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Abstract Mitotic rate is no longer considered a staging criterion for thin melanoma in the 8th edition of the American Joint Committee on Cancer Staging Manual. The aim of this observational study was to identify prognostic factors for thin melanoma and predictors and prognostic significance of sentinel lymph node (SLN) involvement in a large multicenter cohort of patients with melanoma from nine tertiary care hospitals. A total of 4249 consecutive patients with thin melanoma diagnosed from January 1, 1998 to December 31, 2016 were included. The main outcomes were disease‐free interval and melanoma‐specific survival for the overall population and predictors of SLN metastasis (n = 1083). Associations between survival and SLN status and different clinical and pathologic variables (sex, age, tumor location, mitosis, ulceration, regression, lymphovascular invasion, histologic subtype, Clark level, and Breslow thickness) were analyzed by Cox proportional hazards regression and logistic regression. SLN status was the most important prognostic factor for melanoma‐specific survival (hazard ratio, 13.8; 95% CI, 6.1‐31.2; P 2 mitoses/mm2 was the only factor associated with a positive SLN biopsy (odds ratio, 2.9; 95% CI, 1.22‐7; P = 0.01. SLN status is the most important prognostic factor in thin melanoma. A high mitotic rate is associated with metastatic SLN involvement. SLN biopsy should be discussed and recommended in patients with thin melanoma and a high mitotic rate.

Familial melanoma accounts for 10% of cases, being CDKN2A the main high-risk gene. However, the mechanisms underlying melanomagenesis in these cases remain poorly understood. Our aim was to analyze the transcriptome of melanocyte-keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to unveil pathways involved in melanoma development in at-risk individuals. Accordingly, primary melanocyte-keratinocyte co-cultures were established from the healthy skin biopsies of 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P < 0.05). In addition, the PPI network analysis revealed a network that consisted of double-stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes, and regulation of chromosome segregation. The hub gene was BRCA1. In conclusion, the constitutive deregulation of BRCA1 pathway genes and the immune response in healthy skin could be a mechanism related to melanoma risk.

Abstract  There is increasing evidence that, in addition to its function as the main neurotransmitter in the nigrostriatal pathway, dopamine (DA) may be neurotoxic in certain conditions. In this study, the toxicity of DA was assessed by direct injection into the substantia nigra of anaesthetised rats, and its effects were compared with those of 6-hydroxydopamine. Brains were removed 1, 2 and 3 weeks after the lesion for histological or neurochemical analysis. DA caused a significant loss of 35% of tyrosine hydroxylase-positive neurons in the pars compacta of substantia nigra and a 40% reduction of striatal DA content. Cells with signs compatible with both apoptosis and autophagy were observed. GADD153, a parameter of endoplasmic reticulum stress, was strongly induced by 6-hydroxydopamine but not by DA. DA increased the α-synuclein content 1 week after the lesion (but not at the later times analyzed) in tyrosine hydroxylase-positive and in non-dopaminergic fibers of pars reticulata. The α-synuclein increase may be a physiological temporal response to DA accumulation and/or to cell damage, but the simultaneous presence of α-synuclein and DA in the cell cytoplasm at concentration higher than normal is not exempt from risk. In fact, their incubation in a free cell system gives a stable dimerized form of α-synuclein that has been described as the critical rate-limiting step for its abnormal fibrillation. [ABSTRACT FROM AUTHOR]