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Melanoma heterogeneity is a hurdle in metastatic disease management. Although the advent of targeted therapy has significantly improved patient outcomes, the occurrence of resistance makes monitoring of the tumor genetic landscape mandatory. Liquid biopsy could represent an important biomarker for the real-time tracing of disease evolution. Thus, we aimed to correlate liquid biopsy dynamics with treatment response and progression by devising a multiplatform approach applied to longitudinal melanoma patient monitoring. We conceived an approach that exploits Next Generation Sequencing (NGS) and droplet digital PCR, as well as the FDA-cleared platform CellSearch, to analyze circulating tumor DNA (ctDNA) trend and circulating melanoma cell (CMC) count, together with their customized genetic and copy number variation analysis. The approach was applied to 17 stage IV melanoma patients treated with BRAF/MEK inhibitors, followed for up to 28 months. BRAF mutations were detected in the plasma of 82% of patients. Single nucleotide variants known or suspected to confer resistance were identified in 70% of patients. Moreover, the amount of ctDNA, both at baseline and during response, correlated with the type and duration of the response itself, and the CMC count was confirmed to be a prognostic biomarker. This work provides proof of principle of the power of this approach and paves the way for a validation study aimed at evaluating early ctDNA-guided treatment decisions in stage IV melanoma. The NGS-based molecular profile complemented the analysis of ctDNA trend and, together with CMC analysis, revealed to be useful in capturing tumor evolution., (© 2024. The Author(s).)

Background: Immune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization., Methods: In this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies., Results: Serum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1β predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS., Conclusions: Serum IL-1β, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex., (© 2024. The Author(s).)

The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.

Background: Immunotherapy has improved the survival of patients with stage IV melanoma. In responders, clinical benefits may be long-lasting and persist even after treatment discontinuation. The optimal duration of anti-PD1 (anti-Programmed cell death-1) therapy in metastatic melanoma patients remains to be elucidated. Moreover, limited data are available on clinical outcomes of patients that discontinued anti-PD1 immunotherapy in a real-life setting. The aim of this study was to evaluate the progression-free survival (PFS) in patients with metastatic melanoma who interrupted anti-PD-1 treatment in the in the absence of disease progression., Methods: We retrospectively reviewed patients with advanced/metastatic melanoma treated with anti-PD1 immunotherapy at 23 Italian Melanoma Intergroup (IMI) centres. The study investigated the risk of relapse in patients who stopped anti-PD1 therapy due to CR (Complete response), treatment-related toxicity, or by their own choice after a long period of treatment. Clinical and biological factors associated with or without recurrence were evaluated., Results: The study population included 237 patients. The median age of patients was 68.9 years (standard deviation: 13; range 33-95). The median time on treatment was 33 months (standard deviation: 18, 7; range 1-98). Among the 237 patients, 128 (54%) interrupted the anti-PD1 for CR, 74 patients (31.2%) for adverse events (37 patients in CR, 27 patients in partial response (PR), ten patients in stable disease (SD), and 35 patients (14.8%) by their own choice (12 patients in CR, 17 patients in PR, and 6 patients in SD). After a mean follow-up of 21 months (range 1-81), PFS after anti-PD1 discontinuation was 85.7%. Thirty-four patients (14.3%) developed disease progression after a median of 12 months (range 1-35): ten patients (29.4%) after discontinuation in CR, 17 patients (50%) after discontinuation for treatment-related toxicity (seven in CR, five in PR, five in SD), and seven (20.6%) after discontinuation due to the patient's decision (two in CR, four in PR, one in SD). Only 7.8% of patients who interrupted in CR (10/128), along with 23% of patients who interrupted for limiting toxicity (17/74) and 20% of patients who interrupted by their own choice (7/35), developed recurrence. Regarding patients who discontinued therapy because of CR, we observed a negative association between recurrence and site of primary melanoma, especially mucosal sites (p = <0.05, HR (Hazard ratio) 15.57 IC (confidence interval) 95% 2.64-91.73). Moreover, M1b patients who achieved a CR showed a lower number of relapses (p = <0.05, HR 3.84 IC 95% 1.40-8.48)., Conclusions: This study shows in a real-life setting that, with anti-PD-1 therapy, long-lasting responses, can be maintained after anti-PD1 interruption. In 70.6% of cases, recurrences were observed among patients who did not obtain a CR at treatment discontinuation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marco Rubatto: nothing to declare, Paolo Fava: nothing to declare, Ignazio Stanganelli: nothing to declare, Simone Ribero: nothing to declare, Jacopo Pigozzo Advisory board BMS, MSD, Novartis, Anna Maria Di Giacomo: has served as a consultant and/or advisor to Incyte, Pierre Fabre, Glaxo Smith Kline, Bristol-Myers Squibb, Merck Sharp Dohme, Immunocore, SunPharma and Sanofi and has received compensated educational activities from Bristol-Myers Squibb, Merck Sharp Dohme, Pierre Fabre and Sanofi, Laura Ridolfi: nothing to declare, Maria Chiara Tronconi: nothing to declare, Claudia Trojaniello: sanofi, Melissa Bersanelli: nothing to declare, Mattia Garutti honoraria or consultation fees from Novartis, Eli Lilly, Pierre Fabre and Roche, and travel fees from Daichii Sankyo, all outside the submitted work, Alice Indini: nothing to declare, Ivana De Risi: nothing to declare, Michele De Tursi: nothing to declare, Barbara Merelli: nothing to declare, Francesca Morgese: nothing to declare, Marcella Occelli: nothing to declare, Gian Carlo Antonini Cappellini: nothing to declare, Stefano Poletto: nothing to declare, Dahlia Fedele: nothing to declare, Sonia Brugnara: nothing to declare, Michela Frisinghelli: nothing to declare, Luigi Formisano: LF has received research funding from Lilly outside the submitted work. LF is on the Advisory Board for Janssen-Cilag, Sanofi, MSD and BMS, Raffaele Conca: nothing to declare, Marco Tucci: nothing to declare, Michelangelo Russillo: nothing to declare, Luca Ceroni: nothing to declare, Paola Queirolo: nothing to declare, Giada Targato: nothing to declare, Sabino Strippoli: nothing to declare, Mario Mandalà: Advisory board and lectures for: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma Research grant: Novartis, Michele Guida: nothing to declare, Pietro Quaglino: nothing to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma., Patients and Methods: In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup., Results: At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients., Conclusion: Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals which could be associated with cancer development, such as kidney and testicular cancers, pancreatic and hepatocellular carcinoma and thyroid tumor. Available scientific literature offers no information on the role of PFAS in melanoma development/progression. Since 1965, a massive environmental contamination by PFAS has occurred in northeastern Italy. This study compared histopathology and prognosis between melanoma patients exposed (n = 194) and unexposed (n = 488) to PFAS. All patients were diagnosed and/or treated for melanoma at the Veneto Oncological Institute and the University Hospital of Padua (Italy) in 1998-2014. Patients were categorized in exposed or unexposed groups according to their home address and the geographical classification of municipalities affected by PFAS contamination as provided by Veneto Government in 2018. Presence of mitoses was found in 70.5% of exposed patients and 58.7% of unexposed patients (p = 0.005). Median follow-up was 90 months (IQR 59-136). 5-year overall survival was 83.7% in exposed patients and 88.0% in unexposed patients (p = 0.20); 5-year disease-specific survival was 88.0% in exposed patients and 90.9% in unexposed patients (p = 0.50); 5-year disease-free survival was 83.8% in exposed patients and 87.3% in unexposed patients (p = 0.20). Adjusting for imbalanced characteristics at baseline (presence of mitoses), survival was not statistically different between exposed and unexposed patients (overall survival: HR 1.10, 95% CI 0.77 to 1.58, p = 0.57; disease-specific survival: HR 0.99, 95% CI 0.62 to 1.59, p = 0.99; disease-free survival: HR 1.10, 95% CI 0.74 to 1.64, p = 0.62). Although the magnitude of PFAS exposure was not quantifiable, our findings suggested that exposure to PFAS was associated with higher level of mitosis in melanoma patients, but this did not translate into a survival difference. Further studies are required to investigate this relationship and all effects of PFAS on prognosis., (© 2022. The Author(s).)

The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option.

Background: To evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and platelets-to-lymphocytes ratio, PLR) in predicting the response to immune checkpoint inhibitors (ICI) in metastatic melanoma (MM)., Methods: We performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Δ) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve., Results: At baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p < 0.001), neutrophils (p < 0.001) and PLR (p = 0.022), while DCR by LDH (p = 0.03) and neutrophils (p = 0.004). In the longitudinal analysis, PFS negatively correlated with higher Δplatelets (p = 0.039), ΔWBC (p < 0.001), and Δneutrophils (p = 0.020), and with lower Δlymphocytes (p < 0.001). Moreover, higher ΔNLR and ΔPLR identified patients with worse PFS, OS and DCR. In the multivariable model, only ΔNLR influenced PFS (p = 0.004), while OS resulted affected by higher ΔWBC (p < 0.001) and lower Δlymphocytes (p = 0.038). Higher ΔWBC also affected the DCR (p = 0.003). When clustering patients in 4 categories using basal LDH and ΔNLR, normal LDH/lower ΔNLR showed a higher PFS than high LDH/higher ΔNLR (20 vs 5 months). Moreover, normal LDH/higher Δlymphocytes had a higher OS than high LDH/lower Δlymphocytes (50 vs. 10 months)., Conclusions: Baseline and early variations of blood cells, together with basal LDH, strongly predict the efficacy of ICI in MM. Our findings propose simple, inexpensive biomarkers for a better selection of patient treatments. Prospective multicenter studies are warranted to confirm these data., (© 2022. The Author(s).)

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC., Methods: A retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens., Results: 143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor., Conclusions: Autoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rastrelli, Del Fiore, Russo, Tartaglia, Dal Monico, Cappellesso, Nicolè, Piccin, Fabozzi, Biffoli, Di Prata, Ferrazzi, Dall’Olmo, Vecchiato, Spina, Russano, Bezzon, Cingarlini, Mazzarotto, Parisi, Scarzello, Pigozzo, Brambullo, Tropea, Vindigni, Bassetto, Bertin, Gregianin, Dei Tos, Cavallin, Alaibac, Chiarion-Sileni and Mocellin.)

The "Veneto Cancer Registry" records melanoma as the most common cancer diagnosed in males and the third common cancer in females under 50 years of age in the Veneto Region (Italy). While melanoma is rare in children, it has greater incidence in adolescents and young adults (AYA), but literature offers only few studies specifically focused on AYA melanoma. The aim of this study was to describe the characteristics, surgical treatment, and prognosis of a cohort of AYA melanoma in order to contribute to the investigation of this malignancy and provide better patient care. This retrospective cohort study included 2,752 Caucasian patients (702 AYA and 2,050 non-AYA patients) from the Veneto Region who were over 15 years of age at diagnosis, and who received diagnosis and/or treatment from our institutions between 1998 and 2014. Patients were divided in adolescents and youth (15-25 years), young adults (26-39 years) and adults (more than 39 years) for the analysis. We found statistically significant differences in gender, primary site, Breslow thickness, ulceration, pathologic TNM classification (pTNM) stage and tumor subtype among the age groups. Disease-specific survival and disease-free survival were also different among the age groups. Our findings suggest that the biological behavior of melanoma in young people is different to that in adults, but not such as to represent a distinct pathological entity. Additional and larger prospective studies should be performed to better evaluate potential biological and cancer-specific differences between AYAs and the adult melanoma population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Del Fiore, Russo, Ferrazzi, Monico, Cavallin, Filoni, Tropea, Russano, Di Prata, Buja, Collodetto, Spina, Carraro, Cappellesso, Nicolè, Chiarion-Sileni, Pigozzo, Dall’Olmo, Rastrelli, Vecchiato, Benna, Menin, Di Carlo, Bisogno, Dei Tos, Alaibac and Mocellin.)

Background: Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis., Methods: We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival., Results: Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy., Conclusion: The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.

Background: Melanoma of unknown primary (MUP), accounts for up to 3% of all melanomas and consists of a histologically confirmed melanoma metastasis to either lymph nodes, (sub)cutaneous tissue, or visceral sites without any evidence of a primary cutaneous, ocular, or mucosal melanoma. This study aimed to investigate the characteristics, treatment strategies, and prognostic factors of MUP patients, in order to shed some light on the clinical behavior of this malignancy., Methods: All the consecutive patients with a diagnosis of MUP referring to our institutions between 1985 and 2018 were considered in this retrospective cohort study. The records of 173 patients with a suspected diagnosis of MUP were retrospectively evaluated for inclusion in the study. Patient selection was performed according to the Das Gupta criteria, and a total of 127 MUP patients were finally included in the study, representing 2.7% of the patients diagnosed with melanoma skin cancer at our institutions during the same study period. A second cohort of all consecutive 417 MKP patients with AJCC stages IIIB-IV, referring tions in the period considered (1985-2018), was included in the study to compare survival between MUP and MKP patients. All the diagnoses were based on histopathologic, cytologic and immunohistochemical examination of the metastases. All tumors were re-staged according to the 2018 American Joint Committee on Cancer (AJCC) 8 th Edition., Results: Median follow-up was 32 months (IQR: 15-84). 3-year progression-free survival (PFS) was 54%, while 3-year overall survival (OS) was 62%. Worse OS and PFS were associated with older age (P = 0.0001 for OS; P = 0.008 for PFS), stage IV (P < 0.0001 for OS; P = 0.0001 for PFS) and higher Charlson Comorbidity Index (P < 0.0001 for OS and P = 0.01 for PFS). Patients with lymph node disease showed longer PFS (P = 0.001) and OS (P = 0.0008) than those with (sub)cutis disease. Complete lymph node dissection (CLND) was the most common surgical treatment; a worse OS in these patients was associated with the number of positive lymph nodes (P = 0.01), without significant association with the number of retrieved lymph nodes (P = 0.79). Survival rates were lower in patients undergoing chemotherapy (CT) and target therapy (TT), and higher in those receiving immunotherapy (IT). 417 patients with AJCC stages IIIB-IV of Melanoma Known Primary (MKP) were included for the survival comparison with MUP. 3-year PFS rates were 54 and 58% in MUP and MKP, respectively (P = 0.30); 3-year OS rates were 62 and 70% in MUP and MKP, respectively (P = 0.40)., Conclusions: The most common clinical scenario of our series was a male patient around 59 years with lymph node disease. We report that CLND associated with IT was the best treatment in terms of survival outcome. In the current era of IT and TT for melanoma, new studies have to clarify the impact of novel drugs on MUP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Del Fiore, Rastrelli, Dall’Olmo, Cavallin, Cappellesso, Vecchiato, Buja, Spina, Parisi, Mazzarotto, Ferrazzi, Grego, Rotondi, Benna, Tropea, Russano, Filoni, Bassetto, Tos, Alaibac, Rossi, Pigozzo, Sileni and Mocellin.)

Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF V600 wild-type advanced melanoma., Patients and Methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population., Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab., Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF V600 wild-type advanced melanoma., Competing Interests: Disclosure HG reports honoraria payments from Merck Sharp & Dohme, Bristol Myers Squibb, and Novartis; consulting/advisory roles for Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Pierre Fabre, and Amgen; research funding from Merck Sharp & Dohme, Bristol Myers Squibb, and Roche; and travel/accommodations/expenses from Bristol Myers Squibb, Amgen, and Merck Sharp & Dohme. BD reports a consulting/advisory role for Roche. JL reports honoraria payments from, consulting/advisory roles for, and travel/accommodations/expenses from Achilles, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; and research funding from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo. LD reports consulting/advisory roles for, speaker's bureau for, and travel/accommodations/expenses from Roche, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, and BIOCAD; and research funding from Roche, Novartis, Bristol Myers Squibb, BIOCAD, and Amgen. DS reports consulting/advisory roles for Bristol Myers Squibb, Roche, Merck Sharp & Dohme, and Novartis; travel/accommodations/expenses from Bristol Myers Squibb, Roche, and Merck Sharp & Dohme; and support from the NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre. ZE reports consulting/advisory roles for Array and Regeneron, and research funding from Novartis. PFF reports consulting/advisory roles for Bristol Myers Squibb, Roche, Merck Sharp & Dohme, and Novartis; and travel/accommodations/expenses from Bristol Myers Squibb, Roche, and Merck Sharp & Dohme. JP reports consulting/advisory roles for Bristol Myers Squibb and Merck Sharp & Dohme. PR reports honoraria payments from Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Pierre Fabre, Pfizer, and Eli Lilly; consulting/advisory roles for Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; travel/accommodations/expenses from Orphan Drugs; and officer/board of director's roles for the Polish Society of Surgical Oncology and the European Society of Medical Oncology. JM reports consulting/advisory roles for Bristol Myers Squibb and Merck Sharp & Dohme; speaker's bureau for Bristol Myers Squibb, GlaxoSmithKline, Roche, Merck Sharp & Dohme, and Novartis; and travel/accommodations/expenses from Bristol Myers Squibb, GlaxoSmithKline, Roche, Merck Sharp & Dohme, Novartis, and Pierre Fabre. IR reports employment with stock/stock options from, and travel/accommodations/expenses from Roche. AV reports employment with and stock/stock options from Roche. ST reports employment with Genentech. BP reports employment with Roche. YG reports employment with Genentech. YY reports employment with Genentech and stock/stock options from Roche. MC reports employment with Roche. SM reports employment with Roche and stock/stock options from Roche. KF reports consulting/advisory roles for X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Array BioPharma, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm; stock/stock options from Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals, X4 Pharmaceuticals, PIC Therapeutics, Fount, Shattuck Labs, Apricity, Oncoceutics, Fog Pharma, Tvardi, and xCures; research funding from Sanofi, Novartis, Array BioPharma, Bristol Myers Squibb, Merck, Takeda, and Debiopharm; and officer/board of directors roles for Clovis Oncology, Strata Oncology, Vivid Biosciences, and Checkmate Pharmaceuticals. AA reports consulting/advisory roles for and travel/accommodations/expenses from Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, and Merck., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM)., Objectives: To investigate whether the extent of ulceration (EoU) predicts relapse-free survival (RFS) and overall survival (OS) in PCM., Materials and Methods: We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU., Results: A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1-mm increase) 1·26, 95% confidence interval (CI) 1·08-1·48, P = 0·0047] and OS [HR (1-mm increase) 1·25, 95% CI 1·05-1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour-infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01-4 mm and > 4 mm BT., Conclusions: This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports., (© 2020 British Association of Dermatologists.)

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group ( p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7-18) versus 9 months (95% CI, 6-16) and 32 (95% CI, 23-49) versus 27 months (95% CI, 16-35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

Background: Obesity is a risk factor for malignancy; however, its prognostic role in patients with metastatic melanoma is controversial. We aim to investigate the prognostic role of body mass index (BMI) in patients with metastatic melanoma receiving mitogen-activated pathway kinase inhibitors (MAPKi), immune checkpoint inhibitors (ICIs) alone or their sequence., Methods: Data on patients with metastatic melanoma receiving ≥1 line of systemic treatment were retrieved from prospectively collected databases. Progression-free survival (PFS) and overall survival (OS) were analyzed by means of multivariable stratified Cox regression models; disease control rate (DCR) was analyzed by multivariable stratified logistic regression models. Subgroup analyzes according to the type of treatments received, and in BRAF -mutated patients were pre-planned. All multivariable models included BMI, age, gender, American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment sequencing strategy as covariates., Results: Between November 2010 and November 2018, 688 patients from three Italian and two Polish centers were enrolled. 379 (57%) patients had M1c/d disease, 273 (41%) were female and the mean BMI was 27.1 (SD=4.9). Considering first-line treatment, 446 patients (66.8%) received ICIs and 222 MAPKi. No impact of BMI on OS was detected either considering the first line of ICIs, or ICIs sequencing (HR=1.02, 95% CI: 0.99 to 1.05, p=0.202, and HR=1.02, 95% CI: 0.99 to 1.04, p=0.237, respectively). A late effect of BMI on OS was found in patients treated with MAPKi: for five units increment, a 51% of risk reduction at 18 months and a 76% of risk reduction at 30 months were observed. No significant effect of BMI on PFS and DCR was found in any of the subgroup analyzes., Conclusion: In patients with metastatic melanoma receiving ICIs, there is no impact of BMI on DCR, PFS and OS. The late prognostic effect of BMI in patients treated with MAPKi should be considered hypothesis generating and needs to be further investigated., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma., Patients and Methods: A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs., Results: Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT., Conclusion: Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation., (Copyright © 2020 Mannavola, Mandala, Todisco, Sileni, Palla, Minisini, Pala, Morgese, Di Guardo, Stucci, Guida, Indini, Quaglino, Ferraresi, Marconcini, Tronconi, Rossi, Nigro, Occelli, Cortellini, Quadrini, Palmieri, Pigozzo, Ascierto, Vitale, Strippoli, Ferrucci, Berardi, Randon, Cardone, Schinzari, Silvestris and Tucci.)

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAF V600 mutant melanoma. Reportedly, TERTprom, and BRAF V600 mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2-3.2; p = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1-3.3, p = 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade.

Background: Advanced age is associated with comorbidities and immune system impairment, which may influence the efficacy and tolerability of immune checkpoint inhibitors. There is evidence that anti-PD1 antibodies in advanced melanoma are equally effective in patients >65 years. However, data on patients >75 years are lacking as co-morbidities and logistics often exclude them from clinical trials., Methods: We retrospectively reviewed the clinical records of older patients with advanced melanoma undergoing any-line treatment with an anti-PD1 (nivolumab/pembrolizumab) to investigate its clinical effectiveness and toxicity in a real-life setting. Clinical response was assessed using RECIST criteria and toxicity was evaluated according to CTCAE 4.0. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the Cox model was used to assess potential prognostic factors., Results: 174 patients were considered; 59.2% males, median age 79 years (range 75-93). The majority had a performance status of 0 and normal lactate dehydrogenase (LDH) levels (55.2% and 52.4%, respectively). 69.1% had multiple co-morbidities. 56.9% received nivolumab. 36.7% of cases showed an objective response and the disease control rate was 56.3%. Median OS was 17.2 months [95% CI: 8.87-not reached] and a better prognosis was observed for patients with normal LDH (p < .001) and lower performance status (p < .001). Treatment was well tolerated, only 11 patients experiencing severe (grade 3/4) toxicity. There were no treatment-related deaths. Adverse events were managed with corticosteroids and additional immunosuppressive agents were unnecessary., Conclusions: Anti-PD1 antibodies appear effective and well tolerated in older patients with advanced melanoma., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: In a scenario of new expensive cancer therapies entering the market, strategies of optimisation and cost containment are crucial in oncology care. Better management of drug waste and centralization of drug preparation can be effective strategies to achieve these goals. The aim of this work is to describe the economic management of a high cost anticancer drug (ipilimumab) in some Italian reference centres., Methods: This was an observational, multicentred study in which economical and clinical data of 21 cancer centres (418 patients) were collected during the enrollment period from February 2013 to August 2014. The follow-up period ended in July 2015., Results: Participants purchased 10.7% more vials of ipilimumab than necessary for compounding. The results were variable among centres, and only five centres had a deviation lower than 5% between the drug purchased and the drug prescribed. Hospitals applying the drug day reached a statistically significant residual of drug effectively used compared to the amount prescribed (P = 0.018). Consequently, the price for treating a model patient was significantly lower in those hospitals (median spare of 7456 euro per patient)., Conclusions: This study demonstrated that the careful management of drug waste and the application of drug-day, through a proper selection of vial and the ability to use the leftover drug, can generate economic savings. However, tailoring the drug stock to clinical need is still an open issue which deserves further analysis.

Purpose: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) is approved for first-line treatment of patients with advanced melanoma in several countries. We conducted a phase IIIb/IV study (CheckMate 511) to determine if nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) improves the safety profile of the combination., Patients and Methods: Patients (N = 360) age 18 years or older with previously untreated, unresectable stage III or IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for four doses. After 6 weeks, all patients received NIVO 480 mg once every 4 weeks until disease progression or unacceptable toxicity. The primary end point was a comparison of the incidence of treatment-related grade 3 to 5 adverse events (AEs) between groups. Secondary end points included descriptive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points., Results: At a minimum follow-up of 12 months, incidence of treatment-related grade 3 to 5 AEs was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 ( P = .006). In descriptive analyses, objective response rate was 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with complete responses in 15.0% and 13.5% of patients, respectively. Median progression-free survival was 9.9 months in the NIVO3+IPI1 group and 8.9 months in the NIVO1+IPI3 group. Median overall survival was not reached in either group., Conclusion: The CheckMate 511 study met its primary end point, demonstrating a significantly lower incidence of treatment-related grade 3-5 AEs with NIVO3+IPI1 versus NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy end point, although longer follow up may help to better characterize efficacy outcomes.

The management of metastatic melanoma is a difficult matter. Nevertheless, the advent of target therapy has significantly improved patient outcome, provided that tumor molecular characteristics become available: the detection of drug-resistant clones can contribute to understanding the reasons for resistance onset, influencing the choice of subsequent therapy. This work aimed to provide a possible explanation for the early resistance to vemurafenib developed by a patient with melanoma, and concurrently to assess the extent, and role, of the tumor clonal heterogeneity. We analyzed tissue samples from different sites and time points: first/second primary, three lymph node metastases, and circulating melanoma cells (CMCs). We first investigated these samples by the routine Sanger sequencing for BRAF, NRAS, and KIT, and then, we focused on specific hotspots by droplet digital PCR. We detected a BRAF V600E mutation by Sanger sequencing in the second primary and distant lymph node metastases, but not in the first primary or sentinel lymph node. Interestingly, by droplet digital PCR, the V600E mutation was also detected in the first primary, and the V600K in the second primary and metastases. Moreover, we identified a rare KIT V569G mutation, appearing to be CMC exclusive. This finding confirms the potential of CMCs as a source of tumor material for genetic analysis, reflecting real-time systemic disease evolution and, most likely, the most aggressive, treatment-resistant clones. In summary, this work underlines the importance of CMCs in the early identification of tumor clones putatively responsible for therapy resistance.

Merkel Cell Carcinoma (MCC) is a rare but highly aggressive neuroendocrine neoplasm of the skin. This study aimed at describing characteristics, treatment, and prognosis of a series of consecutive cases of MCC patients, in order to contribute to the investigation of this rare malignancy and provide better patient care. This is a retrospective cohort study including all 90 patients diagnosed and/or treated for MCC between 1991 and 2018 at the Veneto Institute of Oncology in Padua (Italy). Patient and tumor characteristics, treatment, and immunohistochemical data were extracted from a prospectively collected local database. There were 68 primary (76%) and 22 non-primary (15 occult primary, three metastatic, four recurrence) tumors (24%). CK20 expression was associated with reduced overall (HR 2.92, 95% CI 1.04⁻8.16) and disease-specific (HR 4.62, 95% CI 1.31⁻16.28) survival. Immunomodulatory regimens for treatment of other comorbidities were associated with reduced disease-specific ((HR 2.15, 95% CI 1.06⁻4.36) and recurrence-free (HR 3.08, 95% CI 1.44⁻6.57) survival. Iatrogenic immunomodulation resulted as the main factor associated with impaired prognosis. Lack of CK20 expression was associated with better survival.

Metastatic melanoma is characterized by complex genomic alterations, including a high rate of mutations in driver genes and widespread deletions and amplifications encompassing various chromosome regions. Among them, chromosome 7 is frequently gained in BRAF -mutant melanoma, inducing a mutant allele-specific imbalance. Although BRAF amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if BRAF copy-number variation and BRAF mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess BRAF copy number and mutant allele frequency in pretreatment melanoma samples from 46 patients who received MAPK inhibitor-based therapy, and we analyzed the association with progression-free survival. We found that 65% patients displayed BRAF gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced BRAF -mutant/wild-type allele ratio, whereas 14% and 23% patients had low and high BRAF mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid BRAF status versus those with BRAF gains [HR, 2.86; 95% confidence interval (CI), 1.29-6.35; P = 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95% CI, 1.33-15.53; P = 0.016). Our data suggest that quantitative analysis of the BRAF gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors. Mol Cancer Ther; 17(6); 1332-40. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. The use of ipilimumab is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features and blood biomarkers capable of predicting ipilimumab related toxicity., Methods: We performed a prospective study aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w). We enrolled 140 consecutive melanoma patients treated with ipilimumab for metastatic disease. The following prospectively collected data were utilized: patient characteristics, previous therapies, level of circulating biomarkers associated with tumour burden or immune-inflammation status (lactic dehydrogenase, C-reactive protein, β2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases) and blood cells subsets (leukocyte and lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data., Results: Out of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity. Female patients had a further increase of immune-related adverse events. Low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34-6.03, P = 0.007) and sex female (OR = 1.5, 95% CI 1.06-2.16 P = 0.022) and were significant and independent risk factors for immune related adverse events., Conclusions: Baseline IL6 serum levels and female sex were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in patients treated with ipilimumab.

In patients with metastatic melanoma, ipilimumab has been shown to improve long-term survival. This observational multicenter study reports clinical outcomes of 418 patients treated with second-line ipilimumab from February 2013 to August 2014. Median overall survival (OS) was 6.43 months (95%CI: 5.45-7.42; n = 300), while median progression-free survival (PFS) was 3.7 months (95%CI: 3.23-4.17; n = 188). Demographic factors, such as sex or number of previous therapies did not affect OS. Survival was shorter in patients with ECOG > 0 (Eastern Cooperative Oncology Group, Performance Status) (p < 0.001), while a longer OS was found in patients who completed all four therapy cycles (p < 0.001). Adverse events of any grade were reported for 66% of patients (mainly cutaneous and gastrointestinal), but most were low grade and easily managed. Adverse events of grades 3-4 were observed in 13% of patients. This study confirmed the efficacy and safety of this treatment in real practice.

Background: The 7th edition of the TNM American Joint Committee on Cancer classification incorporates mitotic rate (MR) only for primary cutaneous melanoma (PCM) with Breslow thickness (BT) ≤1 mm., Objective: To investigate whether and to what extent MR is able to predict sentinel lymph node (SLN) status and clinical outcome of PCM patients with BT >1 mm., Methods: The study included consecutive patients with PCM. Logistic regression and Cox regression model were used to analyze the impact of MR on SLN status, disease-free survival (DFS), and overall survival., Results: From 1998 to 2015, 1524 PCM (median age 57.8 years) cases were diagnosed with a BT >1 mm in six centers of the Italian Melanoma Intergroup. Median follow-up was 5.0 years. By multivariate analysis, MR was associated with SLN positivity (odds ratio 1.98, 95% confidence interval [CI] 1.12-3.50, P = .018). After adjusting for BT, ulceration, age, sex, and SLN status, MR correlated with a poor DFS (hazard ratio 1.52, 95% CI 1.18-1.97, P = .002) and overall survival (hazard ratio 1.63, 95% CI 1.17-2.29, P = .004)., Limitations: Retrospective analysis., Conclusion: MR is an independent prognostic factor for PCM patients with BT >1 mm. Incorporating this tissue biomarker could provide a better stratification of patients entering clinical trials in the adjuvant setting., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Ipilimumab is the first licensed immune checkpoint inhibitor for treatment of melanoma. The promising results of the registration clinical study need confirmation in real practice and its clinical success comes together with a relevant budget impact due to the high price of this drug. The aim of this work is to describe a new model of economical sustainability of ipilimumab developed in an Italian reference center for melanoma treatment., Methods: This retrospective, observational, and monocentric study was carried out at the Veneto Institute of Oncology. Ipilimumab was administered to fifty-seven patients with advanced melanoma. Overall survival, progression free survival, and toxicity were evaluated. A local management procedure was evaluated together with the cost-saving strategies implemented by the Italian Medicines Agency (AIFA)., Results: We demonstrated that the use of ipilimumab for metastatic melanoma in real practice had an efficacy and toxicity similar to that reported in the literature. In this scenario, our management model (centralization of compounding + drug-day) permitted savings up to the 11.1 percent of the gross cost for the drug (calculated assuming that no cost saving procedures were applied) while the policy of cost containment designed by AIFA produced an additional 6.2 percent of savings., Conclusions: In real practice conditions, the centralized administration of ipilimumab allows to replicate the results of clinical studies and in the meantime to contain the cost associated with this drug. The local strategy of management can be readily applied to most of the high cost drugs compounded in the hospital pharmacy. Impact of findings on practice: (i) We describe a new model of economic sustainability (drug-day, centralization of compounding, payback systems) of an expensive and innovative drug, ipilimumab, for treatment of melanoma within an Italian cancer center. (ii) This pivotal study demonstrated that a cost containment strategy is feasible and it needs the cooperation of all healthcare providers (oncologists, pharmacists, nurses, and technicians) to guarantee the full efficiency of the process.

Ipilimumab, the first immune-checkpoint inhibitor extending overall survival (OS) in metastatic melanoma patients, has a survival benefit only in a proportion of patients and the development of reliable predictive biomarkers is still an unmet need. To meet this request, we used a multivariate statistical approach to test whether myeloid-derived suppressor cells (MDSC) or other tumor-associated and immunological parameters may serve as predictive or prognostic biomarkers in melanoma patients receiving ipilimumab. By using a standardized approach to determine the circulating levels of four MDSC subsets, we observed a significant expansion of three MDSC subsets at baseline, as compared to controls and, upon treatment, that high levels of CD14 + /IL4Rα + MDSCs were an independent prognostic factor of reduced OS. On the contrary, longer OS was associated to low levels of the proinflammatory proteins IL-6 and CRP and tumor-associated factors S100B and LDH both at baseline and after treatment. Increasing number of total T cells and especially of PD-1 + /CD4 + T cells were associated with better prognosis, and upregulation of PD-1 + expression on CD4 + T cells upon treatment was associated with lower toxicity. As several parameters were associated to OS, we included these factors in a multivariate survival model, and we identified IL-6 and ECOG PS as independent biomarkers associated with improved OS, whereas high levels of LDH and CD14 + /IL4Rα + MDSCs were negative independent markers of reduced OS.

Background: Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need., Patients and Methods: Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out., Results: The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR., Conclusions: Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.)

We retrospectively evaluated the benefit of transarterial chemoembolization with CPT-11 charged microbeads (TACE) in 58 of 141 uveal melanoma patients with liver metastases. This was a retrospective analysis of a prospectively maintained database ranging from September 1990 to April 2014. Statistical analyses adjusting for possible confounding effects of extent of liver metastases were carried out using the Cox regression model under the verified hypothesis of proportional hazards. Among 141 patients with liver metastases, 58 were treated with TACE as first-line therapy and 36 were dead at the time of the analysis; 83 patients received other first-line treatments (deaths=83). The treatment with TACE conferred a survival advantage (median 16.5 vs. 12.2 months, respectively); when the two cohorts were analyzed comparing the two groups according to the percentage of liver involvement, there was significant evidence that patients with worse hepatic involvement benefited most from the treatment (liver metastases=20-50%: hazard ratio=0.50, P=0.048 and liver metastases ≥50%: hazard ratio=0.17, P=0.009). Liver function tests (transaminases and γ-glutamyl-transpeptidase) and age were higher in the historic group, and LDH tended to show higher values. There were no high-grade toxicities with TACE. TACE seems to be a tolerable regimen that confers an improvement in the survival of uveal melanoma patients with liver metastases. Confirmation of the clinical efficacy of TACE is recommended in a phase III trial, possibly with the inclusion of a targeted therapy such as a MEK inhibitor., (Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians., Patients and Methods: Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram., Results: The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2-3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated., Conclusions: The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials.

Background: Small molecules that inhibit V600 mutated BRAF protein, such as vemurafenib and dabrafenib, are effective in treatment of metastatic melanoma., Case Report: We here describe the clinical course of a V600E BRAF mutated metastatic melanoma patient with systemic disease, who developed tumor progression on superficial soft-tissue metastases during treatment with dabrafenib. Bleomycin electrochemotherapy during dabrafenib treatment was administered to control the soft-tissue progressing metastases and ensured sustained local control without significant toxicity., Conclusions: The new combined approach maintained the patient quality of life and allowed for the prosecution of the target therapy, which proved to be still effective on systemic disease, up to 17 months.

The impact of BRAF mutations in metastatic melanoma on the incidence of brain metastases and melanoma prognosis and the effect of BRAF inhibitors on the incidence of brain metastases has not been defined. Therefore, a retrospective analysis of patients with metastatic melanoma treated at three institutions was carried out to examine the impact of BRAF mutations and a BRAF inhibitor, vemurafenib, on the incidence of brain metastases. A retrospective review of 436 records revealed no difference in the incidence of brain metastases between patients with BRAF-mutated tumors versus those without (incidence rate ratio=1.11, 95% confidence interval: 0.80-1.53; P=0.53). A lower incidence of brain metastases was observed in patients with BRAF-mutated tumors who took vemurafenib before the development of brain metastases versus those who did not (incidence rate ratio=0.51, 95% confidence interval: 0.30-0.86; P=0.009). Although treatment with vemurafenib led to improvement in extracranial disease control, it did not significantly affect progression of existing intracranial disease and survival in these patients (P=0.7). Although our previous preclinical data have indicated that penetration of vemurafenib into the brain is limited, our retrospective analysis showed that there was a lower incidence of brain metastases in patients with BRAF-mutated tumors who took vemurafenib before the diagnosis of brain metastases.

Background: Ipilimumab improves survival in patients with advanced melanoma. The activity and safety of ipilimumab outside of a clinical trial was assessed in an expanded access programme (EAP)., Methods: Ipilimumab was available upon physician request for patients aged 16 or over with pretreated stage III (unresectable)/IV melanoma, for whom no other therapeutic option was available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12. Patients were monitored for adverse events (AEs) within 3 to 4 days of each scheduled visit., Results: Of 855 patients participating in the EAP in Italy, 833 were evaluable for response. Of these, 13% had an objective immune response, and the immune-related disease control rate was 34%. Median progression-free survival and overall survival were 3.7 and 7.2 months, respectively. Efficacy was independent of BRAF and NRAS mutational status. Overall, 33% of patients reported an immune-related AE (irAE). The frequency of irAEs was not associated with response to ipilimumab., Conclusions: Outside of a clinical trial setting, ipilimumab is a feasible treatment option in patients with pretreated metastatic melanoma, regardless of BRAF and NRAS mutational status. Data from this large cohort of patients support clinical trial evidence that ipilimumab can induce durable disease control and long-term survival in patients who have failed to respond to prior treatment.

Patients with melanoma brain metastases have a poor prognosis and historically have been excluded from clinical trials. The Expanded Access Program (EAP) provided an opportunity to evaluate the feasibility of ipilimumab (3 mg/kg every 3 weeks for four doses) in patients with stage 3 (unresectable) or 4 melanoma and asymptomatic brain metastases, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Tumor assessments were conducted at baseline and week 12 using immune-related response criteria and patients were monitored for adverse events (AEs). Of 855 patients participating in the EAP in Italy, 146 had asymptomatic brain metastases. With a median follow-up of 4 months, the global disease control rate was 27%, including 4 patients with a complete response and 13 with a partial response. Median progression-free survival and overall survival were 2.8 and 4.3 months, respectively and approximately one-fifth of patients were alive 1 year after starting ipilimumab. In total, 29% of patients reported a treatment-related AE of any grade, which were grade 3/4 in 6% of patients. AEs were generally reversible with treatment as per protocol-specific guidelines. Ipilimumab shows durable benefits in some patients with advanced melanoma metastatic to the brain, with safety results consistent with those previously reported in clinical trials.

This article reviews the epidemiology, pathogenesis, diagnosis, prognostic factors and treatment of metastatic melanoma, including the most recent developments in the specific field. It examines the sequential and non-linear models of development and progression of melanoma and the main molecular disorder involved in these processes. Clinical and diagnostic aspects have been divided according to clinical staging. Surgical resectability, the site and number of metastases, the number of involved organs, the duration of remission, serum lactate dehydrogenase levels and tumor doubling-time have the greatest prognostic value. Surgical treatment has been analyzed considering its rational function and examining all sites involved in metastasis. We also discuss the palliative role of radiotherapy in relation to various metastatic sites, chemotherapy and recently introduced targeted-therapy. The association of newer drugs and new biological therapies such as ipilimumab and verumafenib have improved the treatment landscape of stage IV melanoma.

Background: Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. Data from clinical trials and expanded access programmes (EAPs) suggest ipilimumab confers a consistent survival benefit and has a similar safety profile across different age groups of patients with metastatic melanoma. Here we report the efficacy and safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy., Methods: Patients aged > 70 years with pretreated melanoma received ipilimumab 3 mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated at baseline and after completion of induction therapy using immune-related response criteria and patients were monitored throughout the treatment period for adverse events (AEs), including immune-related AEs., Results: The immune-related disease control rate among 188 evaluable patients was 38%, including four patients with an immune-related complete response, 24 with an immune-related partial response and 44 with immune-related stable disease. Median progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1- and 2-year OS rates were 38% and 22%, respectively. The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines., Conclusions: These results suggest ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.

Background: Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg(-1) among patients participating in an expanded access programme in Italy., Methods: Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg(-1) every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events., Results: Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported., Conclusions: For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials.

Background: Mucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma., Methods: Ipilimumab was available upon physician request for patients aged ⩾16years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3mg/kg every 3weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4days of each scheduled visit., Results: Of 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines., Conclusion/interpretation: Ipilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute development of pancerebellar dysfunction as a remote effect of a systemic cancer and usually develops in patients affected by gynecological tumors. Uveal melanoma is a very rare disease with a severe prognosis. A 58-year-old man affected by uveal melanoma developed anti-Yo positive paraneoplastic cerebellar degeneration (PCD) 42 months after the initial diagnosis. The onset and worsening of the neurological symptoms were parallel to the course of liver metastasis. To our knowledge this is the first case of PCD in a patient with uveal melanoma. We speculate that the cerebellar degeneration-related protein 2 (CDR2), to which the anti-Yo antibodies are directed, may have been expressed in melanoma cells and conferred proliferative advantage to the disease., (© 2013.)

Background: Patients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited., Patients and Methods: Pre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events., Results: Among 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting ≥3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression-free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma., Conclusions: These data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population.

Background: In recent decades, melanoma incidence has been increasing in European countries; in 2006, there were approximately 60,000 cases leading to 13,000 deaths. Within Europe there is some geographical variation in the incidence of melanoma, with the highest rates reported in Scandinavia (15 cases per 100,000 inhabitants per year) and the lowest in the Mediterranean countries (5 to 7 cases per 100,000 inhabitants per year)., Methods: The present article is based on the information collected in the MELODY study (MELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal survey).In that study, the medical charts of patients were reviewed to document current treatment patterns and to analyse information on patients, disease characteristics and healthcare resource utilization related to the treatment of advanced melanoma regarding patients who presented with a diagnosis of malignant melanoma (stage I to IV) at participating sites between 01 July, 2005 and 30 June, 2006., Results: Summarizing, though the length of the follow-up period varies among sample patients, an amount of the yearly cost per patient can be estimated, dividing the average per patient total cost (€ 5.040) by the average follow-up duration (17.5 months) and reporting to one year; on these grounds, unresectable stage III or stage IV melanoma in Italy would cost € 3,456 per patient per year.

Background: This study compared the central nervous system (CNS) metastasis incidence between a temozolomide- and a dacarbazine-based regimen in untreated stage IV melanoma patients., Methods: A total of 150 patients were randomly assigned to receive either oral temozolomide (200 mg m(-2) per day; days 1-5) or intravenous dacarbazine (800 mg m(-2); day 1), in combination with intravenous cisplatin (75 mg m(-2); day 1) and subcutaneous interleukin-2 (3 MU twice daily; days 9-18), every 28 days (CTI and CDI)., Results: A total of 149 patients were eligible for an intention-to-treat analysis (CTI: n=74, CDI: n=75). The 1-year cumulative CNS incidence failure was 20.6% for CTI and 31.1% for CDI (P=0.22). In all 24 patients in CTI (32%) and 34 (45%) in CDI developed CNS metastases; 31 patients died of early systemic progression, before CNS evaluation. Median survival time was 8.4 months in the CTI and 8.7 in the CDI arm; in patients with CNS metastases the median survival time was 13.5 months in the CTI and 11.5 in the CDI arm. No difference in toxicity was observed between the two arms., Conclusion: The incidence of CNS failures in metastatic melanoma was not significantly reduced and the clinical course was not modified substituting a dacarbazine-based regimen with a temozolomide-based regimen. Patients who developed CNS metastases did not have a worse prognosis than patients progressing in other sites and should not be excluded from new investigational studies.