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BACKGROUND: The objective of this study is to evaluate the diagnostic accuracy of plasma-based liquid biopsy for the detection of the BRAF V600E mutation in circulating cell-free DNA from patients with ameloblastoma. METHODS: This is a prospective diagnostic accuracy study conducted based on the Standards for Reporting Diagnostic Accuracy recommendations. The index test was the plasma-based liquid biopsy, whereas the reference standard was the conventional tissue biopsy. The target condition was the detection of BRAF V600E mutation. The study population consisted of individuals with ameloblastoma recruited from three tertiary hospitals from Brazil. A negative control group composed of three individuals with confirmed wild-type BRAF lesions were included. The participants underwent plasma circulating cell-free DNA and tumor tissue DNA isolation, and both were submitted to using competitive allele-specific TaqMan™ real-time polymerase chain reaction technology mutation detection assays. Sensitivity and specificity measures and positive and negative predictive values were calculated. RESULTS: Twelve patients with conventional ameloblastoma were included. BRAF V600E mutation was detected in 11/12 (91.66%) ameloblastoma tissue samples. However, the mutation was not detected in any of the plasma-based liquid biopsy circulating cell-free DNA samples in both ameloblastomas and negative control group. The sensitivity and specificity of plasma-based liquid biopsy for the detection of the BRAF V600E mutation in circulating cell-free DNA was 0.0 and 1.0, respectively. The agreement between index test and reference standard results was 26.66%. CONCLUSION: Plasma-based liquid biopsy does not seem to be an accurate method for the detection of the BRAF V600E mutation in circulating circulating cell-free DNA from patients with ameloblastoma, regardless of tumor size, anatomic location, recurrence status, and other clinicopathological features.

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Anaplastic thyroid cancer (ATC) is an infrequent thyroid tumor that usually occurs in elderly patients. There is often a history of previous differentiated thyroid cancer suggesting a biological progression. It is clinically characterized by a locally invasive cervical mass of rapid onset. Metastases are found at diagnosis in 50% of patients. Due to its adverse prognosis, a prompt diagnosis is crucial. In patients with unresectable or metastatic disease, multimodal therapy (chemotherapy and external beam radiotherapy) has yielded poor outcomes with 12-month overall survival of less than 20%. Recently, significant progress has been made in understanding the oncogenic pathways of ATC, leading to the identification of BRAF V600E mutations as the driver oncogene in nearly 40% of cases. The combination of the BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) showed outstanding response rates in BRAF-mutated ATC and is now considered the standard of care in this setting. Recently, it was shown that neoadjuvant use of DT followed by surgery achieved 24-month overall survival rates of 80%. Although these approaches have changed the management of ATC, effective therapies are still needed for patients with BRAF wild-type ATC, and high-quality evidence is lacking for most aspects of this neoplasia. Additionally, in real-world settings, timely access to multidisciplinary care, molecular testing, and targeted therapies continues to be a challenge. Health policies are warranted to ensure specialized treatment for ATC.The expanding knowledge of ATC´s molecular biology, in addition to the ongoing clinical trials provides hope for the development of further therapeutic options.

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BACKGROUND: The BRAF p.V600E genetic variant facilitates the pathogenesis of various tumors by triggering tumor proliferation and progression. The aim of this study was to analyze the prevalence of BRAF p.V600E in benign mixed epithelial and mesenchymal and malignant odontogenic tumors. In addition, we discussed the different detection methods used to assess for aberrant BRAF. METHODS: This systematic review followed the PRISMA guidelines and was registered in Prospero (CRD42023445689). A comprehensive search of the PubMed/MEDLINE, Scopus, Web of Science, and Embase electronic databases was performed to answer the question "What is the prevalence of the BRAF p.V600E mutation in benign mixed and malignant odontogenic tumors?" The methodological quality of the selected studies was assessed using the JBI's Critical Appraisal Tool. RESULTS: Initially, 387 records were identified, but only 11 articles met the inclusion criteria. A total of 70 patients with benign mixed epithelial and mesenchymal odontogenic tumors and 63 with malignant odontogenic tumors were included in the analysis. We found that the BRAF p.V600E mutation had a prevalence of 31.42% in mixed tumors and 26.98% in malignant odontogenic tumors. Moreover, immunohistochemistry showed high concordance with DNA-based molecular methods. CONCLUSION: In general, the BRAF p.V600E variant exhibited a prominent prevalence in mixed and malignant odontogenic tumors. However, most of the findings are based on small cohorts of patients and further studies with larger cohorts are needed.

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Over the last years, the incidence of melanoma, the deadliest form of skin cancer, has risen significantly. Nearly half of the melanoma patients exhibit the BRAFV600E mutation. Although the use of BRAF and MEK inhibitors (BRAFi and MEKi) showed an impressive success rate in melanoma patients, durability of response remains an issue because tumor quickly becomes resistant. Here, we generated and characterized Lu1205 and A375 melanoma cells resistant to vemurafenib (BRAFi). Resistant cells (Lu1205R and A375R) exhibit higher IC50 (5-6 fold increase) and phospho-ERK levels and 2-3 times reduced apoptosis than their sensitive parents (Lu1205S and A375S). Moreover, resistant cells are 2-3 times bigger, display a more elongated morphology and have a modulation of migration capacity. Interestingly, pharmacological inhibition of sphingosine kinases, that prevents sphingosine-1-phosphate production, reduces migration of Lu1205R cells by 50 %. In addition, although Lu1205R cells showed increased basal levels of the autophagy markers LC3II and p62, they have decreased autophagosome degradation and autophagy flux. Remarkably, expression of Rab27A and Rab27B, which are involved in the release of extracellular vesicles are dramatically augmented in resistant cells (i.e. 5-7 fold increase). Indeed, conditioned media obtained from Lu1205R cells increased the resistance to vemurafenib of sensitive cells. Hence, these results support that resistance to vemurafenib modulates migration and the autophagic flux and may be transferred to nearby sensitive melanoma cells by factors that are released to the extracellular milieu by resistant cells.

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OBJECTIVE: The objective of this systematic review with meta-analysis was to critically evaluate the available data on the association of the BRAF V600E mutation and recurrence rate of ameloblastomas. MATERIALS AND METHODS: This systematic review was registered in Prospero (CRD42020183645) and performed based on the PRISMA statement. A comprehensive search in PubMed, Web of Science, Scopus and Cochrane Library databases was performed in order to answer the question "Does BRAF V600E mutation affect recurrence rate of ameloblastomas?" Methodological quality and risk of bias of the selected studies were assessed with JBI Critical Appraise Tool. Meta-analysis of quantitative data was conducted with RevMan 5.3 and Jamovi 2.3. RESULTS: The initial search identified 302 articles, and 21 met the inclusion criteria. A total of 855 subjects with ameloblastoma were included in the analysis. The pooled measures for frequency of BRAF V600E mutation was 65.30% (95% CI: 0.56-0.75; p < .001; I2 = 90.85%; τ = 0.205; p < .001), and the pooled recurrence rate was 25.30% (95% CI: 0.19-0.31; p < .001; I2 = 79.44%; τ = 0.118; p < .001). No differences in recurrence rate were observed between the BRAF V600E and wild type BRAF ameloblastomas, with a pooled Odds Ratio of 0.93 (95% CI: 0.56-1.54; p = .78; I2 = 31%; p = .09). CONCLUSIONS: BRAF V600E mutation is a frequent event in ameloblastomas, but does not increase nor reduce its recurrence rate, and thus have a limited value in predicting its prognosis.

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Research from the last 20 years has provided important insights into the molecular pathogenesis of craniopharyngiomas (CPs). Besides the well-known clinical and histological differences between the subtypes of CPs, adamantinomatous (ACP) and papillary (PCP) craniopharyngiomas, other molecular differences have been identified, further elucidating pathways related to the origin and development of such tumors. The present minireview assesses current knowledge on embryogenesis and the genetic, epigenetic, transcriptomic, and signaling pathways involved in the ACP and PCP subtypes, revealing the similarities and differences in their profiles. ACP and PCP subtypes can be identified by the presence of mutations in CTNNB1 and BRAF genes, with prevalence around 60% and 90%, respectively. Therefore, ß-catenin accumulates in the nucleus-cytoplasm of cell clusters in ACPs and, in PCPs, cell immunostaining with specific antibody against the V600E-mutated protein can be seen. Distinct patterns of DNA methylation further differentiate ACPs and PCPs. In addition, research on genetic and epigenetic changes and tumor microenvironment specificities have further clarified the development and progression of the disease. No relevant transcriptional differences in ACPs have emerged between children and adults. In conclusion, ACPs and PCPs present diverse genetic signatures and each subtype is associated with specific signaling pathways. A better understanding of the pathways related to the growth of such tumors is paramount for the development of novel targeted therapeutic agents.

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ABSTRACT Research from the last 20 years has provided important insights into the molecular pathogenesis of craniopharyngiomas (CPs). Besides the well-known clinical and histological differences between the subtypes of CPs, adamantinomatous (ACP) and papillary (PCP) craniopharyngiomas, other molecular differences have been identified, further elucidating pathways related to the origin and development of such tumors. The present minireview assesses current knowledge on embryogenesis and the genetic, epigenetic, transcriptomic, and signaling pathways involved in the ACP and PCP subtypes, revealing the similarities and differences in their profiles. ACP and PCP subtypes can be identified by the presence of mutations in CTNNB1 and BRAF genes, with prevalence around 60% and 90%, respectively. Therefore, β-catenin accumulates in the nucleus-cytoplasm of cell clusters in ACPs and, in PCPs, cell immunostaining with specific antibody against the V600E-mutated protein can be seen. Distinct patterns of DNA methylation further differentiate ACPs and PCPs. In addition, research on genetic and epigenetic changes and tumor microenvironment specificities have further clarified the development and progression of the disease. No relevant transcriptional differences in ACPs have emerged between children and adults. In conclusion, ACPs and PCPs present diverse genetic signatures and each subtype is associated with specific signaling pathways. A better understanding of the pathways related to the growth of such tumors is paramount for the development of novel targeted therapeutic agents.

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OBJECTIVE: The objective of this systematic review with meta-analysis was to critically evaluate the available data on sensitivity and specificity of IHC compared with molecular tests in the detection of BRAF V600E mutation in ameloblastomas. MATERIALS AND METHODS: This systematic review was performed based on the PRISMA statement and registered in Prospero (CRD42021259117). PubMed, Web of Science, Scopus, and Cochrane Library databases were searched for observational studies to answer the question "What is the diagnostic accuracy of immunohistochemistry compared with molecular tests for the diagnosis of BRAF V600E mutation in ameloblastomas?". Methodological quality and risk of bias assessment of the selected studies were based on the QUADAS-2. Meta-analysis based on hierarchical SROC curve model and summary measures for sensitivity and specificity were computed. RESULTS: A total of 226 records were found, but only 05 articles met the inclusion criteria, with 277 FFPE specimens of ameloblastoma included in the quantitative analysis. The sensitivity of the IHC compared to molecular tests ranged from 0.71 to 1.00, while all of the included studies showed perfect specificity (1.00). Pooled measures for sensitivity and specificity were 0.95 [95% CI 0.89, 1.00] and 1.00 [95% CI 0.95, 1.00], respectively. The diagnostic odds ratio was 4.05, and the AUC for SROC curve was calculated as 0.979. CONCLUSIONS: BRAF V600E-specific IHC using VE1 antibody showed extremely high sensitivity and specificity when compared with molecular tests in the detection of the mutation in ameloblastomas.

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Juvenile xanthogranuloma (JXG) is the most common form of non-Langerhans cell histiocytosis and oral mucosal involvement is exceedingly rare. Histiocytic disorders harbor activating mutations in MAPK pathway, including the report of BRAF V600E in JXG of extracutaneous site. However, no information is available for oral JXG. Herein, the clinicopathological and immunohistochemical features of five new oral JXG were evaluated in conjunction with literature review. Also, we assessed the BRAF V600E in oral samples. Five oral JXG were retrieved from pathology archives. Morphological and immunohistochemical analyses were performed. The BRAF V600E status was determined with TaqMan allele-specific qPCR. The series comprised of three female and two male patients, most of them adults, with a median age of 39 years (range 13-68 years). Clinically, the lesions appeared as asymptomatic solitary nodules, measuring until 2.5 cm, with more incident to the buccal mucosa. Morphologically, most of the cases presented classical histological features of JXG, with histiocytic cells consistent with the non-Langerhans cell immunophenotype. BRAF V600E was not detected in the cases tested. This is the first and largest published series of oral JXG affecting adults and a Brazilian population. The molecular pathogenesis of oral JXG remains unknown. Clinicians and pathologists must recognize JXG to avoid misdiagnoses with oral benign or malignant lesions.

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