In the huge spectrum of lung neuroendocrine neoplasms, typical and atypical carcinoids should be considered as a separate biological entity from poorly differentiated forms, harboring peculiar molecular alterations. Despite their indolent behavior, lung carcinoids correlate with a worse survival. To date, only limited therapeutic options are available and novel drugs are strongly needed. In this work, we extensively reviewed scientific literature exploring available therapeutic options, new molecular targets and future perspectives in the management of well differentiated neoplasms of bronchopulmonary tree. Systemic therapy represents the main option in advanced and unresectable disease; accepted choices are somatostatin analogs, peptide receptor radionuclide therapy, everolimus and chemotherapy. To date, an univocal treatment strategy has not been identified yet, thus tailored therapeutic algorithms should consider treatment efficacy as well as safety profiles. Several molecular alterations found in carcinoid tumors might act as molecular targets leading to development of new therapeutic options. Further studies are necessary to identify new potential “druggable” molecular targets in the selected subset of low‐grade lung carcinoids. Furthermore, evaluating the available therapies in more homogeneous population might improve their efficacy through a perfect tailoring of treatment options.

In recent years, BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi), together with immune checkpoint inhibitors (ICIs), have changed the therapeutic strategy of cutaneous melanoma, both in adjuvant and metastatic settings. These inhibitors have significantly improved the clinical outcome for patients with melanoma, including in both BRAF‑mutated and BRAF‑wild type disease. Some preclinical and clinical studies have revealed that BRAFi and MEKi are able to influence T‑ and B‑cell activation, and to modulate immune system activation within the tumor microenvironment. Dabrafenib and trametinib have been shown to enhance the expression of melanoma antigens on BRAF‑mutated cells, and to favor both a cytotoxic and immune response against melanoma cells. Thereby, the present study described a case series of five women treated with BRAFi and MEKi, in both adjuvant and metastatic settings, that experienced potential immune‑related adverse events. In particular, these patients exhibited sarcoidosis, mesenteric panniculitis, lymphocytic colitis and neuropathy of phrenic nerve. Considering that T and B cells are responsible for immune‑related adverse events, as observed in patients treated with ICIs, the present study suggested a possible role of BRAFi and MEKi as triggers of immune system activation and subsequent immune‑related toxicities.

Background: Melanoma is the fourth and sixth most common malignancy in men and women, respectively, and the 5-year survival rate critically depends on disease stage (American Cancer Society, 2016). MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs endogenously produced by the cells, which regulate the expression of hundreds of target genes. Circulating miRNAs actively secreted by tumor cells or released as the consequence of tumor cell death, have been proposed as potential biomarkers in cancer patients because of their stability in body fluids, resistance to endogenous RNase and constant expression in healthy individuals (Mitchell et al. 2008; Chen et al. 2008). Materials and methods: In the current study, the expression profiles of a selected panel of circulating miRNAs were analysed in plasma samples derived from patients and healthy donors to identify possible candidate biomarkers for diagnosis, prognosis and/or surveillance of human cutaneous melanoma. The study protocol was approved by local Ethics Committee and conducted in accordance to the principles of the Declaration of Helsinki. Blood samples were collected from melanoma patients (n = 30) at different disease stages, and from healthy age- and sex-matched volunteers (n = 32). Plasma miRNAs were isolated by miRNeasy Serum/Plasma Kit (Qiagen) and real-time PCR were carried out using miRCURY LNATM Universal RT microRNA PCR system (Exiqon, Denmark). Data analysis was carried out using two different strategies for normalization: Global Mean Normalization (GMN) and NormFinder model. Results: The GMN approach and NormFinder algorithm provided 13 and 7 significantly dysregulated miRNAs (p < 0.05), respectively, and those that resulted significantly dysregulated after normalizations and the Bonferroni correction were selected. Circulating miR-15b-5p (p = 1.34e−05), miR-149-3p (p = 3.40e−12), and miR- 150-5p (p = 2.85e−12) were up-regulated, while miR-193a-3p (p = 1.30e−06) and miR-524-5p (p = 2.41e−05) were down-regulated in patients (regardless of disease stage) compared to healthy controls. Linear regression and following receiving operator curves (ROC) analyses were performed to evaluate the diagnostic value of these five selected miRNAs (i.e., the ability to discriminate between cases and controls). The area under ROC curve (AUCs) for individual miRNAs ranged from 0.801 to 0.951. Although the predictive power of all selected miRNAs was clearly demonstrated, miR-150-5p and miR-149-3p gave the best performance (AUCs of 0.9489, 95% CI from0.8852 to 1.017 and 0.9510, 95% CI from 0.8852 to 1.017, respectively). Noteworthy, predictive performance was further improved when considering the double combination of miR-150-5p and miR-149-3p. The double classifier has indeed an increased area under ROC curve (AUC) of 0.966 (95% CI 0.938–0.994) with 90% sensitivity, 68% specificity. Conclusions: In conclusion, findings of the current pilot study identified five circulating miRNAs in melanoma patients, of which three detected for the first time as circulating in this type of cancer, as potential diagnostic biomarkers with high sensitivity and specificity. In particular, the combined miR-149-3p, miR-150-3p and miR-193a-3p signature showed a high capacity to discriminate between healthy subjects and affected individuals. This feature make the signature suitable to be used in controversial melanoma diagnosis. Indeed, these preliminary data that identify a new panel of three miRNAs, including two identified for the first time as circulating in melanoma, deserve to be validated in a larger number of patients, in order to confirm their diagnostic power not only as a possible support to controversial pathology reports histological results but also in early diagnosis of melanoma

Background/Objective: Dabrafenib and trametinib (D + T) have been approved for the treatment of stage III melanoma with BRAF V600E V600K mutations in an adjuvant setting, based on the results from the COMBI-AD trial. To provide early access to this combination therapy prior to its commercial availability in Italy, a Managed Access Program (MAP) was run in Italy from June 2018 to December 2019. Methods: The MADAM (Maximing ADjuvAnt MAP) study is an Italian retrospective–prospective observational study that included patients who received at least one dose of D + T through the MAP. The primary endpoints were relapse-free survival (RFS) and overall survival (OS). Results: This interim analysis presents findings after the first 24 months of follow-up. A total of 310 patients were included in the study; 240 completed the 12-month treatment with D + T, while 70 discontinued the combination. RFS rates were 93.2% at 12 months and 80.2% at 24 months. The median RFS was not reached for the overall population or any subgroups. Similarly, the median OS was not reached, with OS rates of 96.4% at 12 months and 92.5% at 24 months. Conclusions: D + T achieved an RFS benefit, with effects sustained beyond the treatment period, indicating positive outcomes in this patient population.