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BRAF is a mediator that activates the mitogen‐activated protein kinase pathway. A mutation in BRAF can cause abnormal pathway activation, leading to cell proliferation. In a Phase II study, the combination therapy of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was found to be effective in non‐small cell lung cancer (NSCLC) patients with the BRAF mutation. However, this study has limited efficacy and safety data for elderly patients. We present a case of a patient who started treatment at 87 years old and showed a good prognosis, remaining alive 73 months from the start of treatment with no significant adverse events. The patient also maintained a partial response (PR) according to RECIST 1.1 at the last follow‐up. This case suggests that the dabrafenib and trametinib combination therapy is safe and effective for elderly NSCLC patients with the BRAF mutation. [ABSTRACT FROM AUTHOR]

Colorectal cancer usually develops from stepwise, multiple mutations involving oncogenes and tumor suppressor genes. Mutations in the BRAF and RAS genes that dysregulate MAPK signaling are strongly associated with human malignancies. Colorectal cancer with the BRAF V600E mutation that causes cell proliferation without the need for growth factors has a worse prognosis than those without mutations. A BRAF V600E mutation was identified as an adverse prognostic factor for progression-free and overall survival. In this study, we analyze two cases of colorectal cancer with the BRAF V600E mutation and the literature data to investigate potential pathophysiologic mechanisms underlying metastatic colorectal cancer.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Intraglandular dissemination is an important pathological feature of thyroid cancer, yet the biological characteristics of this phenomenon remain relatively underexplored. This paper aims to provide a comprehensive overview of its biological behaviors, protein expressions, and identification methods. Several retrospective studies have found that thyroid cancers with intraglandular dissemination have higher rates of lymph node metastasis, capsule invasion, and vascular invasion, exhibiting more aggressive biological behavior. Immunohistochemistry results show abnormal expression of proteins such as FKBP5, CENPF, CX26, KIF11, PTK7, which are associated with poor prognosis in thyroid cancers with intraglandular dissemination, offering potential guidance for specific targeted therapy in the future. Moreover, adjunctive techniques including ultrasound, fine-needle aspiration, and genetic testing offer valuable support in accurately identifying these cases, facilitating moreproactive treatment and closer follow-up. [ABSTRACT FROM AUTHOR]

Complete surgical resection of differentiated papillary thyroid cancer (PTC) is associated with an excellent prognosis. However, for locally invasive PTC, disease-specific morbidity and mortality increases when microscopic margin negative resection (R0) or complete macroscopic resection (R1) is not feasible. Neoadjuvant dabrafenib and trametinib (DT) used in BRAF V600E-positive, unresectable anaplastic thyroid cancer has allowed for R0 or R1 resection and improved survival rates. We demonstrate feasibility of using neoadjuvant DT in a patient with BRAF V600E and TERT-mutated PTC for whom R0/R1 resection was initially aborted due to predicted unacceptable morbidity. The patient was treated with neoadjuvant DT for 5 months, at which time disease was undetectable on imaging with near resolution on final pathology; however, subsequent rapid recurrence after discontinuation of neoadjuvant DT occurred. Neoadjuvant DT offers promise in future cohorts of patients with locally invasive BRAF V600E and TERT-mutated PTC for whom neoadjuvant therapy can reduce surgical morbidity while still allowing for R0/R1 resection. [ABSTRACT FROM AUTHOR]

Different pathological types of colorectal cancer have distinguished immune landscape, and the efficacy of immunotherapy will be completely different. Colorectal medullary carcinoma, accounting for 2.2–3.2%, is characterized by massive lymphocyte infiltration. However, the attention to the immune characteristics of colorectal medullary carcinoma is insufficient. We searched the literature about colorectal medullary carcinoma on PubMed through November 2023to investigate the hallmarks of colorectal medullary carcinoma's immune landscape, compare medullary carcinoma originating from different organs and provide theoretical evidence for precise treatment, including applying immunotherapy and BRAF inhibitors. Colorectal medullary carcinoma is a pathological subtype with intense immune response, with six immune characteristics and has the potential to benefit from immunotherapy. Mismatch repair deficiency, ARID1A missing and BRAF V600E mutation often occurs. IFN-γ pathway is activated and PD-L1 expression is increased. Abundant lymphocyte infiltration performs tumor killing function. In addition, BRAF mutation plays an important role in the occurrence and development, and we can consider the combination of BRAF inhibitors and immunotherapy in patients with BRAF mutant. The exploration of colorectal medullary carcinoma will arouse researchers' attention to the correlation between pathological subtypes and immune response, and promote the process of precise immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian serous borderline tumor (SBT) is a known precursor of low-grade serous carcinoma, and it has been reported that about 50% of SBTs are BRAF-mutated and that these tumors have a better prognosis. Therefore, early identification of the mutation is important for accurate treatment and follow-up of patients with SBT. It has been shown that eosinophilic cells (ECs) can be a histologic sign of a BRAF mutation. Therefore, the aim of our retrospective study was to evaluate the interobserver reproducibility for these cells. A BRAFV600E mutation was found in 45% of cases. The interobserver reproducibility in the assessment of ECs was substantial. The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively, so ECs in ovarian SBTs can be used for initial screening of the BRAFV600E mutation to stratify patients and establish a prognosis. According to recent reports, ovarian serous borderline tumor (SBT) harboring the BRAF V600E mutation is associated with a lower risk of progression to low-grade serous carcinoma. Preliminary observations suggest that there may be an association between eosinophilic cells (ECs) and the above-mentioned mutation, so this study aimed to evaluate interobserver reproducibility for assessing ECs. Forty-two samples of SBTs were analyzed for ECs with abundant eosinophilic cytoplasm. Immunohistochemical staining and genetic pro-filing were performed in all cases to verify the BRAF V600E mutation. A BRAF V600E mutation was found in 19 of 42 (45%) cases. Inter-observer reproducibility in the assessment of ECs was substantial (κ = 0.7). The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively. Patients with BRAF-mutated SBTs were significantly younger than those without mutation (p = 0.005). SBTs with BRAF mutation were less likely to be accompanied by non-invasive implants than wild-type SBT: 12% (2/17) versus 33% (6/18). Seven cases were excluded due to incomplete cytoreductive surgery. Nevertheless, Fisher's exact test showed no significant differences between the two groups (p = 0.228). Overall, this study strengthens the idea that ECs in ovarian SBTs may represent a mutation with prognostic significance, which can serve as a primary screening test for BRAF V600E mutation in this pathologic entity. [ABSTRACT FROM AUTHOR]

Objective: This Bayesian network meta‐analysis was performed to analyze the associations between clinicopathological characteristics and BRAF mutations in ameloblastoma (AM) patients and to evaluate the diagnostic accuracy. Materials and Methods: Four electronic databases were searched from 2010 to 2024. The search terms used were specific to BRAF and AM. Observational studies or randomized controlled trials were considered eligible. The incidence of BRAF mutation and corresponding clinicopathological features in AM patients were subjected to Bayesian network analyses and diagnostic accuracy evaluation. Results: A total of 937 AM patients from 20 studies were included. The pooled prevalence of BRAF mutations in AM patients was 72%. According to the Bayesian network analysis, BRAF mutations are more likely to occur in younger (odds ratio [OR], 2.3; credible interval [CrI]: 1.2–4.5), mandible site (OR, 3.6; 95% CrI: 2.7–5.2), and unicystic (OR, 1.6; 95% CrI: 1.1–2.4) AM patients. Similarly, higher diagnostic accuracy was found in the younger, mandible, and unicystic AM groups. Conclusions: The incidence, risk, and diagnostic accuracy of BRAF mutation in AM were greater in younger patients, those with mandible involvement, and those with unicystic AM than in patients with other clinicopathological features. In addition, there was a strong concordance in the diagnostic accuracy between molecular tests and immunohistochemical analysis. [ABSTRACT FROM AUTHOR]

Detecting low-abundance mutations is of particular interest in the fields of biology and medical science. However, most currently available molecular assays have limited sensitivity for the detection of low-abundance mutations. Here, we established a platform for detecting low-level DNA mutations with high sensitivity and accuracy by combining enhanced-ice-COLD-PCR (E-ice-COLD-PCR) and pyrosequencing with di-base addition (PDBA). The PDBA assay was performed by selectively adding one di-base (AG, CT, AC, GT, AT, or GC) instead of one base (A, T, C, or G) into the reaction at a time during sequencing primer extension and thus enabling to increase the sequencing intensity. A specific E-ice-COLD-PCR/PDBA assay was developed for the detection of the most frequent BRAF V600E mutation to verify the feasibility of our method. E-ice-COLD-PCR/PDBA assay permitted the reliable detection of down to 0.007% of mutant alleles in a wild-type background. Furthermore, it required only a small amount of starting material (20 pg) to sensitively detect and identify low-abundance mutations, thus increasing the screening capabilities in limited DNA material. The E-ice-COLD-PCR/PDBA assay was applied in the current study to clinical formalin-fixed paraffin-embedded (FFPE) and plasma samples, and it enabled the detection of BRAF V600E mutations in samples that appeared as a wild type using PCR/conventional pyrosequencing (CP) and E-ice-COLD-PCR/CP. E-ice-COLD-PCR/PDBA assay is a rapid, cost-effective, and highly sensitive method that could improve the detection of low-abundance mutations in routine clinical use. [ABSTRACT FROM AUTHOR]

Simple Summary: The diagnosis of hairy-cell leukemia (HCL) and HCL-like disorders including the variant form of HCL (HCL-V), splenic diffuse red pulp lymphoma (SDRPL) and splenic marginal zone lymphoma (SMZL) is a challenge in clinical practice. We discuss the major points for the diagnosis of HCL and HCL-like disorders and we propose recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients. Introduction: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAFV600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton's tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates. Results: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAFV600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) (IGHV) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment. Conclusion: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL). [ABSTRACT FROM AUTHOR]

Abstract BRAF is a mediator that activates the mitogen‐activated protein kinase pathway. A mutation in BRAF can cause abnormal pathway activation, leading to cell proliferation. In a Phase II study, the combination therapy of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was found to be effective in non‐small cell lung cancer (NSCLC) patients with the BRAF mutation. However, this study has limited efficacy and safety data for elderly patients. We present a case of a patient who started treatment at 87 years old and showed a good prognosis, remaining alive 73 months from the start of treatment with no significant adverse events. The patient also maintained a partial response (PR) according to RECIST 1.1 at the last follow‐up. This case suggests that the dabrafenib and trametinib combination therapy is safe and effective for elderly NSCLC patients with the BRAF mutation.

The v-raf murine sarcoma viral oncogenic homolog B1 (BRAF) V600E is a rare mutation that functions as an oncogenic driver in patients with non-small cell lung cancer (NSCLC) leading to the overactivation of the RAS-RAF-MEK-ERK (MAPK) pathway and the subsequent uncontrolled cell proliferation. Understanding the mechanism behind BRAF mutation, its inhibition, and relationship to the upstream and downstream effector is essential for advancing treatment strategies for NSCLC patients with the BRAF V600E mutation. Next-generation sequencing studies have identified the presence of breast cancer susceptibility gene 1/2 (BRCA1/2) mutations in NSCLC patients, which are pathogenic variants associated with breast, ovarian, and prostate cancers. Although poly ADP-ribose polymerase (PARP) inhibitors are currently an approved treatment option for malignant tumors linked to BRCA1/2 pathogenic variants, the therapeutic potential of PARP inhibitors in NSCLC remains unclear. The development of genetic testing provides a platform for investigating the pathophysiological mechanisms of genetic mutations above. Here, we report a novel case of a middle-aged non-smoking female diagnosed with BRAF V600E and BRCA2 germline mutated lung adenocarcinoma, who had previously undergone a diverse array of cancer-targeted therapies, including PARP inhibitor, before the identification of the BRAF V600E mutation. Following this, a combination of dabrafenib and trametinib was administered and induced a rapid and positive response within two months. Our case not only highlights the importance of dynamic and repetitive genetic testing in managing patients, but contributes to the growing body of clinical evidence supporting the efficacy of BRAF/MEK co-inhibition in patients harboring a BRAF V600E mutation and provokes thinking for further research into the impact of PARP inhibitors in BRCA1/2-mutated NSCLC. [ABSTRACT FROM AUTHOR]

Background: The advantages of the dissecting the metastatic lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) remain a great deal of controversies in papillary thyroid carcinoma (PTC) patients without clinical evidence. The purpose of our retrospective research was to investigate the predictive factors of the LN-prRLN in cN0 PTC patients. Methods and Materials: Altogether 251 consecutive cN0 PTC participants accepted unilateral or bilateral thyroidectomy accompanied with LN-prRLN dissection between June 2020 and May 2023 were included in the research. Then, univariate and multivariate logical regression analysis were conducted to analyze the relationship between the LN-prRLN and these predictive factors, and a predictive model was also developed. Surgical complications of LN-prRLN dissection were also presented. Results: The rate of LN-prRLN was 17.9% (45/251) in cN0 PTC patients after the analysis of postoperative histology. The age < 55 years, multifocality, microcalcification, and BRAFV600E mutation were identified to be predictive factors of LN-prRLN in cN0 PTC patients. The risk score for LN-prRLN was calculated: risk score = 1.192 × (if age < 55 years) + 0.808 × (if multifocality) + 1.196 × (if microcalcification in nodule) + 0.918 × (if BRAFV600E mutation in nodule). The rates of the transient hypoparathyroidism and hoarseness were 1.2% (3/251) and 2.0% (5/251), respectively. Conclusion: The age < 55 years, multifocality, microcalcification, and BRAFV600E mutation are independent predictors of the LN-prRLN in cN0 PTC patients. An effective predictive model was established for predicting the LN-prRLN in cN0 PTC patients, with the aim to better guide the surgical treatment of PTC. A thorough inspection of the lateral compartment is recommended in PTC patients with risk factors. The multicenter research with long-term follow-up should be carried out to ascertain the optimal surgical approach for patients with PTC. [ABSTRACT FROM AUTHOR]

Context The role of B-Raf proto-oncogene (BRAF) in papillary thyroid carcinoma (PTC) with Hashimoto thyroiditis (HT) is unknown. Objective We aimed to explore risk factors affecting lymph node (LN) metastasis and interaction effect of BRAF in PTC patients with HT. Methods We retrospectively collected the data of 994 PTC patients with HT who underwent surgery at the West China Hospital. We analyzed the correlations between preoperative characteristics and LN metastasis in overall, and different BRAFV600E -mutation patients. Logistic regression was applied to analyze the risk factors for LN metastasis. Finally, we performed an interaction effect analysis to identify the interaction effect of BRAF. Results The overall LN metastasis rate was 52.71% (524/994); the overall BRAF mutation rate was 26.9% (268/994). BRAF mutation rates were significantly different in LN metastasis and nonmetastasis patients (31.7% vs 21.5%; P <.001). In all 994 patients, age, body mass index (BMI), hypertension, tumor maximum diameter, BRAF mutation, tumor location, aspect ratio, calcification, and extrathyroidal invasion were risk factors for LN metastasis (P <.05). In BRAF -mutant patients, smoking, hypertension, maximum diameter, calcification, and multifocality were risk factors for LN metastasis (P <.05). In BRAF wild-type patients, age, BMI, maximum diameter, tumor location, aspect ratio, tumor shape, calcification, and extrathyroidal invasion were risk factors (P <.05). Additionally, we found statistically significant interactions between BRAF and BMI, hypertension, maximum diameter, and calcification (P <.05), suggesting the potential interaction effect of BRAF. Conclusion BRAF is a risk factor for LN metastasis in PTC with HT. Meanwhile, BRAF can interact with age, BMI, hypertension, and calcification, which together influence LN metastasis. [ABSTRACT FROM AUTHOR]

Background and Objectives: The most common mutation in malignant melanoma (MM) is the single-point mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) oncogene. Our study aims to evaluate BRAF V600E mutation, highlighting its frequency differences in primary versus metastatic MM. Materials and Methods: The study group comprised 133 patients diagnosed with MM in several county hospitals of the north-eastern region of Romania who have been assigned for investigation into BRAF V600E mutation in the private medical system. The material consisted of archived formalin-fixed paraffin-embedded (FFPE) blocks. BRAF V600E mutation was identified using the fully automated IdyllaTM BRAF mutation test system. Results: Out of the total of 133 cases, 78 cases were primary tumors, while 55 cases were metastatic MMs. Genetic analysis revealed the presence of BRAF V600E mutation in 66 cases (49.62%) and the wild-type genotype in 67 cases (50.37%). We found a statistically significant difference of the mutation frequency according to age (p = 0.0072). The mutated genotype was found in 45 cases out of 78 primary MMs (57.69%) and in 21 cases out of 55 secondary MMs (38.18%), with a statistically significant difference in favor of primary tumors (p = 0.0413). The correlations between the histopathological types, Clark's level, Breslow index, ulceration, and lymphovascular invasion, respectively, and the mutated genotype were not statistically significant. BRAF V600E mutation was identified in 15 out of 40 secondary tumors with lymph node location (37.5%) and in 6 out of 15 secondary tumors with another location (40%) without statistically significant differences between the mutation frequency and the location of the secondary tumors. Conclusions: Our results support MM high genetic heterogeneity, pointing out the relationship between BRAF V600E mutation and several clinicopathological characteristics, in primary and metastatic MMs, stressing the importance of BRAF testing implementation in Romania. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The predictive value of allele frequency (AF) of BRAF V600E and TERT mutations in papillary thyroid carcinoma (PTC) remains controversial. We aimed to investigate the AF of BRAF V600E and TERT mutations in intermediate-to-high risk PTC and their association between tumor invasiveness, prognosis, and other mutations. Probe hybridization capture and high-throughput sequencing were used to quantitatively test 40 gene loci in 94 intermediate-to-high recurrence risk PTC patients, combined with clinical characteristics and follow-up for retrospective analysis. BRAF V600E mutation AF was linked to a increased risk of thyroid capsule penetration, recurrence, and concurrent mutations. Concurrent mutations could lead to a worse prognosis and increased invasiveness. TERT promoter mutation frequently accompanied other mutations and resulted in a poorer prognosis. However, there was no clear association between the TERT mutation AF and tumor invasiveness or recurrence. The sensitivity and specificity of predicting recurrence in intermediate-to-high risk PTC with BRAF V600E mutation AF > 28.2% were 60 and 80%. Although genetic alterations in PTC can differ among different ethnicities, the AF of BRAF V600E and TERT mutations may be similar. The AF of BRAF V600E has the potential to be a novel indicator in predicting PTC invasiveness and prognosis. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the correlation among mutations in cancer-related genes, clinicopathologic features, and clinical outcome in classical papillary thyroid carcinoma (PTC). A total of 130 patients with classical PTC who underwent curative surgery between April 2012 and June 2023 at Hokuto Hospital were included. Mutations in targeted regions of 160 cancer-related genes were detected by next-generation sequencing (NGS)-based cancer panel testing. The BRAF V600E mutation was detected in 108 (83.1%) of 130 PTC patients. Among the 108 patients with the BRAF V600E mutation, other co-existing oncogenic mutations were found in 12 (9.2%) patients. When we divided into 3 groups of no mutations, BRAF V600E mutation alone, and BRAF V600E and other oncogenic mutations, significant differences were observed in terms of tracheal invasion (P = 0.0024), and bilateral neck lymph node metastasis (P = 0.0047). Kaplan–Meier analysis of overall survival (OS) revealed patients with BRAF V600E and other oncogenic mutations had significantly poorer survival than those with BRAF V600E mutation alone (P = 0.0026). Multivariate cox proportional hazard analysis revealed BRAF V600E and other oncogenic mutations was an independent prognostic factor for OS (HR: 10.559; 95%CI: 1.007-110.656, P = 0.0493). The BRAF V600E mutation co-existing with other oncogenic mutations but not the BRAF V600E mutation alone was associated with aggressive clinicopathologic features, resulting in poor prognosis in patients with classical PTC. Detection of oncogenic mutations using NGS-based cancer panel testing could enhance understanding of the clinical features of classical PTC. [ABSTRACT FROM AUTHOR]

Simple Summary: The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers. This study uses a proteolysis targeting chimera (PROTAC) to probe the role of BRAF V600E in colorectal and triple-negative breast cancer cells. The study reveals a diverse set of biochemical and proliferative responses to BRAF V600E degradation: some cancer cells are killed by BRAF degradation, while others utilize additional oncogenic drivers, such as Src kinase phosphatidylinositol 3-kinase, to resist the effect of BRAF degradation. These responses provide a mechanistic explanation for the efficacy of BRAF-targeted therapy for some cancers and the intrinsic resistance in others. The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the malignant tumors that pose a serious threat to human health. A particularly bad prognosis might be expected for colorectal tumors with the unique molecular subtype BRAF V600E mutation. With the development of precision therapy, the advent of molecularly targeted therapies and immune checkpoint inhibitors has improved the outcome of intermediate to advanced colorectal cancer. However, the duration of drug benefit is usually short, and overall survival and progression-free survival remain suboptimal. Therefore, investigators are exploring more rational, safe, and effective drug combination regimens through clinical trials to provide longer survival for patients with such genetic mutations with metastatic colorectal cancer (mCRC). This article reviews the progress of clinical research on molecularly targeted drugs, immune checkpoint inhibitors, first-line chemotherapeutic agents, and different combination therapy regimens (including different targeted drug combinations, immune combination targeting, and chemotherapy combination targeting) for colorectal cancer patients with BRAF V600E mutation, which provides a reference for further in-depth clinical exploration of the treatment of colorectal cancer patients with BRAF V600E mutation. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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. Results: 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-thecurve 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective was to evaluate the diagnostic performance of BRAFV600E mutation for malignant, and to identify clinical characteristics associated with positive BRAFV600E mutation in low-risk cytological and ultrasound diagnostic thyroid nodules. This aims to identify patients who may benefit from BRAFV600E mutation testing and subsequent surgical intervention.Patients and Methods: We analysis the clinical characteristics correlated with BRAFV600E mutation in our detection cohort, including 204 patients with 217 thyroid nodules, and separate analyses were performed in 103 thyroid nodules with benign cytological result. Signaling pathway and immune response associated with age and BRAFV600E mutation status were also evaluated in Asian patients with thyroid cancer from the Cancer Genome Atlas (TCGA) dataset.Results: The positive BRAFV600E mutation was significantly associated with higher Ultrasound (US) classification (p< 0.001) and fine-needle aspiration (FNA) categories (p< 0.001). BRAFV600E mutation as a risk factor for malignancy, showing the optimal diagnostic efficacy for malignancy combined with FNA categories, with the AUC was 0.923. Otherwise, BRAFV600E mutation is a risk factor in screening malignancy in low-risk FNA and US classification, which is significant correlation with patients age. Patients over 50 years old exhibiting a higher percentage of positive BRAFV600E mutation when both ultrasound and FNA results indicate benign conditions, with higher risk of malignancy.Conclusion:BRAFV600E mutation is an accurate adjunctive diagnostic marker on FNA to screen malignancy. In low risk of both ultrasound and FNA results, the positive BRAFV600E was significant increased in patients over 50 years old, which have higher risk of malignancy. Thus, the BRAFV600E mutation detection and further surgery should be strengthened in older patients with benign cytological and US results thyroid nodules. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) metastasizes to various organs, while cutaneous metastases are rare. Although there have been several previous reports of axillary cutaneous metastases with other metastases of CRC, there has never been a report of axillary cutaneous metastasis of CRC that could be treated with curative-intent surgery. Case presentation A 68-year-old female was diagnosed with an axillary cutaneous tumor and ascending colon cancer with invasion to the duodenum. Histopathological and immunohistochemical analysis revealed that the axillary cutaneous tumor showed adenocarcinoma and the same expression pattern for cytokeratin 7, cytokeratin 20, and CDX2 as the ascending colon cancer, and that proved to be KRAS–NRAS wild type, MSI-H, and with a BRAF V600E mutation. The patient underwent a two-stage resection with curative intent after receiving neoadjuvant chemotherapy which consisted of one cycle of modified FOLFOX6 followed by two cycles of FOLFOXIRI. During and after the two operations, the patient received a total of nine cycles of modified FOLFOX6 as adjuvant chemotherapy. Two years after the initial surgery, and 1 year and 8 months after the second surgery, the patient is alive without recurrence. Conclusions To the best of our knowledge, this is the first report of axillary cutaneous metastasis of CRC with microsatellite instability-high and BRAF V600E mutation that could be treated with curative-intent surgery. It is important to recognize the presence of such cases for the accurate diagnosis and treatment of CRC with cutaneous metastasis.

We report a case of congenital multisystem Langerhans cell histiocytosis with cutaneous and hematopoietic involvement. After the failure of first‐line (vinblastine and prednisolone) and second‐line (vincristine and cytarabine) therapies, treatment with cobimetinib, a mitogen‐activated protein kinase (MEK) inhibitor, led to the remission of disease and a sustained response after 11 months of ongoing treatment. Protein kinase inhibitors targeting BRAF or MEK could represent a promising future therapeutic option, also in children with LCH. [ABSTRACT FROM AUTHOR]

Abstract Background Metanephric stromal tumors (MST) are rare benign renal tumors that mainly occur in infants and children. Approximately 72% of MST in children have the B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutation. To date, only five cases of adult MSTs have been reported and no clear genetic alterations have been found. Case presentation We report a case of MST in a 45-year-old woman who complained of left lower back pain for a week, accompanied by hypertension (150/79 mmHg). Magnetic resonance imaging (MRI) showed an abnormally enhanced nodule (1.1 cm in the middle of the left kidney), which was histopathologically consistent with an MST. The BRAF V600E mutation was not detected in tumor cells using PCR and next-generation sequencing (NGS). However, a platelet-derived growth factor receptor alpha (PDGFRA) mutation was detected in this case using NGS. The patient showed no recurrence or metastasis nine months after partial nephrectomy, and her blood pressure was consistently normal. Conclusion This is the first report of alterations in PDGFRA in MSTs. This result advances our knowledge of genetic variations in adult MSTs, which may have different gene alterations from MSTs in children.

Background: Colorectal cancer (CRC) metastasizes to various organs, while cutaneous metastases are rare. Although there have been several previous reports of axillary cutaneous metastases with other metastases of CRC, there has never been a report of axillary cutaneous metastasis of CRC that could be treated with curative-intent surgery. Case presentation: A 68-year-old female was diagnosed with an axillary cutaneous tumor and ascending colon cancer with invasion to the duodenum. Histopathological and immunohistochemical analysis revealed that the axillary cutaneous tumor showed adenocarcinoma and the same expression pattern for cytokeratin 7, cytokeratin 20, and CDX2 as the ascending colon cancer, and that proved to be KRAS–NRAS wild type, MSI-H, and with a BRAF V600E mutation. The patient underwent a two-stage resection with curative intent after receiving neoadjuvant chemotherapy which consisted of one cycle of modified FOLFOX6 followed by two cycles of FOLFOXIRI. During and after the two operations, the patient received a total of nine cycles of modified FOLFOX6 as adjuvant chemotherapy. Two years after the initial surgery, and 1 year and 8 months after the second surgery, the patient is alive without recurrence. Conclusions: To the best of our knowledge, this is the first report of axillary cutaneous metastasis of CRC with microsatellite instability-high and BRAF V600E mutation that could be treated with curative-intent surgery. It is important to recognize the presence of such cases for the accurate diagnosis and treatment of CRC with cutaneous metastasis. [ABSTRACT FROM AUTHOR]

Background: Determining the clinical and subclinical characteristics related to the recurrence status in patients with a thyroid carcinoma has great significance for prognosis, prediction of recurrence and monitoring of treatment outcomes. This study aimed to determine the association between recurrence rate and some characteristics in patients with thyroid carcinoma. Patients and Methods: The study was conducted by descriptive method with longitudinal follow-up on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam, from July 2013 to December 2016. Results: Univariate analysis showed that there was a relationship between the recurrence characteristics in the studied patients and the characteristics of lymph node metastasis (P = 0.026; OR = 15; 95% CI = 1.4-163.2) and BRAF V600E mutation status (P = 0.01; OR = 3.41; 95% CI = 1.31-8.88). When analysing the multivariable Logistic regression model, there was a positive correlation between the occurrence of BRAF V600E gene mutation (P = 0.032; OR = 17.649; 95% CI = 1.290-241.523) and male sex (P = 0.036; OR = 12.788; 95% CI = 1.185-137.961) and the occurrence of recurrence in study patients. The mean time to relapse was earlier in male patients than in female patients (P = 0.02). The mean time to relapse in patients with the BRAF V600E mutation (31.81 ± 1.14 months) was shorter than the mean time to relapse in the group without the mutation (57.82 ± 2.08 months) (P = 0.01). The group of patients with mutations in the BRAF V600E gene increased the risk of recurrence compared with the group without the mutation (HR = 9.14, P = 0.04). Conclusion: There is a positive correlation between recurrence and masculinity, lymph node metastasis and the occurrence of BRAF V600E mutations in thyroid carcinoma patients. [ABSTRACT FROM AUTHOR]

Context: To date there is no study on the feasibility of radiofrequency ablation (RFA) for papillary thyroid microcarcinomas (PTMCs) with BRAF V600E mutation. Objective: This study was designed to evaluate the efficiency, safety, and prognosis of ultrasound (US)-guided percutaneous RFA for unifocal PTMCs with BRAF V600E mutation. Materials and Methods: Sixty patients with 60 unifocal BRAF V600E mutation-positive PTMCs who received US-guided RFA between January 2020 and December 2021 were retrospectively analyzed. The mean maximum PTMC tumor diameter was 5.8 ± 1.7 mm (range, 2.5-10.0 mm). All PTMCs were pathologically confirmed by fine needle aspiration or core needle biopsy, and BRAF V600E mutation was confirmed to be positive by real-time fluorescent quantitative polymerase chain reaction. Contrast-enhanced ultrasound (CEUS) was performed immediately after RFA to evaluate whether PTMCs were extendedly ablated. Ultrasound was performed 1, 3, 6, and 12 months after RFA and every 6 months thereafter to evaluate the changes in the ablation zone, local recurrence, and cervical lymph node metastasis (LNM). The complications were recorded and evaluated. Results: Extended ablation was achieved in all enrolled patients. The ablation zone sizes increased immediately after RFA compared with those of tumors before treatment. One month later, the ablation zone sizes were smaller than immediately after RFA. At the last follow-up assessment, 42 nodules (70.0%) completely disappeared and the ablation zones of 18 nodules (30.0%) showed fissure-like changes. No local recurrence or cervical LNM was detected. Voice change (1.7%) was the only major complication. Conclusion: RFA is effective and safe in treating unifocal PTMCs with BRAF V600E mutation, especially when surgery is not feasible or refused by patients who are unwilling to continue active surveillance. [ABSTRACT FROM AUTHOR]

Craniopharyngiomas (CPs) are rare primary brain epithelial tumors arising in the suprasellar region from remnants of Rathke's pouch. About 50% originate at the level of the third ventricle floor, including the hypothalamus (HT). CPs are characterized by a low proliferation rate and symptoms due to mass effect and local infiltration and are managed primarily with surgery and radiotherapy. Gross total removal of a CP will reduce the recurrence rate but increases the risk of HT damage. Today, subtotal resection is the goal and will reduce the risk of HT damage. There are two histological subtypes of CP—adamantinomatous (ACP) and papillary CP (PCP)—that differ in their genesis and age distribution. ACPs are driven by somatic mutations in CTNNB1 gene (encoding β‐catenin), and PCPs frequently harbor somatic BRAF V600E mutations. There are also two phenotypes of outcome, the one with a rather good outcome without HT damage and the other with HT damage where recurrent operation with additional cranial radiotherapy results in HT obesity (HO), affecting psychosocial life and cognitive dysfunction. The group with HO suffers from metabolic syndrome, lower basal metabolic rate, and leptin and insulin resistances. There is currently no successful treatment for HO. The group with HT damage suffers from cognitive dysfunction with attention deficits, impaired episodic memory, and processing speed. Diffusion tensor imaging has shown significant microstructural white matter alteration in several areas important for cognition. Recently, complete or partial tumor response was shown to targeted therapy, with BRAF and Mekinist inhibitors for PCPs with BRAF V600E mutation. [ABSTRACT FROM AUTHOR]

Mutation in the BRAF V600E gene in metastatic colorectal cancer (CRC) occurs in 510% of cases and is a significant problem due to the aggressive course and extremely unfavorable prognosis. In recent years, new treatment options for BRAF mutated CRC have been emerging, for example, combinations of BRAF inhibitors, anti-EGFR antibodies with optional addition of MEK inhibitors. The possibility of local treatment methods is also being discussed. Objective: to evaluate the effectiveness of triple targeted therapy in BRAF-mutated metastatic colorectal cancer. On the example of 2 clinical cases of long-term treatment of patients with this molecular subtype, possible treatment options are discussed.

Langerhans cells, often referred to as the "macrophages of the skin", are dendritic cells that normally reside in the epidermis and papillary dermis. Just like macrophages, they function as antigenpresenting cells that activate naive T cells. Certain mutations such as those involving the BRAF gene can cause unopposed production of Langerhans cells, which is known as Langerhans cell histiocytosis (LCH). LCH triggers an inflammatory immune response that causes systemic manifestations such as fever and fatigue, as well as other manifestations depending on the affected organs. The pathogenesis behind LCH remains poorly understood. It is still unknown whether it is a neoplastic process or a reactive cancer-mimicking illness. Diagnosis of LCH is confirmed by biopsy, and treatment is largely dependent on the extent and severity of the disease. Common treatments include corticosteroids, excision, radiation, and chemotherapy. We present a case of a 1- year-old Saudi male with LCH. [ABSTRACT FROM AUTHOR]

Simple Summary: Although papillary thyroid carcinoma (PTC) is generally a highly curable disease, there is a small subgroup of PTC cases that behaves more aggressively, with high rates of disease recurrence, tumor progression and distant metastases. These patients need to be accurately identified for an appropriate, more-aggressive therapeutical approach. BRAFV600E mutation is the most prevalent genetic event in PTC. However, its role as a prognostic factor remains unclear. Herein, we aimed to assess the prognostic value of BRAFV600E mutation as a single factor, as well as in synergic interaction with other demographic and pathological risk factors in a series of 127 PTCs. Our results highlight a significant impact of BRAFV600E mutation on event-free survival among PTC patients. Nevertheless, BRAFV600E mutation status should not be used as an independent predictive factor in PTC patients, but rather should be integrated in the context of other clinicopathological risk factors. We aimed to evaluate the prognostic value of BRAFV600E mutation in a series of 127 papillary thyroid carcinoma (PTC) cases as a single factor, and in synergic interaction with other standard risk factors. BRAFV600E mutation was assessed by real-time PCR. Event-free survival (EFS) was calculated between the date of the first evaluation and the date of occurrence of an adverse event or the date of the last known status. The prevalence of BRAFV600E mutation was 57.2%. The Kaplan–Meier analysis showed a significant reduction of EFS among cases harboring BRAFV600E mutation compared to non-mutated cases (p = 0.010). In addition, BRAFV600E mutation was found to better predict adverse outcomes when associated with the following risk factors: age ≥ 55 years old (p < 0.001), male gender (p < 0.001), conventional (p = 0.005) and tall cell (p = 0.014) histology, tumor size > 40 mm (p = 0.001), extrathyroidal extension (p = 0.001), multifocality (p = 0.001) and lymph node metastasis (p < 0.001). In univariate analysis, a 3.74-fold increased risk for a reduced EFS (p = 0.018) was found for BRAFV600E-mutated cases, but no increased risk was further confirmed by multivariate analysis. Our results highlight that BRAFV600E mutation cannot be used alone as an independent predictive factor in PTC patients, but is prognostically valuable if integrated in the context of other clinicopathological risk factors. [ABSTRACT FROM AUTHOR]

BRAF and cMET exon 14 skipping are rare mutations of NSCLC. The treatment sequence in these cases for the first and second line is not clear. An international registry was created for patients with advanced NSCLC harboring BRAF or cMET exon 14 skipping mutations, diagnosed from January 2017 to June 2022. Clinicopathological and molecular data and treatment patterns were recorded. Data on 58 patients, from eight centers across five countries, were included in the final analysis. We found that 40 patients had the cMET exon 14 skipping mutation and 18 had the BRAF V600E mutation. In total, 53 and 28 patients received first- and second-line treatments, respectively, among which 52.8% received targeted therapy (TT) in the first line and 53.5% in the second line. The overall response rate (ORR) and disease control rate (DCR) for first-line treatment with TT vs. other treatment such as immune checkpoint inhibitors ± chemotherapy (IO ± CT) were 55.6% vs. 21.7% (p = 0.0084) and 66.7% vs. 39.1% (p = 0.04), respectively. The type of treatment in first-line TT vs. other affected time to treatment discontinuation (TTD) was 11.6 m vs. 4.6 m (p= 0.006). The overall survival for the whole group was 15.4 m and was not statistically affected by the type of treatment (19.2 m vs. 13.5 m; p = 0.83). [ABSTRACT FROM AUTHOR]

Background: The pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of NSCLC with rapid progression and poor prognosis, and is resistant to conventional chemotherapy. Most PSC cases have potential targetable genomic alterations. Approximately 7% of PSC patients have BRAF mutations, and the efficacy of dabrafenib and trametinib in BRAFV600E mutated PSC is unclear. Case presentation: Our report describes a patient with mutated BRAFV600E PSC who underwent surgery and adjuvant chemotherapy early but quickly relapsed. Both chemotherapy and immunotherapy were ineffective for him, combined dabrafenib and trametinib produced a 6-month progression-free survival, and a partial response was observed in the tumor response evaluation. As a result of financial pressure, he stopped taking the targeted drugs, and his disease rapidly progressed. Conclusion: Dabrafenib combined with trametinib provides partial remission in patients with advanced PSC with BRAFV600E mutations, and large-scale NGS panels could offer more options for PSC treatment. [ABSTRACT FROM AUTHOR]

The presence of a BRAF-V600E mutation in metastatic colorectal cancer (mCRC) is observed in approximately 12% of cases and is associated with poor prognosis and aggressive disease. Unlike melanoma, the development of successful BRAF blockade in colorectal cancer has been complex. The phase III BEACON trial made significant progress in the development of BRAF inhibitors by establishing encorafenib-cetuximab as the new standard of care for patients with mCRC who have progressed to one or two previous lines of treatment. Nonetheless, not all patients respond to encorafenib-based combinations, and some responses are short-lived. Identifying new strategies to boost antitumor activity and improve survival is paramount. The development of targeted therapy for BRAF-V600E mCRC starting with BRAF inhibitors as monotherapy through novel combinations with anti-VEGF or anti-PD1 agents to enhance antitumor activity is reviewed, with a particular focus on the development of predictive and prognostic biomarkers. There is a crucial need to better understand tumor biology and develop accurate and reliable biomarkers to enhance the antitumor activity of encorafenib-based combinations. The RNF43 mutation is an accurate and reliable predictive biomarker of response, and combinations that target crosstalk between the MAPK pathway, the immune system, and WNT pathways seem promising. [ABSTRACT FROM AUTHOR]

Background: Metanephric stromal tumors (MST) are rare benign renal tumors that mainly occur in infants and children. Approximately 72% of MST in children have the B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutation. To date, only five cases of adult MSTs have been reported and no clear genetic alterations have been found. Case presentation: We report a case of MST in a 45-year-old woman who complained of left lower back pain for a week, accompanied by hypertension (150/79 mmHg). Magnetic resonance imaging (MRI) showed an abnormally enhanced nodule (1.1 cm in the middle of the left kidney), which was histopathologically consistent with an MST. The BRAF V600E mutation was not detected in tumor cells using PCR and next-generation sequencing (NGS). However, a platelet-derived growth factor receptor alpha (PDGFRA) mutation was detected in this case using NGS. The patient showed no recurrence or metastasis nine months after partial nephrectomy, and her blood pressure was consistently normal. Conclusion: This is the first report of alterations in PDGFRA in MSTs. This result advances our knowledge of genetic variations in adult MSTs, which may have different gene alterations from MSTs in children. [ABSTRACT FROM AUTHOR]

Abstract 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. Conclusion 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.

Purpose: 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. Methods: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). Results: 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). Conclusion: 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: Determining the clinical and subclinical characteristics related to the recurrence status in patients with a thyroid carcinoma has great significance for prognosis, prediction of recurrence and monitoring of treatment outcomes. This study aimed to determine the association between recurrence rate and some characteristics in patients with thyroid carcinoma. Patients and Methods: The study was conducted by descriptive method with longitudinal follow-up on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam, from July 2013 to December 2016. Results: Univariate analysis showed that there was a relationship between the recurrence characteristics in the studied patients and the characteristics of lymph node metastasis (P = 0.026; OR = 15; 95% CI = 1.4–163.2) and BRAF V600E mutation status (P = 0.01; OR = 3.41; 95% CI = 1.31–8.88). When analysing the multivariable Logistic regression model, there was a positive correlation between the occurrence of BRAF V600E gene mutation (P = 0.032; OR = 17.649; 95% CI = 1.290–241.523) and male sex (P = 0.036; OR = 12.788; 95% CI = 1.185–137.961) and the occurrence of recurrence in study patients. The mean time to relapse was earlier in male patients than in female patients (P = 0.02). The mean time to relapse in patients with the BRAF V600E mutation (31.81 ± 1.14 months) was shorter than the mean time to relapse in the group without the mutation (57.82 ± 2.08 months) (P = 0.01). The group of patients with mutations in the BRAF V600E gene increased the risk of recurrence compared with the group without the mutation (HR = 9.14, P = 0.04). Conclusion: There is a positive correlation between recurrence and masculinity, lymph node metastasis and the occurrence of BRAF V600E mutations in thyroid carcinoma patients.

Abstract 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. Discussion 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. Trial registration EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.

Background & Objective: Epithelial ovarian cancer (EOC) is the most prevalent type of ovarian cancer. Previous studies have elucidated different pathways for the progression of this malignancy. The mutation in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene, a member of the MAPK/ERK signaling pathway, plays a role in the development of EOC. The current study aimed to determine the frequency of the BRAF V600E mutation in ovarian serous and mucinous tumors, including borderline and carcinoma subtypes. Methods: A total of 57 formalin-fixed paraffin-embedded samples, including serous borderline tumors (SBTs), low-grade serous carcinomas (LGSCs), high-grade serous carcinomas (HGSCs), mucinous borderline tumors (MBTs), and mucinous carcinomas, and 57 normal ovarian tissues were collected. The BRAF V600E mutation was analyzed using polymerase chain reaction (PCR) and sequencing. Results: While 40% of the SBT harbor BRAF mutation, we found no BRAF mutation in the invasive serous carcinoma (P=0.017). Also, there was only 1 BRAF mutation in MBT and no mutation in mucinous carcinomas. In addition, we found no mutation in the control group. Conclusion: The BRAF mutation is most frequent in borderline tumors but not in invasive serous carcinomas. It seems that 2 different pathways exist for the development of ovarian epithelial neoplasms: one for borderline tumors and the other for high-grade invasive carcinomas. Our study supports this hypothesis. The BRAF mutation is rare in mucinous neoplasms. [ABSTRACT FROM AUTHOR]

Langerhans cells, often referred to as the “macrophages of the skin”, are dendritic cells that normally reside in the epidermis and papillary dermis. Just like macrophages, they function as antigen-presenting cells that activate naive T cells. Certain mutations such as those involving the BRAF gene can cause unopposed production of Langerhans Cells, which is known as Langerhans Cell Histiocytosis (LCH). LCH triggers an inflammatory immune response that causes systemic manifestations such as fever and fatigue, as well as other manifestations depending on the affected organs. The pathogenesis behind LCH remains poorly understood. It is still unknown whether it is a neoplastic process or a reactive cancer-mimicking illness. Diagnosis of LCH is confirmed by biopsy, and treatment is largely dependent on the extent and severity of the disease. Common treatments include corticosteroids, excision, radiation, and chemotherapy. We present a case of a 1-year-old Saudi male with LCH.

BackgroundThe pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of NSCLC with rapid progression and poor prognosis, and is resistant to conventional chemotherapy. Most PSC cases have potential targetable genomic alterations. Approximately 7% of PSC patients have BRAF mutations, and the efficacy of dabrafenib and trametinib in BRAFV600E mutated PSC is unclear.Case presentationOur report describes a patient with mutated BRAFV600E PSC who underwent surgery and adjuvant chemotherapy early but quickly relapsed. Both chemotherapy and immunotherapy were ineffective for him, combined dabrafenib and trametinib produced a 6-month progression-free survival, and a partial response was observed in the tumor response evaluation. As a result of financial pressure, he stopped taking the targeted drugs, and his disease rapidly progressed.ConclusionDabrafenib combined with trametinib provides partial remission in patients with advanced PSC with BRAFV600E mutations, and large-scale NGS panels could offer more options for PSC treatment.

Background and Objectives: The most common mutation in malignant melanoma (MM) is the single-point mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) oncogene. Our study aims to evaluate BRAF V600E mutation, highlighting its frequency differences in primary versus metastatic MM. Materials and Methods: The study group comprised 133 patients diagnosed with MM in several county hospitals of the north-eastern region of Romania who have been assigned for investigation into BRAF V600E mutation in the private medical system. The material consisted of archived formalin-fixed paraffin-embedded (FFPE) blocks. BRAF V600E mutation was identified using the fully automated IdyllaTM BRAF mutation test system. Results: Out of the total of 133 cases, 78 cases were primary tumors, while 55 cases were metastatic MMs. Genetic analysis revealed the presence of BRAF V600E mutation in 66 cases (49.62%) and the wild-type genotype in 67 cases (50.37%). We found a statistically significant difference of the mutation frequency according to age (p = 0.0072). The mutated genotype was found in 45 cases out of 78 primary MMs (57.69%) and in 21 cases out of 55 secondary MMs (38.18%), with a statistically significant difference in favor of primary tumors (p = 0.0413). The correlations between the histopathological types, Clark’s level, Breslow index, ulceration, and lymphovascular invasion, respectively, and the mutated genotype were not statistically significant. BRAF V600E mutation was identified in 15 out of 40 secondary tumors with lymph node location (37.5%) and in 6 out of 15 secondary tumors with another location (40%) without statistically significant differences between the mutation frequency and the location of the secondary tumors. Conclusions: Our results support MM high genetic heterogeneity, pointing out the relationship between BRAF V600E mutation and several clinicopathological characteristics, in primary and metastatic MMs, stressing the importance of BRAF testing implementation in Romania.

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.