Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.

Worldwide, the total incidence of cutaneous melanoma is higher in men than in women, with some differences related to ethnicity and age and, above all, sex and gender. Differences exist in respect to the anatomic localization of melanoma, in that it is more frequent on the trunk in men and on the lower limbs in women. A debated issue is if—and to what extent—melanoma development can be attributed to gender-specific behaviors or to biologically intrinsic differences. In the search for factors responsible for the divergences, a pivotal role of sex hormones has been observed, although conflicting results indicate the involvement of other mechanisms. The presence on the X chromosome of numerous miRNAs and coding genes playing immunological roles represents another important factor, whose relevance can be even increased by the incomplete X chromosome random inactivation. Considering the known advantages of the female immune system, a different cancer immune surveillance efficacy was suggested to explain some sex disparities. Indeed, the complexity of this picture emerged when the recently developed immunotherapies unexpectedly showed better improvements in men than in women. Altogether, these data support the necessity of further studies, which consider enrolling a balanced number of men and women in clinical trials to better understand the differences and obtain actual gender-equitable healthcare.

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients.

Cutaneous Melanoma classification is constantly looking for specific and sensitive biomarkers capable of having a positive effect on diagnosis, prognosis and risk assessment, eventually affecting clinical outcome. Classical morphological, immunohistochemical and the well-known BRAF and NRAS genetic biomarkers do not allow the correct categorization of patients, being melanoma conditioned by high genetic heterogeneity. At the same time, classic prognostic methods are unsatisfactory. Therefore, new advances in omics and high-throughput analytical techniques have enabled the identification of numerous possible biomarkers, but their potentiality needs to be validated and standardized in prospective studies. Melanoma is considered an immunogenic tumor, being the first form of cancer to take advantage of the clinical use of the immune-checkpoint blockers. However, as immunotherapy is effective only in a limited number of patients, biomarkers associated with different responses are essential to select the more promising therapeutic approach and maximize clinical benefits. In this review, we summarize the most utilized biomarkers for Cutaneous Melanoma diagnosis, focusing on new prognostic and predictive biomarkers mainly associated with immunotherapy.

Gender medicine studies how health status and diseases differ between men and women in terms of prevention, therapeutic approach, prognosis, and psychological and social impact. Sex and gender analyses have been demonstrated to improve science, contributing to achieving real appropriateness and equity in the cure for each person. Therefore, it is fundamental to consider, both in preclinical and clinical research, the different clinical and biological features associated with sex and/or gender, where sex differences are mainly influenced by biological determinants and gender ones by socio-cultural and economic matters. This article was developed to provide knowledge and methodological tools for the development of studies/research protocols in which sex and gender should be taken into account.