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Background: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients., Methods: A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m 2 on days 1 and 2 and FM iv 100 mg/m 2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients., Results: We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status., Conclusion: This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed., Trial Registration: EUDRACT 2009-016487-36l ; date of registration 23 June 2010.

Melanoma represents 2-3% of all cancers, 95% of them arise from skin, while only 5% are non-cutaneous melanoma. Despite an optimal surgery management, the risk of a local and systemic relapse remains high, particularly in high-risk patients (node-positive or node-negative T3b, T4 a/b). We conducted a systematic review of the main published and ongoing phase I/II/III trials between 2000 and June 2015 on the adjuvant treatment of cutaneous melanoma. The IFN remains the only option currently available for this aim. Ipilimumab represents a possible breakthrough in this setting, considering the positive results of the EORTC 18701 trials in terms of disease free survival (DFS), while data regarding OS are pending. Recent advances in the understanding of the biology of melanoma result in the identification of MAPK pathway role in the melanoma development. Based on these features, B-RAF inhibitors and their combination with immunotherapy could represent the upcoming therapeutic strategy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oral cavity mucosal melanomas (OCMM) represent only 3% of all malignant melanomas. Surgery is the mainstay of treatments and it is often followed by adjuvant radiotherapy. The role of adjuvant immunotherapy and/or chemotherapy is still debated and to date neither treatment is routinely used. From January 1990 to January 2010, we have collected from our database data of 20 patients with a histologically proven diagnosis of OCMM. Upfront surgery, followed by adjuvant radiotherapy was performed in 16/20 (80%) patients. Immunohistochemical analysis was carried out on all tissue samples and the following markers were assessed: Ki-67, HMG-45, Melan-A, S-100, CD31, CD35, CD20, CD21, and CD3. Although Ki-67, HMG-45, Melan-A, and S-100 were assessed in tumor cells, the analysis of CD31, CD21, CD20, CD3, and CD35 was carried out on the tumor-infiltrating lymphocytes. Patient outcome was analyzed and associated with clinical and Immunohistochemical tumor characteristics. The median overall survival (OS) was 12 months, with a 2-year OS rate of 30%. The median progression-free survival (PFS) was 9 months, with a 2-year PFS rate of 25%. Grade of lymphocyte infiltration (CD20 and CD3 expression) correlated strongly with prognosis. Interestingly, overexpression of CD21 along with downregulation of CD31 was significantly associated with better OS and PFS, whereas the reversal features correlated with a poor prognosis. Our report shows that patients affected by OCMM have a poor prognosis despite the administration of multimodal treatments. Moreover, our analysis suggests that the evaluation of several biomarkers, especially in tumor-infiltrating lymphocytes, may identify categories of patients with distinct immune response against the tumor and possibly different treatment response and prognosis.

Introduction: Metastatic melanoma is one of the most resistant tumors to standard chemotherapy, with a median overall survival of 6 - 8 months. Previously approved drugs offer only marginal survival advantages. Advances in the understanding of melanoma biology and host immunity have recently opened the field to new therapeutic approaches. Thus, after many years of disappointing results, a new era in the treatment of melanoma is beginning., Areas Covered: This review discusses new advances in the treatment of metastatic melanoma. Current data regarding the new agents under clinical development are reviewed, including emerging data from recently completed clinical trials, as well as preliminary data from ongoing studies testing novel therapeutic strategies., Expert Opinion: The new agents specifically targeted against melanoma are changing the standard of care for this disease. The monoclonal antibody ipilimumab is the first new agent approved for first- and second-line treatment of metastatic melanoma, based on improved overall survival compared -with standard therapy. Other drugs, such as BRAF inhibitors, have demonstrated high activity in the advanced disease and will be reaching clinical approval. Researchers are already planning ways to combine some of these new drugs in order to render possible a longer control of tumor.