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CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.

Purpose: The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab., Experimental Design: The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, β2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively., Results: Median survival was 8.3, 4.9 and 7.1 months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months., Conclusion: Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort., Methods: A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival., Results: Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.