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Purpose: Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown.Methods: Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment.Results: We demonstrated that SFN strongly decreased cell viability and proliferation, induced G2/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1).Conclusion: Overall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent. [ABSTRACT FROM AUTHOR]

Intermittent sun exposure and sunburns are strongly related to the development of melanoma (MM); however, MM can also arise in non-sun exposed areas, where other biological pathways may cause the disease, with different outcomes. At the same time, evidences of serum levels of vitamin D in melanoma patients according to sun-exposed or not-sun-exposed areas are still lacking, especially if compared with the percentage of BRAF mutation. We performed a retrospective analysis with patients registered in our electronic database and an observational study in patients with a recent diagnosis of MM. Performing Kaplan-Meier product and log-rank test, median disease-free survival was 78 months in non-shield-sites (NST-MM) patients and 20.5 months in shield-sites (ST-MM) patients ( p < 0.0001); also in the long term, a better behavior was observed for NST-MM (80 vs. 42 months; p < 0.0001). Among 87 melanoma patients with a recent history of MM (≤30 days), we found that ST-MM patients showed lower values of vitamin D compared with NST-MM patients. Regarding BRAF status, a BRAF mutation was present in 13 % of ST-MM and in 41 % of NST-MM. Performing Mc-Nemar test, we found a statistical significant correlation between low serum levels of vitamin D in ST-MM and low percentage of BRAF mutation ( p = 0.03), as well as between serum levels of vitamin D and high percentage of BRAF mutation in NST-MM ( p < 0.001). All these aspects confirm that in ST-MM, other pathways play pivotal points, if compared with NST-MM. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are one of the most frequent neurological complications of cancers. Melanoma is the third most common tumor to metastasize to the brain with a reported incidence of 10-40 %, and many patients have subclinical BM (>73 %). We computer-searched the clinical records of all our patients registered into a database to identify patients that presented or developed BM. A total of 49 patients with melanoma BM were included in our analysis. General time to brain metastases (TTBM) was 23 months. The nonparametric test between TTBM and the single variables showed an association between TTBM and Breslow thickness ( p < 0.0076; Spearman's coefficient-0.411), ulceration ( p = 0.0656; Spearman's coefficient-0.287) and positive sentinel lymph node ( p < 0.0015; Spearman's coefficient-0.475). Performing multiple regression, positive SLN remained the only, statistically significant, predictive variable ( p < 0.01). Regarding the first melanoma site, the axial sites were more likely to develop BM than peripheral ones ( p < 0.001). The analysis of brain metastasis survival (BMS) with Kaplan-Meier curves has resulted in a median survival rate of 6 months (range 1-134 months) and was strongly related to response to treatment, number of parenchymal lesions, presence or absence of symptoms. The results of the current analysis revealed clinical and primary tumor characteristics associated with the development of BM, TTBM, and BMS. The SNL was found to be the strongest predictor for BM development. [ABSTRACT FROM AUTHOR]

In the literature, there are some papers reporting on patients with metastatic melanoma from an unknown primary lesion (MUP). The pathogenesis of this phenomenon and the prognosis of these patients are still debatable. Therefore, we reviewed our casistics on MUP patients. We identified 24 MUP patients out of all patients registered into a melanoma database from June 1996 to June 2011. The incidence was 1.4 %. We compared the survival rate of all patients with MUP stage III-IV with all patients with metastatic melanoma known primary (MMKP) stage III-IV observing a clear survival improvement for MUP patients in front of MMKP patients ( p < 0.01). In a second instance, we compared stage III MUP patients with only lymph nodal involvement with stage III MMKP patients with only lymph nodal involvement, and again we found statistically significant better survival for MUP patients ( p < 0.05) . In this retrospective study, the number of lymph nodes involved ( p = 0.8), the sex ( p = 0.9), and S100 value ( p = 0.2) were not statistically relevant for prognosis. The better prognosis for these patients is very similar to better survival rate for metastatic melanoma patients and vitiligo. This correlation may be in accord with the hypothesis of a regression of primary lesion by immunological system of the host and also the median age of patients at the time of diagnosis, commonly older than melanoma patients, may correspond to a long period of immunological interferences between the host and the melanoma disease. [ABSTRACT FROM AUTHOR]

In the absence of risk factors, thin melanomas (TM) present a long-term survival; however, recurrences may occur. We describe the predictive clinicopathological features of patients with metastatic TM. Kaplan-Meier product was performed for the survival analysis, while Cox proportional hazards regression was used to evaluate the effect of the clinicopathological features on disease-free survival (DFS) and overall survival (OS). Median DFS of the entire cohort was 26 months and three patients developed late metastases. Nine patients developed extra-nodal metastases as first recurrence, while cases of positive sentinel lymph node biopsy (SLNB) were not found. DFS and OS varied according to the clinicopathological features, but only ulceration remained the main statistical significance value. According to our results, a hypothetical use of SLNB in TM without other risk factors is not currently feasible. No consensus exists as to which patients with TM are at risk for metastases or late recurrences. [ABSTRACT FROM AUTHOR]