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Background: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date., Materials and Methods: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors., Results: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together., Conclusions: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker., Competing Interests: Declaration of Competing Interest Dr. Queirolo served on the Advisory Boards of Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi and Pierre-Fabre. All other authors have declared no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction : In recent years, the introduction of targeted therapy and immunotherapy into clinical practice has radically changed the management of advanced melanoma. More recently, these treatments also became the standard of care in the adjuvant setting. However, high-risk resectable stage III melanoma (i.e. with clinically detected regional lymph node involvement and/or satellites/in transit metastases) still has a high risk of relapse, even after adjuvant treatment, suggesting that the activity of immunotherapy and targeted therapy may play a relevant role in a neoadjuvant setting. Area covered : In this review, we discuss the results of the main clinical trials conducted in the neoadjuvant setting for patients with resectable stage III and stage IV melanoma, with a focus on the hot topics and a look at the future perspectives of the field. Expert opinion : The long-term effects of immunotherapy and the high response rate of targeted therapy provided the strong rationale to start neoadjuvant clinical trials for patients with resectable stage III and oligometastatic stage IV melanoma. Neoadjuvant therapy may play an important role not only for its possible impact on overall survival, but also as a predictive biological marker to allow for a more accurate personalization of adjuvant treatments.

Immune checkpoint inhibitors, including ipilimumab (IPI), achieve a clinical benefit in a small proportion of melanoma patients highlighting the need to investigate predictive biomarkers. In this study, we characterized tumor infiltrating lymphocytes (TILs), focusing on the CTLA-4 + subset, and evaluated their possible predictive significance. We characterized TIL density, cell type, and localization in 40 melanoma lesions from 17 patients treated with IPI. Associations of TILs with IPI timing, tissue localization, and response to IPI were estimated using a linear mixed-effects modelling approach. We found that most of TIL subsets increased in situ upon IPI therapy, with particular reference to FoxP3 + cells. TILs and TIL subsets, such as CD3 + , CD45RO + , CTLA-4 + , CD4 + , CD8 + T cells, CD20 + B cells, and NKp46 + NK cells, showed significantly different spatial distributions in the tumor microenvironment being higher at the invasive margin (IM) as compared to the tumor center (TC) (P value < 0.001 for TIL score and P value < 0.05 for all subsets). Remarkably, high TIL score and density of CD3 + , CD8 + T cells, and CTLA-4 + immune cells were significantly associated with a better response to IPI (P values = 0.002, 0.023, 0.007, and 0.001, respectively, for responders vs non-responders). In conclusion, we provide a detailed analysis of CTLA-4 + TIL distribution in melanoma tissues taking into account localization, relationship with CD3 + /CD8 + TILs, and changes in response to IPI treatment. We identified that CTLA-4 + TILs may represent a marker of IPI response, alone or with CD3 + /CD8 + subsets, although this requires confirmation in larger studies.

Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF-), including dermoscopic findings of melanomas and dysplastic nevi., Methods: we retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available., Results: After excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF-. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF-). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF- patients, whose most prevalent pattern was the multicomponent., Conclusions: MITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF- patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.

The past 5 years have witnessed the results of many practice-changing studies that have dramatically improved the landscape of adjuvant therapy in patients with resected, high-risk melanoma. After a 20-year era of adjuvant interferon, the anti-CTLA-4 and anti-PD-1 immune-checkpoint inhibitors, and MAPK-directed targeted therapy brought a revolution into the adjuvant treatment of melanoma. These results came along with the practice-changing results of two large multicenter studies showing no benefit in terms of overall survival for completion lymph node dissection after positive sentinel node biopsy. In this review, we summarized the current state of the art of the adjuvant treatment of high-risk melanoma, with a view on future perspectives., (Copyright © 2019. Published by Elsevier Ltd.)

Melanoma has always been described as an immunogenic tumor. Despite that, until 2011 the standard of care in metastatic melanoma was chemotherapy, with low response rates and no clear impact on overall survival. Melanoma was the first cancer type to drive the use of immune-checkpoint inhibitors into clinical practice, which revolutionized the therapeutic paradigm not only in melanoma, but also in an increasing number of tumors. In this review, the preclinical bases and the main clinical studies that led to the approval of immune-checkpoint inhibitors in advanced melanoma will be described with insights on novel combinations of treatments and on prognostic and predictive biomarkers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

Uveal melanoma is a rare and biologically distinct type of melanoma arising from melanocytes of the uveal tract; it is associated with a poor prognosis due to the lack of effective systemic treatments. Recent advances in the pathogenesis of uveal melanoma offer an unprecedented opportunity for investigation of new compounds. The purpose of this paper was to analyse the existing evidence about the molecular pathology and immunobiology of advanced uveal melanoma and their implications for systemic targeted therapies and immunotherapy, as well as to discuss future treatment strategies based on data provided by clinical and translational research studies.