BACKGROUND: Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined.
METHODS: In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated.
RESULTS: In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively.
CONCLUSIONS: Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.

In the present study, we employed the ddPCR and IHC techniques to assess the prevalence and roles of RAS and RAF mutations in a small batch of melanoma (n = 22), benign moles (n = 15), and normal skin samples (n = 15). Mutational screening revealed the coexistence of BRAF and NRAS mutations in melanomas and nevi and the occurrence of NRAS G12/G13 variants in healthy skin. All investigated nevi had driver mutations in the BRAF or NRAS genes and elevated p16 protein expression, indicating cell cycle arrest despite an increased mutational burden. BRAF V600 mutations were identified in 54% of melanomas, and NRAS G12/G13 mutations in 50%. The BRAF mutations were associated with the Breslow index (BI) (p = 0.029) and TIL infiltration (p = 0.027), whereas the NRAS mutations correlated with the BI (p = 0.01) and the mitotic index (p = 0.04). Here, we demonstrate that the \"young\" ddPCR technology is as effective as a CE-IVD marked real-time PCR method for detecting BRAF V600 hotspot mutations in tumor biopsies and recommend it for extended use in clinical settings. Moreover, ddPCR was able to detect low-frequency hotspot mutations, such as NRAS G12/G13, in our tissue specimens, which makes it a promising tool for investigating the mutational landscape of sun-damaged skin, benign nevi, and melanomas in more extensive clinical studies.

Thyroid cancer is the most prevalent endocrine malignancy, with its global incidence increasing annually in recent years. Papillary carcinoma is the most common subtype, frequently accompanied by cervical lymph node metastasis early on. Central lymph node metastasis (CLNM) is particularly the common metastasis form in this subtype, and the presence of lymph node metastasis correlates strongly with tumor recurrence. However, effective preoperative assessment methods for CLNM in patients with papillary thyroid carcinoma (PTC) remain lacking.
Data from 400 patients diagnosed with PTC between January 1, 2018, and January 1, 2022, at the Shandong Provincial Hospital were retrospectively analyzed. This data included clinicopathological information of the patients, such as thyroid function, BRAF V600E mutation, whether complicated with Hashimoto\'s thyroiditis, and the presence of capsular invasion. Univariate and multivariate logistic regression analyses were performed to assess the risk factors associated with cervical CLNM in patients with PTC. Subsequently, a clinical prediction model was constructed, and prognostic risk factors were identified based on univariate and multivariate Cox regression analyses.
Univariate and multivariate analyses identified that age >45 years (P=0.014), body mass index ≥25 (P=0.008), tumor size ≥1 cm (P=0.001), capsular invasion (P=0.001), and the presence of BRAF V600E mutation (P<0.001) were significantly associated with an increased risk of CLNM. Integrating these factors into the nomogram revealed an area-under-the-curve of 0.791 (95% confidence interval 0.735-0.846) and 0.765 (95% confidence interval: 0.677-0.852) for the training and validation sets, respectively, indicating strong discriminative abilities. Subgroup analysis further confirmed that patients with papillary thyroid microcarcinoma and BRAF V600E mutations who underwent therapeutic central compartment neck dissection had significantly better 3-year disease-free survival than those who had prophylactic central compartment neck dissection (P<0.001).
The study revealed that age >45 years, body mass index ≥25, tumor size ≥1 cm, BRAF V600E mutation, and capsular invasion are the related risk factors for CLNM in patients with PTC. For patients with clinically nodal-negative (cN0) papillary thyroid microcarcinoma, accurately identifying the BRAF V600E mutation is essential for guiding the central lymph node dissection approach and subsequent treatments.

BACKGROUND: Combined thyroid fine-needle aspiration (FNA) cytology and valine-to-glutamate substitution at codon 600 of B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E) mutation detection are procedures used for diagnosing thyroid nodules in many Chinese tertiary institutions. This retrospective study at our institution aimed to explore the effectiveness and challenges of the combined approach in diagnosing thyroid nodules and the correlation between BRAF V600E mutation status and behavior of papillary thyroid carcinoma.
METHODS: Thyroid FNA cytology and BRAF V600E mutation detection results were reviewed between November 2020 and July 2022. A total of 623 patients, each of whom underwent thyroidectomy and final pathological examination after FNA cytology diagnosis, were included in the study. The relationship between the BRAF V600E mutational status and pathological parameters was analyzed using the χ2 test. The effectiveness and challenges of FNA cytology alone and the combined procedure were also evaluated based on the final pathology.
RESULTS: Of 623 patients, 591 were diagnosed with papillary thyroid carcinoma (PTC), of which 456 were positive for the BRAF V600E mutation. It demonstrated near-perfect specificity for identifying PTC, and its incidence rate showed an age-specific curve with an inverted U-shaped distribution. The final pathological examination showed that the combined procedure had a higher sensitivity (83.91%) than FNA cytology alone (63.45%) for distinguishing PTC from other lesions (p < 0.001). Mutational status was associated with a larger maximum tumor diameter (p = 0.003) and a tendency of capsular invasion (p = 0.0542) but possibly unrelated to central lymph node metastasis (p = 0.1846). Nodular goiters accounted for most benign entities initially designated as Bethesda categories III-V.
CONCLUSIONS: BRAF V600E mutational analysis complements cytopathology and improves the PTC detection rate in FNA cytology samples due to the high prevalence of the mutation in China. BRAF V600E mutation does not show a statistical correlation with tumor aggressiveness. Morphological pitfalls such as histocyte aggregation, cystic-lining cells in nodular goiters, and oncocytes in Hashimoto\'s thyroiditis, were overwhelmingly found in BRAF V600E-negative specimens.

BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time. Treatment approaches vary depending on whether or not the metastases are initially resectable. The benefit of metastasectomy remains unclear, and the optimal first-line treatment is controversial. This study aimed to describe the prognosis of BRAF V600E mutant-mCRC, analyze the recurrence pattern in resectable patients, and explore the optimal first-line treatment for unresectable patients.
Patients diagnosed with BRAF V600E mutant-mCRC between February 2014 and January 2022 in five hospitals were enrolled. Date on clinical and pathological characteristics, treatment features, and survival outcomes were collected.
Of the 220 included patients, 64 initially resectable patients had a significantly longer overall survival (OS) (37.07 vs. 20.20 months, P < 0.001) than initially unresectable patients. Of 156 unresectable patients, 54 received doublet (FOLFOX, XELOX or FOLFIRI) or triplet (FOLFOXIRI) chemotherapies (Chemo), 55 received Chemo plus Bevacizumab (Chemo+Bev), and 33 received vemurafenib plus cetuximab and irinotecan (VIC). The VIC regimen had a better progression-free survival (PFS) (12.70 months) than the Chemo (6.70 months, P < 0.001) and Chemo+Bev (8.8 months, P = 0.044) regimens. Patients treated with VIC had the best overall response rate (60.16%, P < 0.001), disease control rate (93.94%, P < 0.001) and conversional resection rate (24.24%, P = 0.003).
Metastasectomy is beneficial to the survival of patients with BRAF V600E mutant-mCRC. For initially unresectable patients, VIC as first-line therapy is associated with a better prognosis and efficacy than doublet and triplet chemotherapy with or without bevacizumab.

BACKGROUND: Patients with V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated advanced colorectal cancer (CRC) have a poor prognosis, and treatment options that can improve outcome are still under investigation. The purpose of this study was to discuss the differences of overall survival (OS) and progression-free survival (PFS) between patients with BRAF V600E-mutated advanced CRC who were treated with chemotherapy alone and chemotherapy combined with targeted therapy in advanced first-line therapy.
METHODS: Grouping of 61 patients according to first-line treatment regimen (chemotherapy alone/chemotherapy combined with bevacizumab). Kaplan-Meier method and log-rank test were used to compare OS and PFS. Cox proportional hazards regression model was used to measure the risk of first-line medication therapies while correcting for confounding factors that may affect PFS and OS.
RESULTS: There was no significant difference in OS between patients treated with chemotherapy alone and those treated with chemotherapy combined with bevacizumab (P = 0.93; HR, 1.027; 95% CI, 0.555-1.901). Likewise, there was no significant difference in PFS between the two groups (P = 0.29; HR, 0.734; 95% CI, 0.413-1.304). Subgroup analysis showed that OS and PFS of different treatment regimens were not significantly different among subgroups. Multivariate analysis suggested that surgical treatment of primary tumor (P = 0.001; HR, 0.326; 95% CI, 0.169-0.631) and presence of liver metastasis (P = 0.009; HR, 2.399; 95% CI, 1.242-4.635) may serve as independent prognostic indicators in patients with BRAF-mutated advanced CRC. Surgical treatment of the primary tumor (P = 0.041; HR, 0.523; 95% CI, 0.280-0.974) was significantly associated with PFS too.
CONCLUSIONS: For patients with BRAF V600E-mutated advanced CRC, chemotherapy alone did not differ significantly in OS and PFS compared with chemotherapy + bevacizumab for advanced first-line therapy. Chemotherapy combined with targeted therapy did not render a survival benefit to these patients, demonstrating that the importance of developing new treatment options for this population.

Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm2). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs.
Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%).
Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01).
These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA.

BACKGROUND: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome.
METHODS: The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon\'s optimal two stage design. The primary end point of the study is 2 months PFS rate.
CONCLUSIONS: By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further.
BACKGROUND: EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.

BACKGROUND: Cancers arise owing to the accumulation of mutations in critical genes that leads to uncontrolled cell division and the avoidance of apoptosis. Among these oncogenes, BRAF is a potent mitogen-activated protein kinase (MAPK) pathway activator known to be somatically mutated by a glutamic acid to valine substitution at codon 600 (V600E). It is a common finding in various types of human cancers, including malignant melanoma and colorectal cancer (CRC), and is considered a poor prognostic factor and a predictive biomarker. The study aims to determine the incidence of BRAF V600E gene mutation in Lebanese patients with melanoma and CRC and its correlation with gender and age.
METHODS:  We conducted a retrospective cohort design study in which 210 and 132 patients diagnosed to have melanoma and CRC, respectively, were recruited from 2010 to 2019 from \"L\'Institut National de Pathologie,\" where a specific polymerase chain reaction is used to detect BRAF mutations. Data from digitized records were collected, including demographic characteristics (age and gender), cancer type, and BRAF mutation. The collected data were analyzed using SPSS Statistics version 20.0 (IBM Corp., Armonk, NY). A p-value < 0.05 was considered significant.
RESULTS: The incidence of BRAF mutation in melanoma is 88.10%. There is female predominance with a ratio of 2.6:1 (p = 0.240) and the majority of patients aged between 40 and 60 years (51.2%) with a mean age of 53.74 years. While in CRC, BRAF is mutated in 7.5% with a ratio of 1.2:1 of male predominance (p = 0.999). The majority of patients (54.8%) were between the ages of 60 and 80 years, with a mean age of 65.5 years.
CONCLUSIONS: BRAF is a frequent oncogenic mutation that is found in lethal tumors. Targeted therapies for these cancers interfere with developing more effective therapeutic strategies, which affect the treatment response in BRAF mutants and improve the prognosis of the patients.

Current therapeutic regimens for patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated colorectal cancer show unsatisfactory efficacy. To improve outcomes in this area, we assessed the safety and efficacy of a new protocol using vemurafenib and cetuximab combined with FOLFIRI (5-fluorouracil/leucovorin/irinotecan) in patients with BRAF V600E-mutated colorectal cancer.
This was an investigator-initiated, open-label, single-arm, phase II trial conducted in patients with BRAF V600E-mutated advanced colorectal cancer. Patients were eligible to receive FOLFIRI combined with vemurafenib and cetuximab. The primary end-point was the objective response rate, and the secondary end-points included disease control rate, progression-free survival, overall survival and safety. This trial is registered with ClinicalTrials.gov, NCT03727763.
Between 12th January 2018, and 18th June 2021, we screened 27 patients, 21 of which were enrolled in this study. Efficacy analysis showed that objective response rates were 81.0% (17/21; 95% confidence interval [CI] 57.4-93.7) in the intention-to-treat population and 85.0% (17/20, 95%CI 61.0-96.0) in the per-protocol population; two patients achieved complete response, and 15 patients achieved a partial response. In the entire cohort, the median progression-free survival was 9.7 months (95%CI 6.3-10.9), and the median overall survival for all patients was 15.4 months (95%CI 8.5-15.4). The most common adverse events (grade 3 to 4) were neutropenia (8/21), anaemia (3/21) and skin rash (3/21).
Vemurafenib and cetuximab can be safely combined with the FOLFIRI regimen, showing promising antitumour activity and tolerable toxicity in patients with BRAF V600E-mutated advanced colorectal cancer. This regimen warrants a further randomised study in phase III clinical trials.