Sarcoma Viral Oncogene Homolog B1 Research Articles

The impact of the Glasgow Prognostic Score on survival in second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation.

Background:BRAF (v-raf murine sarcoma viral oncogene homolog B1) V600E mutant colorectal cancer is associated with short survival. Recently, clinical trials have been conducted to improve outcomes of second or later lines of chemotherapy. However, there is a paucity of reference data pertaining to outcomes of second-line chemotherapy and prognostic factors that are relevant only to BRAF mutant patients.Patients and methods:We retrospectively reviewed metastatic colorectal cancer patients with BRAF V600E mutation who underwent second-line chemotherapy between January 2007 and March 2017. We evaluated treatment outcomes and performed prognostic analyses.Results:A total of 52 patients were included. The median progression-free survival and overall survival (OS) were 2.5 [95% confidence interval (CI) = 1.91–4.11] and 6.5 (95% CI = 4.30–9.63) months, respectively. Overall response and disease control rates were 7% and 48%, respectively. All the regimens which elicited a partial response included BRAF inhibitors in combination with anti-epidermal growth factor receptor (EGFR) antibodies. Therefore, the overall response was 0% after exclusion of patients treated with study drugs. Multivariate analysis for OS revealed that the Glasgow Prognostic Score (GPS), elevated lactate dehydrogenase, and poor performance status were independent prognostic factors. In particular, survival curves according to the GPS stratified the patients into distinct risk groups. The median OSs in patients with GPS of 0, 1, and 2 were 9.9, 5.0, and 1.9 months, respectively.Conclusions:Outcomes of second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation were extremely poor. GPS may be useful in future clinical trials.

Efficacy and safety of PD-1 inhibitors for treating advanced melanoma: a systematic review and meta-analysis.

We conducted a meta-analysis to systematically review the efficacy and safety of programmed cell death 1 (PD-1) inhibitors for advanced melanoma. The relevant studies of the randomized controlled trials in melanoma patients treated with PD-1 inhibitors were retrieved and the systematic evaluation was conducted. Databases were searched till June 2018. PD-1 inhibitors significantly improved the progression-free survival, overall survival and overall response rate in patients with advanced melanoma. Progression-free survival, overall survival and overall response rate did not vary significantly according to PD-L1 status, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and type of drug, but varied significantly by control therapy. PD-1 inhibitors were associated with a decreased risk of adverse events compared with ipilimumab, but an increased risk of immune-related events compared with chemotherapy. The PD-1 inhibitors-containing therapy was efficacious in treating advanced melanoma.

Targeted Molecular Treatments in Non-Small Cell Lung Cancer: A Clinical Guide for Oncologists.

Targeted molecular treatments have changed the way non-small cell lung cancer (NSCLC) is managed. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and c-ros oncogene 1 (ROS1) mutations are now used to guide specific anti-cancer therapies to improve patient outcomes. New targeted molecular treatments are constantly being developed and evaluated as a means to improve efficacy, overcome resistance, or minimise toxicity. This review article summarises the current evidence for the efficacy, resistance mechanisms, and safety of targeted molecular treatments against specific mutations in NSCLC.

Research advances in the v-raf murine sarcoma viral oncogene homolog gene mutation in ameloblastoma

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) is a pro-oncogene, which is one member of the RAF family. Mutated BRAF is found in approximately 8% of human tumors. BRAF gene mutations lead to continuous activation of the mitogen-activatd protein kinase (MAPK) pathway, which resulting in abnormal cell proliferation and tumorigenesis. In recent years, recurrent MAPK signaling mutations were identified in ameloblastoma, among which BRAF-V600E is the most prominent type. This provides new strategies for the targeted treatment of ameloblastoma. This paper reviewed the latest advances in BRAF gene mutation associated with ameloblastoma and its potential clinical significance.

Squamous Cell Differentiation in Metastatic Papillary Thyroid Carcinoma: Metaplastic

Squamous cell differentiation (SCD) may occur in papillary thyroid carcinoma (PTC) only at metastatic sites. We have studied cytokeratin CK5/6 and P63 along with TTF1 (thyroid transcription factor 1) and B-Raf (V-Raf murine sarcoma viral oncogene homolog B1) immunohistochemical expression in neck lymph node metastases of thyroid PTC showing SCD. The patient (21-years) presented with a neck mass. The check-up revealed bilateral thyroid nodules. Total thyroidectomy and neck lymph node dissection were performed. The diagnosis was that of bilateral PTC with lymph node metastases (pT-1N1Mx). The metastases were peculiar by the presence of cystic change and of SCD. The thyroid PTC expressed P63 focally and, TTF1 and B-Raf diffusely. Cytokeratin 5/6 was expressed only in the lymph node metastases, in the metastatic cyst lining and in the SCD foci. The P63+ cells outnumbered those CK5/6+. TTF1 expression was faint in SCD. Metastatic, both classical PTCand SCD-epithelia expressed B-Raf. The expression patterns of CK5/6, P63, TTF1 suggest a luminal/central-to-abluminal/peripheral direction for SCD development from PTC-epithelia in lymph node metastases. Whether this metaplasia type may reflect a regression to a less aggressive morphotype or a progression-switch to squamous cell carcinoma-type differentiation in a composite tumor remains matter of debate.

EGFR, KRAS, BRAF, PTEN, and PIK3CA mutation in plasma of small cell lung cancer patients.

BackgroundSmall cell lung cancer (SCLC) is an aggressive and deadly neuroendocrine tumor derived from bronchial epithelial cells. Although it results in a 95% mortality rate, the development of targeted therapies for SCLCs has lagged behind. The aim of this study is to better research mutation characteristics of SCLC and identify potential biomarkers for target therapy.MethodsWe utilized high-resolution melting analysis to identify the mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-3-kinase catalytic (PIK3CA) from the blood. A cohort of 99 SCLC patients including 44 limited-stage disease patients and 55 extensive-stage disease patients were prospectively collected.ResultsEGFR 18 (G719X) mutation was found in 5 patients, EGFR 19 (del) mutation in 2, EGFR 20 (T790M) in 3, EGFR 21 (L858R) in 2, KRAS 2 (G13D) in 5, BRAF 15 (V600E) in 1, PIK3CA 9 (E542K) in 1, and no mutations in PTEN 5 (R130G), PTEN 6 (R173C), PTEN 8 (T319fs*1), and PIK3CA 20 (H1047R) were identified. Among these patients, two harbored EGFR double mutation, one patient with EGFR double mutation and KRAS 2 (G13D) mutation.ConclusionThe mutation form of EGFR may differ from lung adenocarcinoma, and mutations of KRAS, BRAF, and PIK3CA were rare in SCLC. These results aided us in comprehensively analyzing genetic features and laid the foundation for exploring the possibility of target therapy.

BRAFV600E mutation is correlated with the biological behaviors of papillary thyroid microcarcinoma: a Meta-analysis

Objective To evaluate the association between V-raf murine sarcoma viral oncogene homolog B1 (BRAF)V600E mutation and biological behaviors of papillary thyroid (PTMC). Methods Published papers about the association between BRAFV600E mutation and aggressiveness of from January 2011 to January 2016 were collected using databases of Wanfang, VIP, China National Knowledge Infrastructure (CNKI), PubMed, Embase and Cochrane library. The key words were PTMC , papillary thyroid microcarcinoma , thyroid microcarcinoma , micropapillary thyroid carcinoma , BRAF . The languages were restricted to English and Chinese. Meta-analysis was performed with RevMan 5.3 software. Results Eighteen studies involving 2 938 patients were included. A total of 1 536 patients showed BRAFV600E mutation-positive results, and 1 402 patients were with wild type. The average prevalence of the BRAFV600E mutation was 52.3%. The BRAFV600E mutation was associated with the multifocality (odds ratio (OR)=1.37, 95% CI: 1.11-1.67), extrathyroid extension(OR=2.25, 95% CI: 1.31-3.86), lymph node metastases(OR=3.05, 95% CI: 1.60-5.79), advanced stage (TNM Ⅲ+ Ⅳ; OR=1.99, 95% CI: 1.54-2.57), recurrence(OR=2.92, 95% CI: 1.84-4.65), male patients(OR=1.70, 95% CI: 1.35-2.14) and tumor diameter >5 mm(OR=1.62, 95% CI: 1.29~2.04)of PTMC. There was no significant association between BRAFV600E mutation and age or distant metastases. Conclusion BRAFV600E mutation is a risk factor for aggressive behaviors of PTMC. Key words: Thyroid neoplasms; Proto-oncogene proteins B-raf; Mutation; Meta analysis

Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma.

Epithelioid glioblastoma (eGBM) is a rare variant of GBM which was adopted in the 2016 WHO classification. eGBM and pleomorphic xanthoastrocytoma (PXA) sometimes show overlapping features histologically and genetically, such as epithelioid pattern and a highly frequent V600E mutation in the gene for vRAF murine sarcoma viral oncogene homolog B1 (BRAF), respectively. Accurate diagnosis of these rare tumors is challenging according to the new criteria in the revised 2016 WHO classification. It is an urgent task to elucidate the biological properties of the tumors and to select appropriate treatment. Twenty consecutive cases diagnosed as PXA or eGBM histologically were investigated. Twelve of the 20 cases were PXAs and eight were eGBMs. Morphologically, mitotic activity, necrosis and degenerative changes such as intracellular lipid accumulation, eosinophilic granular bodies and reticulin fiber deposits were scored. Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA. Of the 20 cases tested, Sanger technique showed no mutation in IDH1/2. BRAF mutation at T1799 > A (V600E) was detected in 4/12 (33.3%) PXA and 4/8 (50.0%) eGBM, while TERT-p mutation was detected at C228 > T in 2/12 (16.7%) PXA and at C250 > T in 1/8 (12.5%) eGBM. Retained nuclear ATRX was observed in 12/12 (100%) PXA and 6/7 (85.7%) eGBM while p53 mutation was observed in 2/10 (20%) PXA and 7/7 (100%) eGBM. All tumors retained INI1 expression in their nuclei. None of the tumors harbored H3F3A mutation. One PXA without BRAF mutation acquired TERT-p mutation at recurrence and one eGBM harbored both BRAF and TERT-p mutation. Molecular biological similarity between eGBM and PXA was suggested in our series, while degenerative changes reflected the features of PXA. It was speculated that the common genetic alterations for development and progression of eGBM and PXA might include BRAF and TERT-p mutations.

Ocular Changes in Metastatic Melanoma Patients Treated with MEK Inhibitor Cobimetinib and BRAF Inhibitor Vemurafenib.

BackgroundMitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combination with vemurafenib.Patients and methodsIn the prospective, observational study, patients with BRAF-mutated metastatic melanoma treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to participate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT).ResultsFive out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid macular edema.ConclusionsMultiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, including the discontinuance of a potentially life-prolonging therapy.

Progress study of circulating V-raf murine sarcoma viral oncogene homolog B1 V600E mutation in papillary thyroid carcinoma

Detection of V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation is important for clinical diagnosis, treatment decision-making, effect judgement and prognosis evaluation in papillary thyroid carcinoma (PTC). Research has shown that peripheral blood BRAF V600E is closely related to the histological level of BRAF V600E. Detection of peripheral blood BRAF V600E mutation will be less traumatic, more convenient and dynamic, indicating that it will be the future development trend of PTC research. Key words: V-raf murine sarcoma viral oncogene homolog B1 oncogene; Circulating tumor DNA; Papillary thyroid carcinoma; Progress

Detection of EGFR, KRAS and BRAF mutations in metastatic cells from cerebrospinal fluid.

In lung adenocarcinoma, molecular profiling of actionable genes has become essential to set up targeted therapies. However, the feasibility and the relevance of molecular profiling from the cerebrospinal fluid (CSF) in the context of meningeal metastasis have been poorly assessed. We selected patients with stage IV lung adenocarcinoma harbouring metastatic cells in the CSF after cytological analysis. Seven samples from six patients were eligible for molecular testing of epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS), v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) and human epidermal growth factor receptor 2 (HER2) mutations using quantitative polymerase chain reaction (PCR) high-resolution melting curve analysis and Sanger sequencing after DNA extraction from the cell pellets of the CSF. Five patients showed mutations in one or two actionable genes, two harboured an EGFR mutation (exons 19 and 21), one only a KRAS mutation, one both EGFR and KRAS mutations and one a BRAF mutation. In all cases, the results of mutation testing provided new major information for patient management, leading to therapeutic adaptation. CSF molecular analysis identified mutations not detected in other neoplastic sites for two patients. In one case, the EGFR p.Thr790Met was identified. CSF was also the only sample available for genetic testing for almost all patients at the time of disease progression. When cancer cells are present in the CSF, the molecular profiling from the cell pellets is relevant, as it can detect supplemental or different mutations compared to a previous analysis of the primitive tumour or plasma cell-free DNA and allows the adaptation of the treatment strategy.

Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas.

CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [11C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAFV600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [11C]CEP-32496 showed high binding affinity for BRAFV600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAFV600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [11C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [11C]CEP-32496 in plasma. Our results indicate that [11C]CEP-32496 has excellent specificity and affinity for the BRAFV600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.

A Comprehensive Method for Detecting Fusion Genes in Paediatric Brain Tumours.

Fusion genes driving tumourigenesis have drawn the attention of researchers and oncologists. Despite the importance of such molecular alterations, there are no comprehensive reproducible methods for detecting fusion genes. Nineteen paediatric brain tumours of five types, namely pilocytic astrocytoma, oligodendroglioma, anaplastic astrocytoma, glioblastoma and, ganglioglioma, were examined to detect fusion genes using a pyrosequencing-based method following RNA isolation, cDNA synthesis and real-time polymerase chain reaction. Our method successfully detected KIAA1549-v-raf murine sarcoma viral oncogene homolog B1 (BRAF) fusion in 14 out of 19 patients suffering from five types of paediatric brain tumours providing information on fusion breakpoints within 2 h. A comprehensive method for detecting fusion genes in paediatric brain tumours was evaluated. This method identified KIAA1549-BRAF fusion variants quickly. Our results may help researchers interested in the role of fusion genes in tumourigenesis.

V-raf murine sarcoma viral oncogene homolog B1 V600E mutations in different subtypes of papillary thyroid carcinoma and the association with pathological features

Objective To investigate the V600E mutations of V-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene in different subtypes of papillary thyroid carcinoma (PTC). Methods We analyzed retrospectively a series of 411 patients, treated for PTC from 2014 to 2016. The BRAF V600E mutation was detected by real-time quantitative polymerase chain reaction (Real-time PCR). Results Among 411 cases, BRAF V600E mutation was found in 88.4% (321/363) of classical PTCs, in 41.7% (5/12) of follicular variant, in 100.0% (23/23) of tall cell PTCs, and in 80.0% (4/5) of oncocytic variant. Chi square analysis showed that there were significant differences in BRAF mutation between the follicular variant and classical PTCs (χ2=18.435, P=0.001), and in the tumor size and capsule invasion between the classical and tall cell PTCs (χ2=13.563, P=0.000; χ2=4.115, P=0.043). Univariat binary Logistic regression analysis revealed that there was no significant correlation between BRAF V600E mutation and age, sex, tumor size, lymph node metastasis and capsule invasion in classical and follicular variant PTCs (P values were 0.529, 0.682, 0.271, 0.623, 0.550 and 0.921, 1.000, 0.560, 0.560, 0.999 respectively). Conclusion The mutation rate of BRAF gene in high-risk subtypes was higher than that of low-risk subtypes of PTC in general, while the tall cell subtype has larger size and further capsule invasion than classical PTCs. There was no significant correlation between BRAF mutation and age, sex, tumor size, lymph node metastasis and capsule invasion in classical, follicular variant PTCs and tall cell PTCs. Key words: Papillary thyroid carcinoma; Pathological subtype; V-raf murine sarcoma viral oncogene homolog B1 V600E

V-raf murine sarcoma viral oncogene homolog B1 V600E mutation and the expression of galectin-3, cytokcratin 19, MK in papillary thyroid microcarcinoma

Objective To explore the significance of the expression levels of galectin-3 (Gal-3), MC and cytokcratin 19 (CK19) proteins, and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation in papillary thyroid microcarcinoma (PTMC). Methods BRAF gene V600E mutation was tested using real-time quantitative polymerase chain reaction (Real-time PCR) and the protein expression levels of Gal-3, MC and CK19 were detected using immunohistochemistry in both PTMC and thyroid benign lesions. Results BRAF mutation rate in PTMC was significantly higher than in thyroid benign disease (67.6% vs. 4.1%, P=0.000). The expression levels of Gal-3, MC and CK19 proteins in PTMC were significantly higher than those in thyroid benign lesions (91.2% vs. 8.1%, 83.8% vs. 13.5%, and 95.9% vs. 4.1, P=0.000). The protein expression of Gal-3, MC and CK19 was associated with cervical lymphatic metastasis (P=0.007, 0.000, 0.036). BRAF gene V600E mutation was associated with capsular invasion and cervical lymphatic metastasis (P=0.005, P=0.000). The sensitivity of BRAF+ Gal-3, BRAF+ MC and BRAF+ CK19 in PTMC was 93.2%, 85.1% and 96.6%, and combination of BRAF+ CK19 showed the highest sensitivity in PTMC. Conclusion BRAF geneV600E mutation and the protein expression of Gal-3, MC and CK19 have important referenced value to PTMC. Combination of BRAF geneV600E mutation and the protein expression of Gal -3, MC and CK19 is helpful to improve the diagnosis of PTMC. The protein expression of Gal-3, MC and CK19 may remind cervical lymphatic metastasis. BRAF gene mutation may make the tumor more aggressive, and lymphatic metastasis can be found more easily. Key words: Papillary thyroid microcarcinoma; Galectin-3; Cytokcratin 19; V-raf murine sarcoma viral oncogene homolog B1

Association between the ALK Gene Status and the Efficacy of First-line Pemetrexed Chemotherapy in Patients with Advanced Lung Adenocarcinoma

背景与目的间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）是非小细胞肺癌（non-small cell lung cancer, NSCLC）的重要驱动基因之一，多项研究显示培美曲塞在ALK阳性肺癌中的疗效存在争议。本研究旨在继续探索以培美曲塞为基础的化疗在ALK阳性和阴性肺腺癌患者中的疗效。方法回顾性分析郑州大学第一附属医院2015年1月-2016年4月经组织病理学证实的98例表皮生长因子受体（epidermal growth factor receptor, EGFR）、鼠类肉瘤病毒癌基因（kirsten rat sarcoma viral oncogene, KRAS）、鼠类肉瘤滤过性毒菌致癌同源体B1（V-rafmurine sarcoma viral oncogene homolog B1, BRAF）均为阴性的晚期肺腺癌患者的临床资料。分析ALK基因状态、临床特征、化疗疗效及无疾病进展生存期（progression-free survival, PFS）之间的关系。结果98例患者均进行了ALK基因检测，ALK基因断裂融合34例（34.7%），未发生断裂融合64例（65.3%）。全部患者均接受一线培美曲塞联合铂类的化疗，客观缓解率（objective response rate, ORR）为21.4%，疾病控制率（disease control rate, DCR）为84.7%。ALK阳性肺腺癌患者的ORR和DCR均高于阴性患者（41.2% vs 10.9%, χ2=23.389, P < 0.001; 91.2% vs 81.3%, χ2=4.153, P=0.042），差异有统计学意义。ALK基因状态与年龄、性别、吸烟史、临床分期均无明显关系。ALK阳性肺腺癌的中位PFS为7.1个月（95%CI: 6.1-8.1），阴性4.7个月（95%CI: 3.818-5.582），二者的PFS差异有统计学意义（χ2=13.269, P < 0.001）。Cox回归多因素分析显示：培美曲塞联合铂类化疗的PFS与性别、年龄、吸烟、分期、与铂类药物的种类均无明显关系，ALK基因断裂融合是PFS相关的唯一变量（HR=0.392, 95%CI: 0.243-0.634, P < 0.001）。结论ALK阳性相比ALK阴性肺腺癌患者一线应用以培美曲塞为基础的化疗有更大的临床获益。

Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations.

Pilocytic astrocytomas and low-grade gliomas are more common compared with glioblastomas in patients with neurofibromatosis 1 (NF1). A recent genome-wide analysis has shown frequent NF1 gene alterations in the mesenchymal subtype of a glioblastoma; however, little is known about clinicopathological features of glioblastomas in NF1 patients (NF1 glioblastomas). We analyzed four NF1 glioblastomas. Radiographical and intraoperative findings showed well-circumscribed tumors from surrounding brain. Pathological analysis presented a paucity of processes with an eosinophilic cytoplasm, bizarre nuclei, xanthomatous-like appearance, multinucleated giant cells, and histiocytoid appearance. During the follow-up period, one patient died at 49months and others remained alive for 60, 87, and 106months; thus, patients with NF1 glioblastoma presented a relatively favorable survival. None of the NF1 glioblastomas harbored isocitrate dehydrogenase 1 (IDH1) gene mutation, v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation, and telomerase reverse transcriptase (TERT) gene promoter mutation. We identified that NF1 glioblastoma is a unique subset of glioblastoma.

Anaplastic gliomas in adults: an update.

The current review summarizes recent advances on the oncogenesis, classification and treatment of adult anaplastic gliomas. According to the 2016 WHO classification, three main molecular subgroups of adult diffuse anaplastic gliomas can be distinguished based on the 1p/19q codeletion and isocitrate dehydrogenase (IDH) mutation status. In the future, this classification may be further refined based on the telomerase reverse transcriptase promoter and alpha thalassemia/mental retardation syndrome X-linked mutation status, gene expression, DNA methylation and genomic profiling. Both newly diagnosed 1p/19q codeleted and 1p/19q-intact anaplastic gliomas benefit from the addition of chemotherapy to radiotherapy. However, in 1p/19q codeleted anaplastic gliomas, Procarbazine, CCNU and Vincristine chemotherapy seems more effective than temozolomide. At recurrence, 1p/19q-intact anaplastic gliomas do not benefit from the addition of bevacizumab to temozolomide. The use of poly(adenosine 5'-diphosphate-ribose) inhibitors may be another way of specifically targeting IDH-mutant gliomas in addition to specific inhibitors, demethylating agents and anti-IDH vaccines. v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant anaplastic xanthoastrocytomas and gangliogliomas may benefit from BRAF and mitogen-activated protein kinase inhibitors. Molecular characterization is mandatory for integrated diagnosis and appropriate management of adult anaplastic gliomas. Both 1p/19q codeleted and 1p/19q-intact anaplastic diffuse gliomas benefit from early chemotherapy. At recurrence, preliminary data suggest a potential role for targeted therapies in specific molecular subgroups.

Clinicopathologic features and treatment efficacy of Chinese patients with BRAF-mutated metastatic colorectal cancer: a retrospective observational study

BackgroundThe prognostic role of the V600E mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) in metastatic colorectal cancer (mCRC) is well established, but the therapeutic regimen targeting this disease is lacking. This study aimed to analyze the clinicopathologic features of and treatment efficacy of commonly used regimens on BRAF-mutated mCRCs.MethodsWe collected and reviewed the medical records of mCRC patients treated at Peking University Cancer Hospital & Institute (Beijing, China) between July 2011 and July 2016. Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and BRAF mutational status was assayed using direct sequencing. The details of clinicopathologic characteristics of patients and their responses to FOLFOXIRI regimen or standard therapy were obtained by reviewing the medical records. The progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis and compared using the log-rank test.ResultsOf 1694 patients studied, 75 had BRAF exon 15 mutations. Of these 75 patients, 71 had V600E mutation, 1 had D594G mutation, 2 had K601E mutation, and 1 had a novel T599_V600insAGA alteration. No patients had KRAS or NRAS mutations. Of 63 patients with BRAF V600E-mutated mCRC and sufficient clinical data, 27 (42.9%) had right-sided colon tumors, 19 (30.2%) had left-sided colon tumors, and 17 (26.9%) had rectal tumors; 26 (41.3%) had peritoneal metastases, and 50 (79.4%) had distant lymph node metastases. The patients with BRAF K601E- and T599_V600insAGA-mutated tumors had similar clinicopathologic features to those with BRAF V600E-mutated tumors. Patients with the BRAF V600E mutation benefited more from FOLFOXIRI regimen compared with patients who underwent standard therapy (overall response rate 83.3% vs. 14.0%; median PFS 6.4 months vs. 2.8 months, P = 0.220; median OS 11.0 months vs. 6.9 months, P = 0.048).ConclusionsBRAF V600E mutations were commonly identified in right-sided tumors and showed a high incidence of peritoneal and distant lymph nodes metastases. This subtype of mCRC was characterized by short OS and unique patterns of metastasis. Compared with standard treatment regimens, the FOLFOXIRI regimen had acceptable and manageable toxicities and favorable efficacy on patients with BRAF-mutated mCRC.

V-raf murine sarcoma viral oncogene homolog B1 V600E mutation and urinary iodine concentration in papillary thyroid carcinoma

Objective To investigate the V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation and urinary iodine concentration in papillary thyroid carcinoma (PTC) and the relationship with clinicopathological features. Methods Polymerase chain reaction (PCR) and gene sequencing were performed to detect BRAF V600E mutation in 110 cases of PTC, 47 cases of nodular goiter and 26 of thyroid adenoma thyroid tissues. Simultaneously, the urinary iodine concentration was determined. The relationship between BRAF V600E mutation and urinary iodine concentration with clinicopathological features was studied. Results In 183 cases, BRAF V600E mutation was detected in 54 out of 110 PTC cases with a detection rate of 49% (χ2=50.838, P=0.000). BRAF V600E mutation was negative in nodular goiter and thyroid adenoma. BRAF V600E mutation in PTC was positively correlated with extra-thymidal extension (χ2=6.031, P=0.014), but not with gender (P=0.363), age (P=0.360), tumor number (P=0.593), tumor size (P=0.497), lymph nodal metastasis (P=0.554) and pTNM staging (P=0.785). The excessive iodine intake rate in PTC patients was 79%, obviously higher than that in nodular goiter (66%) and thyroid adenoma (58%) with significant difference (χ2=6.288, P=0.043). The urinary iodine concentration in PTC was negatively correlated with gender (P=0.187), age (P=0.138), tumor number (P=0.571), tumor size (P=0.454), extra-thymidal extension (P=0.345), lymph nodal metastasis (P=0.248) and pTNM staging (P=0.792). The BRAF V600E mutation was not associated with the concentration of iodide in the PTC (χ2=0.019, P=0.891). Conclusion BRAF V600E mutation was a common molecular event and may increase the ability of invasion in PTC. BRAF V600E mutation was a specificity marker in the diagnosis of PTC. The urinary iodine concentration in PTC was significantly higher than that in the benign thyroid nodule diseases. Key words: V-raf murine sarcoma viral oncogene homolog B1 gene; Mutation; Urinary iodine concentration; Papillary thyroid carcinoma