,Kossard S,"Keratoacanthoma, committed stem cells and neoplastic aberrant infundibulogenesis integral to formulating a conceptual model for an infundibulocystic pathway to squamous cell carcinoma.","Keratoacanthomas (KAs) are distinctive tumors that are defined by their clinical and histopathological features. Their relationship and distinction from squamous cell carcinoma (SCC), however, remain controversial. All cytogenic and immunohistochemical markers that have been applied in this quest have failed. A close relationship of KAs to hair follicles has been recognized. The descriptive term infundibulocystic or infundibular SCC was introduced to define a more broad-based pathway encompassing KAs. The follicular infundibulum roles in respect to neoplasia and wound healing are important elements in understanding the pathogenesis of KAs. Mouse models for KA have provided insights into the relationship of KA to follicles and SCCs. These advances and together with the diverse clinical and histopathological aspects of KA have contributed to the formulation of a conceptual pathway. The central element is that ultraviolet (UV)-mutated or activated committed infundibular stem cells are driven by the combination of a mutated oncogenic RAS pathway linked with the Wnt/beta-catenin pathway responsible for stem cell maintenance, hair follicle development, wound healing and driving KA proliferation and terminal keratinization. The existence and activation of this mutated pathway may form the basis of the paradoxical emergence of KAs and SCCs in patients receiving BRAF and PD-1 inhibitor therapy.",Journal of cutaneous pathology,vol.48:1:184-191,2021,Review,,,"https://orcid.org/0000-0002-9607-5925Kossard Dermatopathologists, Laverty Pathology, Macquarie Park, New South Wales, Australia.",,,,,"BRAF inhibitors,PD-1 inhibitors,infundibulocystic,keratoacanthoma,squamous cell carcinoma,stem cells"
32936899,"Zhi J,Zhang P,Zhang W,Ruan X,Tian M,Guo S,Zhang W,Zheng X,Zhao L,Gao M",Inhibition of BRAF Sensitizes Thyroid Carcinoma to Immunotherapy by Enhancing tsMHCII-mediated Immune Recognition.,"Multiple mechanisms play roles in restricting the ability of T-cells to recognize and eliminate tumor cells.,To identify immune escape mechanisms involved in papillary thyroid carcinoma (PTC) to optimize immunotherapy.,iTRAQ analysis was conducted to identify proteins differentially expressed in PTC samples with or without BRAFV600E mutation. Molecular mechanisms regulating tumor cell evasion were investigated by in vitro modulations of BRAF/MAPK and related pathways. The pathological significance of identified tumor-specific major histocompatibility complex class II (tsMHCII) molecules in mediating tumor cell immune escape and targeted immune therapy was further evaluated in a transgenic mouse model of spontaneous thyroid cancer.,Proteomic analysis showed that tsMHCII level was significantly lower in BRAFV600E-associated PTCs and negatively correlated with BRAF mutation status. Constitutive activation of BRAF decreased tsMHCII surface expression on tumor cells\, which inhibited activation of CD4+ T-cells and led to immune escape. Pathway analysis indicated that the transforming growth factor (TGF)-β1/SMAD3-mediated repression of tsMHCII\, which could be reversed by BRAF inhibition (BRAFi). Targeting this pathway with a combined therapy of BRAF inhibitor PLX4032 and anti-PD-1 antibody efficiently blocked tumor growth by increasing CD4+ T-cell infiltration in a transgenic PTC mouse model.,Our results suggest that BRAFV600E mutation in PTC impairs the expression of tsMHCII through the TGF-β1/SMAD3 pathway to enhance immune escape. Combined treatment with PLX4032 and anti-PD-1 antibody promotes recognition and elimination of PTC by the immune system in a pre-clinical mouse model\, and therefore offers an effective therapeutic strategy for patients with advanced PTC.",The Journal of clinical endocrinology and metabolism,vol.106:1:91-107,2021,Journal Article,,,"Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.,Department of Biochemistry and Molecular Biology\, School of Basic Medical Sciences\, Tianjin Medical University\, Tianjin\, People's Republic of China.,Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.,Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.,Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.,Department of Medical Genetics\, University of Wisconsin-Madison\, Madison\, Wisconsin.,State Key Laboratory of Medicinal Chemical Biology\, Nankai University\, Tianjin\, People's Republic of China.,Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.,Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.,Department of Thyroid and Neck Tumor\, Tianjin Medical University Cancer Institute and Hospital\, National Clinical Research Center for Cancer\, Key Laboratory of Cancer Prevention and Therapy\, Tianjin's Clinical Research Center for Cancer\, Tianjin\, People's Republic of China.",,,,,"BRAFV600E,MHC-II,immunotherapy immune escape,papillary thyroid carcinoma"
33526222,"Hsieh MS,Bishop JA,Yu Fong Chang J",Sialadenoma Papilliferum.,"Sialadenoma papilliferum (SP) is a rare, benign salivary gland neoplasm sharing similar histopathologic features and harboring the same genetic alterations, BRAF V600E or HRAS mutations, with syringocystadenoma papilliferum. SP most commonly occurs in the hard palate and in older adults. Clinically, SP is most likely to be diagnosed as a squamous papilloma. Microscopically, SP shows an exophytic papillary epithelial proliferation and a contiguously endophytic ductal proliferation. Two distinct subtypes are identified: classic SP and oncocytic SP. Conservative surgical treatment seems to be adequate with a low recurrence. SOX10 immunohistochemistry and BRAF analysis may be useful in differential diagnosis.",Surgical pathology clinics,vol.14:1:43-51,2021,Review,,,"Department of Pathology\, National Taiwan University Hospital\, No 7\, Chung-Shan South Road\, Taipei 100\, Taiwan; Graduate Institute of Pathology\, National Taiwan University College of Medicine\, Taipei\, Taiwan.,Department of Pathology\, University of Texas Southwestern Medical Center\, 5323 Harry Hines Boulevard\, Dallas\, TX 75390\, USA.,Department of Dentistry\, National Taiwan University Hospital\, No. 1\, Changde Street\, Zhongzheng District\, Taipei City 100\, Taiwan; Department of Dentistry\, Graduate Institute of Clinical Dentistry\, School of Dentistry\, National Taiwan University\, Taipei\, Taiwan. Electronic address: jyfchang@ntu.edu.tw.",,,,,"BRAF V600E mutation,Classic,HRAS Q61R mutation,Oncocytic,Sialadenoma papilliferum"
33527115,"Abi-Raad R,Prasad ML,Zheng J,Hui P,Ustun B,Schofield K,Cai G,Adeniran AJ",Prognostic Assessment of BRAF Mutation in Preoperative Thyroid Fine-Needle Aspiration Specimens.,"We investigate the potential role of BRAF testing in guiding surgical intervention in papillary thyroid carcinoma (PTC).,Thyroid fine-needle aspiration (FNA) cases with available BRAF result and follow-up thyroidectomy for PTC were included in the study. Cytology and surgical diagnoses were correlated with BRAF status.,There were 151 cases of thyroid FNA specimens with BRAF testing (70 mutant and 81 wild-type BRAF) and histologically confirmed unilateral\, unifocal PTCs. There were no differences in age\, sex\, tumor size\, or lymphovascular invasion on thyroidectomy specimens between mutant and wild-type BRAF cases. BRAF mutation was significantly associated with cytology diagnosis (P < .001)\, PTC subtype (P < .001)\, extrathyroidal extension (ETE) (P = .006)\, and higher tumor (T) stage (P = .04). However\, an analysis within the histologic subtypes of PTC revealed no significant association between BRAF mutation and ETE or higher T stage. There was also no difference in central (P = .847) or lateral (p = 1) neck lymph node (LN) metastasis.,BRAF mutation identified in thyroid FNA specimens correlates with histologic subtypes but is not an independent factor for predicting PTC biological behavior and should not be used to guide the extent of LN dissection.",American journal of clinical pathology,vol.::,2021,Journal Article,,,"Department of Pathology\, Yale University School of Medicine\, New Haven\, CT\, USA.,Department of Pathology\, Yale University School of Medicine\, New Haven\, CT\, USA.,Clinical Research Center\, Wenzhou Medical University\, Wenzhou\, Zhejiang\, China.,Department of Pathology\, Yale University School of Medicine\, New Haven\, CT\, USA.,Department of Pathology\, Montefiore Medical Center\, New York\, NY\, USA.,Department of Pathology\, Yale University School of Medicine\, New Haven\, CT\, USA.,Department of Pathology\, Yale University School of Medicine\, New Haven\, CT\, USA.,Department of Pathology\, Yale University School of Medicine\, New Haven\, CT\, USA.",,,,,"\n BRAF\n ,Fine-needle aspiration,Lymph node metastasis,Papillary thyroid carcinoma (PTC),Prognostic factors"
33197299,"Woischke C,Jung P,Jung A,Kumbrink J,Eisenlohr S,Auernhammer CJ,Vieth M,Kirchner T,Neumann J",Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity.,"We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and β-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of de-differentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).",The journal of pathology. Clinical research,vol.7:1:75-85,2021,Journal Article,,,"https://orcid.org/0000-0003-1804-5904Institute of Pathology\, Medical Faculty\, Ludwig-Maximilians-Universität München\, Munich\, Germany.,Institute of Pathology\, Medical Faculty\, Ludwig-Maximilians-Universität München\, Munich\, Germany.,Institute of Pathology\, Medical Faculty\, Ludwig-Maximilians-Universität München\, Munich\, Germany.,Institute of Pathology\, Medical Faculty\, Ludwig-Maximilians-Universität München\, Munich\, Germany.,Practice of Pathology\, Munich\, Germany.,Medizinische Klinik und Poliklinik 4\, Klinikum der Universität München\, Ludwig-Maximilians-Universität München\, Munich\, Germany.,Institute of Pathology\, Klinikum Bayreuth\, Bayreuth\, Germany.,Institute of Pathology\, Medical Faculty\, Ludwig-Maximilians-Universität München\, Munich\, Germany.,Institute of Pathology\, Medical Faculty\, Ludwig-Maximilians-Universität München\, Munich\, Germany.",,,,,"FBXW7,colorectal cancer,distinct entity,mutations,neuroendocrine carcinoma,squamous cell carcinoma"
33084375,"Pavlick AC,Zhao R,Lee CH,Ritchings C,Rao S",First-line immunotherapy versus targeted therapy in patients with -mutant advanced melanoma: a real-world analysis.,"Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.","Future oncology (London, England)",vol.17:6:689-699,2021,Journal Article,,,"https://orcid.org/0000-0001-7088-0742Weill Cornell Medical Center\, New York\, NY 10021\, USA.,Bristol Myers Squibb\, Princeton\, NJ 08540\, USA.,Bristol Myers Squibb\, Princeton\, NJ 08540\, USA.,Bristol Myers Squibb\, Princeton\, NJ 08540\, USA.,Bristol Myers Squibb\, Princeton\, NJ 08540\, USA.",,Bristol Myers Squibb,,,"BRAF and MEK inhibitors,advanced melanoma,nivolumab plus ipilimumab,real-world study"
33210163,"Nassar A,Phelip JM,Goéré D,Loriau J,Gallois C,Michel P,Penna C,Taieb J,Brouquet A,Benoist S",What is the Best Therapeutic Strategy for Metachronous Resectable Colorectal Liver Metastases After Adjuvant Oxaliplatin-Based Chemotherapy? A Multidisciplinary Inter-Group Survey.,"To report the current clinical practice of French physicians for metachronous resectable liver metastasis (LM) occurring after a FOLFOX adjuvant chemotherapy for primary cancer.,Twenty four clinical situations were proposed to a panel of experts via 4 learned societies. Clinical situations varied according time of recurrence (early between 6 and 12 month or > 12 month)\, extension of LM (limited ≤ 2 or extended > 2 lesions)\, presence of a neuropathy or not\, and of a RAS or BRAF mutation.,A total of 157 physicians participated in this study. A consensus was reached in 17 (71%) clinical situations. For an early limited recurrence\, whatever presence of neuropathy\, the preferred therapeutic approach (45%) was upfront surgery. For an early extended recurrence\, whatever presence of neuropathy\, there was a consensus (64%) for a preoperative chemotherapy by FOLFIRI + biologic agent. For a late recurrence without neuropathy\, there was a consensus (50%) for a preoperative FOLFOX chemotherapy\, whatever the extension of LM. For a late recurrence with neuropathy\, upfront surgery was chosen (52%) for limited LM\, and preoperative chemotherapy by FOLFIRI + biologic agent (73%) for extended LM. No response was influenced by the RAS mutation status. There was a strong consensus for intensified preoperative chemotherapy in all clinical situations for BRAF-mutated LM.,This national survey provides an overview of the practice patterns in the treatment of LM occurring after adjuvant FOLFOX for primary. It could be a basis to establish expert's recommendations for the clinical practice.",World journal of surgery,vol.45:3:822-830,2021,Journal Article,,,"Department of Digestive Surgery and Surgical Oncology\, Bicêtre Hospital\, APHP\, Le Kremlin Bicêtre\, France.,Department of Hepato-Gastroenterology and Digestive Oncology\, St Etienne University Hospital\, St Etienne\, France.,Department of Digestive Surgery\, Saint Louis Hospital\, APHP\, Paris\, France.,Department of Digestive Surgery\, St-Joseph Hospital\, Paris\, France.,Department of Gastroenterology\, Hôpital Européen Georges-Pompidou\, APHP\, Paris\, France.,Department of Hepato-Gastroenterology\, Rouen University Hospital\, Rouen\, France.,Department of Digestive Surgery and Surgical Oncology\, Bicêtre Hospital\, APHP\, Le Kremlin Bicêtre\, France.,Department of Gastroenterology\, Hôpital Européen Georges-Pompidou\, APHP\, Paris\, France.,Department of Digestive Surgery and Surgical Oncology\, Bicêtre Hospital\, APHP\, Le Kremlin Bicêtre\, France.,Department of Digestive Surgery and Surgical Oncology\, Bicêtre Hospital\, APHP\, Le Kremlin Bicêtre\, France. stephane.benoist@aphp.fr.",,,,,
33225752,Specenier P,Cost-effectiveness of nivolumab in advanced melanoma: a drug review.,"Introduction: The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma. Areas covered: This is a narrative review of the published evidence on nivolumab in metastatic melanoma. Expert opinion: In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab-ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511). In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.",Expert review of pharmacoeconomics & outcomes research,vol.21:1:13-28,2021,Journal Article,,,"Department of Oncology, Antwerp University Hospital, Belgium and Faculty of Medicine and Health Sciences , Edegem, Wilrijk, Belgium.",,,,,"Advanced,anti-PD-1,checkpoint inhibitors,melanoma,metastatic,nivolumab,pembrolizumab"
33368052,"Dulgar O,Kutuk T,Eroglu Z",Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies.,"About half of all cutaneous melanomas harbor activating mutations in the BRAF oncogene. Dependence on this pathway makes the tumors vulnerable to BRAF (and downstream MEK) inhibition, and three drug combinations are approved to target this vulnerability in advanced melanomas with BRAFV600 mutations. Responses to BRAF/MEK inhibitors are usually fast, but durability of response can be limited. Five-year data from BRAF/MEK inhibitors show long-term survival benefit for a third of the patients. There is a wide variety of known mechanisms of resistance to BRAF/MEK inhibition, such as mitogen-activated protein kinase reactivation, activation of parallel pathways, alterations in cell-cycle regulation, and non-genetic resistance mechanisms. Strategies that have been explored to overcome these mechanisms include alternative dosing regimens, addition of another kinase inhibitor, and use of anti-PD-1 immunotherapy either in combination or post-relapse on BRAF/MEK inhibitor therapies.",American journal of clinical dermatology,vol.22:1:1-10,2021,Journal Article,,,"Department of Cutaneous Oncology\, Moffitt Cancer Center\, Tampa\, FL\, USA.,Department of Cutaneous Oncology\, Moffitt Cancer Center\, Tampa\, FL\, USA.,Department of Cutaneous Oncology\, Moffitt Cancer Center\, Tampa\, FL\, USA. Zeynep.eroglu@moffitt.org.",,,,,
33183426,"Qi M,Liu D,Wang H,Bianba C,Ji W",Correlation of Single Nucleotide Gene Polymorphisms and Gastric Cancer Based on Magnetic Nanoparticles.,"Gastric cancer (GC) is a serious threat to the health and lives of people around the world. In China, the incidence and mortality of gastric cancer are much higher than the world average, coupled with its low early diagnosis rate, low survival rate, poor prognosis, and complex etiology, especially the serious lack of effective early warning methods, which has become the main constraint on the diagnosis and treatment of gastric cancer factor. Therefore, finding reliable, effective, and specific markers that can be applied to early warning and diagnosis of gastric cancer has been a hot issue in gastric cancer research. Magnetic nanoparticles are an ideal molecular carrier for gene separation because they have many advantages such as easy operation, fast, high efficiency, and non-destructive non-recognition biological entities. Changes in gene levels can detect the development of early diagnosis and treatment of prognosis in patients with gastric cancer by affecting susceptibility, clinical phenotype, and drug response. PcG protein can modify chromatin and affect tumorigenesis. The experimental results show that the introduction of magnetic nanoparticles can improve the sensing signal, detection sensitivity and gene differentiation. Combined with the latest magnetic nanoparticle technology to analyze the relationship between SNPs of some genes in the pathways involved in gastric cancer treatment and DNA specificity, screening and identifying specific SNP markers are helpful to the mechanism of gastric cancer development. Understand to achieve the purpose of individualized treatment. By introducing the RAS-BRAF gene on the surface of magnetic nanoparticles, the surface of the magnetic particles was biologically functionalized and used for the separation and detection of proteins and pathogens, respectively. The results show that the system has excellent detection sensitivity and separation selectivity. At present, the research results of susceptible genes screened by coding gene association studies are inconsistent. In this study, PLCE1 gene was found to be used as a DNA gene identification method through high expression of cells to analyze that polymorphisms are closely related to the incidence of gastric cancer. In addition, the study suggests that PLCE1 gene may be a susceptible gene for tumor cells. The signaling pathways involved in the regulation play an important role in tumorigenesis, development, migration, and apoptosis, and are closely related to disease prognosis. Therefore, at the gene level More analysis of the role of these genes in gastric cancer is needed.",Journal of nanoscience and nanotechnology,vol.21:2:928-934,2021,Journal Article,,,"Department of Digestive Medicine\, Jinan City Central Hospital Affiliated to Shandong University\, Jinan City\, 250013\, Shandong Province\, China.,Emergency Infusion Room\, Jinan City Central Hospital Affiliated to Shandong University\, Jinan City\, 250013\, Shandong Province\, China.,School of Medicine\, Affiliated Hospital of Shandong University of Traditional Chinese Medicine\, Jinan City\, 250013\, Shandong Province\, China.,Bailang County Health Service Center\, Bailang\, Tibet Autonomous Region\, 857300\, China.,Clinical Experimental Research Centre\, Jinan City Central Hospital Affiliated to Shandong University\, Jinan City\, 250013\, Shandong Province\, China.",,,,,
33202284,"Porcelli L,Mazzotta A,Garofoli M,Di Fonte R,Guida G,Guida M,Tommasi S,Azzariti A",Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib.,"The crosstalk between Notch and MAPK pathway plays a role in MEK inhibitor resistance in BRAFV600E metastatic melanoma (MM) and promotes migration in GNAQQ209L uveal melanoma (UM) cells. We determined the cytotoxicity of combinatorial inhibition of MEK and Notch by cobimetinib and γ-secretase inhibitor (GSI) nirogacestat, in BRAFV600E and BRAF wt MM and GNAQQ209L UM cells displaying different Erk1/2 and Notch activation status, with the aim to elucidate the impact of Notch signaling in the response to MEK inhibitor. Overall the combination was synergic in BRAFV600E MM and GNAQQ209L UM cells and antagonistic in BRAF wt one. Focusing on UM cells, we found that cobimetinib resulted in G0/G1 phase arrest and apoptosis induction, whereas the combination with GSI increased treatment efficacy by inducing a senescent-like state of cells and by blocking migration towards liver cancer cells. Mechanistically, this was reflected in a strong reduction of cyclin D1, in the inactivation of retinoblastoma protein and in the increase of p27KIP1 expression levels. Of note, each drug alone prevented Notch signaling activation resulting in inhibition of c-jun(Ser63) and Hes-1 expression. The combination achieved the strongest inhibition on Notch signaling and on both c-jun(Ser63) and Erk1/2 activation level. In conclusion we unveiled a coordinate action of MAPK and Notch signaling in promoting proliferation of BRAFV600E MM and GNAQQ209L UM cells. Remarkably, the simultaneous inhibition of MEK and Notch signaling highlighted a role for the second pathway in protecting cells against senescence in GNAQQ209L UM cells treated with the MEK inhibitor.",Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie,vol.133::111006,2021,Journal Article,,,"Experimental Pharmacology Laboratory\, Italia\, 70124\, Bari\, Italy.,Experimental Pharmacology Laboratory\, Italia\, 70124\, Bari\, Italy.,Experimental Pharmacology Laboratory\, Italia\, 70124\, Bari\, Italy.,Experimental Pharmacology Laboratory\, Italia\, 70124\, Bari\, Italy.,Department of Basic Medical Sciences Neurosciences and Sense Organs\, University of Bari\, P.zza Giulio Cesare 11\, 70124 Bari\, Italy.,Medical Oncology Unit\, Italia\, 70124\, Bari\, Italy.,Molecular Diagnostics and Pharmacogenetics Unit IRCCS Istituto Tumori ""Giovanni Paolo II"" di Bari\, Italia\, 70124\, Bari\, Italy.,Experimental Pharmacology Laboratory\, Italia\, 70124\, Bari\, Italy. Electronic address: a.azzariti@oncologico.bari.it.",,,,,"Cobimetinib (PubChem CID: 16222096),MEK,Nirogacestat (PubChem CID:46224413),Notch,Senescence,Uveal melanoma"
33377602,"Wu KJ,Ho SH,Wu C,Wang HD,Ma DL,Leung CH",Simultaneous blocking of the pan-RAF and S100B pathways as a synergistic therapeutic strategy against malignant melanoma.,"Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five-year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF-selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan-RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan-RAF and S100B pathways.",Journal of cellular and molecular medicine,vol.25:4:1972-1981,2021,Journal Article,,,"State Key Laboratory of Quality Research in Chinese Medicine\, Institute of Chinese Medical Sciences\, University of Macau\, Macao SAR\, China.,State Key Laboratory of Urban Water Resource and Environment\, School of Environment\, Harbin Institute of Technology\, Harbin\, China.,Department of Chemistry\, Hong Kong Baptist University\, Kowloon Tong\, Hong Kong.,Graduate Institute of Biomedical Engineering National Chung Hsing University\, Taichung\, Taiwan.,Department of Chemistry\, Hong Kong Baptist University\, Kowloon Tong\, Hong Kong.,https://orcid.org/0000-0003-2988-3786State Key Laboratory of Quality Research in Chinese Medicine\, Institute of Chinese Medical Sciences\, University of Macau\, Macao SAR\, China.",,"Science and Technology Development Fund\, Macau SAR,Science and Technology Development Fund\, Macau SAR,Interdisciplinary Research Clusters Matching Scheme,National Natural Science Foundation of China,National Natural Science Foundation of China,Interdisciplinary Research Matching Scheme,Health and Medical Research Fund,Collaborative Research Fund,University of Macau,Hong Kong Baptist University,SKLEBA and HKBU Strategic Development Fund",",,,,,,,,,,","0072/2018/A2,084/2016/A2,RC-IRCs/17-18/03,21575121,21775131,RC-IRMS/16-17/03,HMRF/14150561,C5026-16G,MYRG2018-00187-ICMS,FRG2/17-18/003,SKLP_1718_P04","S100B-p53 interaction,drug discovery,malignant melanoma,pan-RAF,synergistic"
33547013,"Zhou B,Wei L,Qin J",Does Multifocal Papillary Thyroid Microcarcinoma With a Total Tumor Diameter >1 cm Indicate Poor Biological Behavior? The Evidence is Insufficient.,"Multifocal cancer is common in papillary thyroid microcarcinoma (PTMC). Our aim was to investigate the correlation between multifocal PTMC\, total tumor diameter (TTD)\, and clinicopathologic features.,In total\, 206 patients were included and grouped as stage cT1a or cT1b. The primary tumor diameter and TTD (the sum of the maximal diameter of each focus) were calculated. These patients were further subgrouped as TTD ≤1 cm or 1 cm < TTD ≤ 2 cm. The relationships of clinicopathological features between these groups were analyzed.,Multifocal cancer was more likely to occur with stage cT1a than stage cT1b (P = .028). Stage cT1b papillary thyroid carcinoma was more prone to central lymph node metastasis (CLNM) and capsular invasion than stage cT1a. There was no difference in clinicopathological factors\, such as sex\, age\, CLNM\, number of CLNMs\, capsular invasion\, BRAF mutation\, or recurrence between the multifocal PTMC and TTD >1 cm and primary tumor diameter + TTD ≤1 cm groups. Comparing stage cT1a and cT1b tumors with a 1 cm < TTD ≤ 2 cm using a multivariate analysis\, stage cT1b tumors were more prone to capsular invasion than stage cT1a tumors\, with an odds ratio of 19.013 (95% confidence interval\, 2.295-157.478)\, but there was no significant correlation with CLNM.,Stage cT1b tumors are more prone to capsular invasion and CLNM than than stage cT1a tumors. For multifocal PTMC\, calculating the TTD to evaluate adverse biological behavior is insufficient and limited\, and further research is needed.",Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists,vol.27:2:131-136,2021,Journal Article,,,"Department of Thyroid and Neck\, The Affiliated Cancer Hospital of Zhengzhou University\, Henan Cancer Hospital\, Zhengzhou\, China.,Department of Thyroid and Neck\, The Affiliated Cancer Hospital of Zhengzhou University\, Henan Cancer Hospital\, Zhengzhou\, China.,Department of Thyroid and Neck\, The Affiliated Cancer Hospital of Zhengzhou University\, Henan Cancer Hospital\, Zhengzhou\, China. Electronic address: qinjianwu_62@163.com.",,,,,"biological behavior,clinicopathological feature,multifocal,papillary thyroid microcarcinoma,total tumor diameter"
33603403,"Zhou S,Tang W,Wang Q,Zhang X,Jin X,Xu X,Fu J",A Case Report: Cutaneous Metastasis of Advanced Rectal Cancer with BRAF Mutation.,"Cutaneous metastasis of rectal cancer is rare and typically indicates widespread disease and poor prognosis. We report an exceedingly rare case of BRAF-mutated MSS rectal cancer with metastasis to the skin. A 53-year-old woman presented with stage IV unresectable adenocarcinoma of the rectum and received chemotherapy and molecularly targeted agents. Six months later she developed a focal skin nodule in the left groin. During treatment with four cycles of FOLFIRI plus bevacizumab, the skin nodules gradually increased in size, involving the skin of the left thigh. A portion of the rash was bleeding and painful. The biopsy specimen was consistent with a mucinous adenocarcinoma of rectal origin and expressed reduced CDX-2. Palliative treatment with FOLFIRI plus cetuximab and vemurafenib was initiated. The cutaneous nodules decreased in size but were not stable. The patient had severe electrolyte disturbances and depression and opted for palliative care.",OncoTargets and therapy,vol.14::989-993,2021,Case Reports,,,"Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.,Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.,Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.,Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.,Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.,Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.,0000-0002-3036-1056Department of Medical Oncology\, Jinhua Hospital\, Zhejiang University School of Medicine\, Jinhua\, 321000\, Zhejiang Province\, People's Republic of China.",,,,,"BRAF-mutated,CDX-2,MSS,cutaneous metastasis,rectal cancer"
32597321,"Mammana M,Bergamo F,Procaccio L,Schiavon M,Loupakis F,Lonardi S,Manai C,Schirripa M,Fassan M,Dei Tos AP,Calabrese F,Rea F,Zagonel V",Outcome of patients with colorectal cancer undergoing lung metastases resection: a single-institution retrospective analysis.,"This study was undertaken to review a single-institution cohort of patients with metastatic colorectal cancer undergoing lung resection after a multidisciplinary evaluation and to investigate the main prognostic factors for survival.,Medical records of 129 patients undergoing lung metastasectomy for colorectal cancer with curative intent from 2001 to 2017 were reviewed. Tissue samples from the primary tumor were analyzed with a multiplex genotyping system for the detection of mutations in RAS and BRAF genes. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariable analyses were performed using the log-rank test and the Cox regression model.,Postoperative morbidity and mortality were 13.2% and 0%\, respectively. At a median follow-up time of 62.5 months\, median overall survival was 90.5 months and median relapse-free survival was 42.8 months. Multivariable analysis for overall survival identified synchronous versus metachronous metastatic presentation as the only prognostic factor\, whereas relapse-free survival was independently associated with synchronous versus metachronous metastatic presentation\, number of metastases\, and postoperative chemotherapy.,This study shows particularly favorable survival outcomes for patients undergoing lung metastasectomy. The validity of some of the main prognostic factors was confirmed and a positive effect of postoperative chemotherapy on relapse-free survival was shown. Contrary to other reports\, the presence of KRAS mutations was not associated with significant survival differences. Further studies are needed in order to clarify the interactions between molecular\, clinical\, and pathologic characteristics and treatment-related factors.",Tumori,vol.107:1:46-54,2021,Journal Article,"|Adult|,|Aged|,|Aged\, 80 and over|,|Colorectal Neoplasms|drug therapy|genetics|pathology|surgery|,|Disease-Free Survival|,|Female|,|Genotype|,|Humans|,|Lung Neoplasms|genetics|pathology|secondary|surgery|,|Male|,|Metastasectomy|,|Middle Aged|,|Neoplasm Recurrence\, Local|drug therapy|genetics|pathology|surgery|,|Pneumonectomy|,|Postoperative Period|,|Prognosis|,|Proportional Hazards Models|,|Proto-Oncogene Proteins B-raf|genetics|,|Proto-Oncogene Proteins p21(ras)|genetics|,|Treatment Outcome|",,"Thoracic Surgery Unit\, Department of Cardiac\, Thoracic\, Vascular Sciences and Public Health\, University of Padua\, Padua\, Italy.,https://orcid.org/0000-0002-8795-4653Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.,Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.,Thoracic Surgery Unit\, Department of Cardiac\, Thoracic\, Vascular Sciences and Public Health\, University of Padua\, Padua\, Italy.,Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.,Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.,Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.,Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.,Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, Padua\, Italy.,Surgical Pathology Unit\, Department of Medicine (DIMED)\, University of Padua\, Padua\, Italy.,Thoracic Surgery Unit\, Department of Cardiac\, Thoracic\, Vascular Sciences and Public Health\, University of Padua\, Padua\, Italy.,Thoracic Surgery Unit\, Department of Cardiac\, Thoracic\, Vascular Sciences and Public Health\, University of Padua\, Padua\, Italy.,Department of Clinical and Experimental Oncology\, Medical Oncology Unit 1\, Istituto Oncologico Veneto (IRCSS)\, Padua\, Italy.","KRAS protein\, human,BRAF protein\, human,Proto-Oncogene Proteins B-raf,Proto-Oncogene Proteins p21(ras)",,,,"Colorectal cancer,KRAS mutations,lung metastases,metastasectomy"
32946312,"Ruffinelli JC,Santos Vivas C,Sanz-Pamplona R,Moreno V",New advances in the clinical management of RAS and BRAF mutant colorectal cancer patients.,"In colorectal carcinogenesis\, genetic alterations in RAS and BRAF oncogenes play an important role for cancer initiation and/or progression and represent a key focus in the search for targeted therapies. Despite many years of research and a great amount of studies\, until very recently this pathway was considered extremely hard to downregulate to obtain a significant clinical impact in colorectal cancer patients. But better times are coming with the advent of new promising drugs and combinations strategies.,In this review\, we go over the biological characteristics of the MAPK pathway in colorectal tumors\, while illustrating the clinical correlation of RAS and BRAF mutations\, particularly its prognostic and predictive value. We also present newly data about recent improvements in the treatment strategy for patients harboring these types of tumors.,With great advances in the knowledge of molecular basis of RAS and BRAF mutant colorectal cancer in conjunction with biotechnology development and the constant effort for improvement\, in the near future many new therapeutic options would be available for the management of this group of patient with dismal prognosis.",Expert review of gastroenterology & hepatology,vol.15:1:65-79,2021,Journal Article,,,"https://orcid.org/0000-0003-2947-320XDepartment of Medical Oncology\, Catalan Institute of Oncology (ICO)\, L'Hospitalet De Llobregat \, Barcelona\, Spain.,Department of Medical Oncology\, Catalan Institute of Oncology (ICO)\, L'Hospitalet De Llobregat \, Barcelona\, Spain.,Colorectal Cancer Group\, ONCOBELL Program\, Institut De Recerca Biomedica De Bellvitge (IDIBELL) \, Barcelona\, Spain.,https://orcid.org/0000-0002-2818-5487Colorectal Cancer Group\, ONCOBELL Program\, Institut De Recerca Biomedica De Bellvitge (IDIBELL) \, Barcelona\, Spain.",,,,,"Colorectal cancer,braf,egfr,mapk,mek,ras,targeted therapy"
33046448,"Kiyozumi Y,Matsubayashi H,Higashigawa S,Horiuchi Y,Kado N,Hirashima Y,Shiomi A,Oishi T,Ohnami S,Ohshima K,Urakami K,Nagashima T,Yamaguchi K","Role of Tumor Mutation Burden Analysis in Detecting Lynch Syndrome in Precision Medicine: Analysis of 2,501 Japanese Cancer Patients.","Tumor mutation burden (TMB) is the total exonic mutation count per megabase of tumor DNA. Recent advances in precision medicine occasionally detect Lynch syndrome (LS) by germline sequencing for mismatch-repair (g.MMR) genes but not using TMB. The current study analyzes the utility of TMB in detecting LS.,Whole-exome sequencing (ion-semiconductor sequencing) was performed for somatic and germline DNA from 2\,501 various cancer patients to detect TMB and g.MMR sequencing. MMR IHC was conducted when high TMB (≥10) was detected in LS-related cancers with an additional condition of wild-type BRAF in colorectal cancers. Target sequencing and multiplex ligation-dependent probe amplification (MLPA) were further performed for g.MMR genes in MMR-deficient cancers (TMB-based g.MMR target sequencing). We compared universal sequencing and TMB-based target sequencing in their sensitivity for detecting LS.,LS was detected in 16 (0.6%) of the 2\,501 patients: 1.1% (9/826) of colorectal cancer patients\, 16.2% (6/37) of endometrial cancer patients\, and 14.3% (1/7) of small intestine cancer patients. TMB-based g.MMR target sequencing (81.3%) showed superior sensitivity for detecting LS than universal g.MMR sequencing (56.3%; P = 0.127) but missed 3 LS patients (1 with a low-TMB cancer\, 1 with a BRAF-mutant colorectal cancer\, and 1 with an MMR-proficient cancer). Ion-semiconductor sequencing could detect single-nucleotide substitutions but not large deletions. POL-mutated cancers showed extremely high TMBs (48.4-749.2).,g.MMR target sequencing\, combined with TMB\, somatic BRAF mutation\, and MMR IHC is an effective strategy for detecting LS.,TMB can be a biomarker for detecting LS in precision medicine.","Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology",vol.30:1:166-174,2021,Journal Article,,,"Division of Genetic Medicine Promotion\, Shizuoka Cancer Center\, Shizuoka\, Japan.,Division of Genetic Medicine Promotion\, Shizuoka Cancer Center\, Shizuoka\, Japan. h.matsubayashi@scchr.jp.,Division of Genetic Medicine Promotion\, Shizuoka Cancer Center\, Shizuoka\, Japan.,https://orcid.org/0000-0003-0597-2514Division of Genetic Medicine Promotion\, Shizuoka Cancer Center\, Shizuoka\, Japan.,Division of Genetic Medicine Promotion\, Shizuoka Cancer Center\, Shizuoka\, Japan.,https://orcid.org/0000-0003-0269-9313Division of Gynecology\, Shizuoka Cancer Center\, Shizuoka\, Japan.,https://orcid.org/0000-0001-5657-8686Division of Colon and Rectal Surgery\, Shizuoka Cancer Center\, Shizuoka\, Japan.,Division of Pathology\, Shizuoka Cancer Center\, Shizuoka\, Japan.,Shizuoka Cancer Center Research Institute\, Shizuoka\, Japan.,Shizuoka Cancer Center Research Institute\, Shizuoka\, Japan.,Shizuoka Cancer Center Research Institute\, Shizuoka\, Japan.,Shizuoka Cancer Center Research Institute\, Shizuoka\, Japan.,Shizuoka Cancer Center Research Institute\, Shizuoka\, Japan.",,,,,
33075161,"Poulsen TS,de Oliveira DVNP,Espersen MLM,Klarskov LL,Skovrider-Ruminski W,Hogdall E","Frequency and coexistence of KRAS, NRAS, BRAF and PIK3CA mutations and occurrence of MMR deficiency in Danish colorectal cancer patients.","The MAPK signalling genes KRAS, NRAS and BRAF and the PIK3CA gene are routinely investigated for mutations in the diagnostic routine of colorectal cancer. Few studies have reported co-existing mutations in these genes with clinical relevance, while some have been previously regarded as mutually exclusive. We set to investigate the frequency and co-occurrent mutations in these targets, and the occurrence of mismatch repair deficiency (dMMR) in a large cohort of Danish colorectal cancers. 1000 colorectal tumours were sequenced as part of our diagnostic workflow for KRAS, NRAS, BRAF and PIK3CA mutations using next-generation sequencing (NGS) and analysed by immunohistochemistry (IHC) for loss of the MMR proteins, MLH1, PMS2, MSH2 and MSH6. Co-existing mutations in 12 patients (1.2%) occurred as multiple mutations in the same gene or spread across several genes (KRAS, NRAS and/or BRAF). The frequency of single mutations in the genes occurred with a frequency similar to previously reported, except for a higher frequency of BRAF mutations (18.0%). We found dMMR in 14.6% of the cases with a majority lacking expression of both MLH1 and PMS2. BRAF mutations were only present in dMMR cases involving MLH1 and/or PMS2. Our findings suggest that co-existing mutations occur, except for the hotspot BRAF V600E, which is mutually exclusive with KRAS/NRAS mutations. Therefore, instead of single gene alterations from the MAPK signalling, assessing co-occurrence of mutations within one or more of those genes should also be accounted. This may impact future oncological treatments and should be considered in the diagnostic workflow.","APMIS : acta pathologica, microbiologica, et immunologica Scandinavica",vol.129:2:61-69,2021,Journal Article,,,"Department of Pathology\, Herlev and Gentofte Hospital\, University of Copenhagen\, Herlev\, Denmark.,Department of Pathology\, Herlev and Gentofte Hospital\, University of Copenhagen\, Herlev\, Denmark.,Department of Pathology\, Herlev and Gentofte Hospital\, University of Copenhagen\, Herlev\, Denmark.,Department of Pathology\, Herlev and Gentofte Hospital\, University of Copenhagen\, Herlev\, Denmark.,Department of Pathology\, Herlev and Gentofte Hospital\, University of Copenhagen\, Herlev\, Denmark.,Department of Pathology\, Herlev and Gentofte Hospital\, University of Copenhagen\, Herlev\, Denmark.",,,,,"BRAF,Colorectal cancer,KRAS,MMR deficiency,NRAS,PIK3CA,next-generation sequencing"
33623106,"Abildgaard C,Rizza S,Christiansen H,Schmidt S,Dahl C,Abdul-Al A,Christensen A,Filomeni G,Guldberg P",Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma.,"The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.",Scientific reports,vol.11:1:4390,2021,Journal Article,,,"Molecular Diagnostics Group\, Danish Cancer Society Research Center\, Strandboulevarden 49\, 2100\, Copenhagen\, Denmark.,Redox Biology Group\, Danish Cancer Society Research Center\, Copenhagen\, Denmark.,Lundbeckfonden Center of Excellence NanoCAN\, Institute of Molecular Medicine\, University of Southern Denmark\, Odense\, Denmark.,Lundbeckfonden Center of Excellence NanoCAN\, Institute of Molecular Medicine\, University of Southern Denmark\, Odense\, Denmark.,Molecular Diagnostics Group\, Danish Cancer Society Research Center\, Strandboulevarden 49\, 2100\, Copenhagen\, Denmark.,Molecular Diagnostics Group\, Danish Cancer Society Research Center\, Strandboulevarden 49\, 2100\, Copenhagen\, Denmark.,Molecular Diagnostics Group\, Danish Cancer Society Research Center\, Strandboulevarden 49\, 2100\, Copenhagen\, Denmark.,Redox Biology Group\, Danish Cancer Society Research Center\, Copenhagen\, Denmark.,Molecular Diagnostics Group\, Danish Cancer Society Research Center\, Strandboulevarden 49\, 2100\, Copenhagen\, Denmark. perg@cancer.dk.",,,,,
33370037,"Ruan GJ,Goyal G,Shah MV,Cohen-Aubart F,Amoura Z,Straetmans N,Benameur N,Haroche J,Go RS",Acute Pancreatitis From Treatment With BRAF Inhibitors in Erdheim-Chester Disease: A Report From 2 Tertiary Referral Centers.,,Pancreas,vol.50:1:e6-e8,2021,Journal Article,,,",,,,,,,,",,,,,