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Background: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear., Materials and Methods: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines., Results: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively., Conclusions: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. There are many aetiological reasons by which the risk of a second melanoma increases. Among others, genetic factors may contribute to modulating this risk. The risk of identifying a CDKN2A germline mutation increases with the number of primary melanomas and with the presence of familial history of melanoma. Patients with melanoma are especially encouraged to have regular follow-up visits with their dermatologist to perform clinical and dermatoscopic examination. In particular, dermoscopy could be very useful in multiple primary melanoma (MPM) patients., Objectives: To analyse the clinical and dermatoscopic features of multiple melanomas, focusing on those features that are more frequently found in the same patient to recognize them earlier and understand whether they appear with the similar peculiar dermatoscopic features, especially in CDKN2A carriers., Methods: Medical records of MPM patients were selected from a database including 1065 patients with histopathologically proven melanoma diagnosis, all treated at the dermatology clinic of the University of Florence from 2000 to 2013. Pictures of melanoma were independently and blindly administered to three dermatologist experts in dermoscopy to evaluate the presence or absence of ABCD criteria for each clinical image, and the main pattern for the dermoscopic images. The results were then analyzed and crossed to rate the clinical and dermoscopic features of MPM., Results: Seventy five (7.0%) of 1065 patients included in our database were found to carry an MPM disease. Among them, we selected 12 (16%) patients with three or more MPMs. The presence of the CDKN2A melanoma susceptibility gene was observed in 4/12 (33.33%) patients; two patients presented the C500G and c.5 + 1delG polymorphisms in the CDKN2A gene. In CDKN2A carriers, each patient showed a similar and specific dermatoscopic pattern in their lesions., Conclusions: Even being aware of the limitations of this study, according to hereditary characters and their modes of transmissions, we could speculate that for each patient with a CDKN2A germline mutation, it is possible to find the same kind of dermoscopical pattern among their melanocytic tumours., (© 2014 European Academy of Dermatology and Venereology.)

Prediction of metastatic potential remains one of the main goals to be pursued in order to better assess the risk subgroups of patients with melanoma. Detection of occult melanoma cells in peripheral blood (circulating metastatic cells [CMC]) or in sentinel lymph nodes (sentinel node metastatic cells [SNMC]), could significantly contribute to better predict survival in melanoma patients. An overview of the numerous published studies indicate the existence of several drawbacks about either the reliability of the approaches for identification of occult melanoma cells or the clinical value of CMC and SNMC as prognostic factors among melanoma patients. In this sense, characterization of the molecular mechanisms involved in development and progression of melanoma (referred to as melanomagenesis) could contribute to better classify the different subsets of melanoma patients. Increasing evidence suggest that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic lineage. The different molecular mechanisms may have separate roles or cooperate during all evolutionary phases of melanocytic tumourigenesis, generating different subsets of melanoma patients with distinct aggressiveness, clinical behaviour, and response to therapy. All these features associated with either the dissemination of occult metastatic cells or the melanomagenesis might be useful to adequately manage the melanoma patients with different prognosis as well as to better address the different melanoma subsets toward more appropriate therapeutic approaches.