Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.

The human sirtuins (SIRT1–SIRT7) enzymes are a highly conserved family of NAD⁺‐dependent histone deacetylases, which play a critical role in the regulation of a large number of metabolic pathways involved in stress response and aging. Cancer is an age‐associated disease, and sirtuins may have a considerable impact on a plethora of processes that regulate tumorigenesis. In particular, growing evidence suggests that sirtuins may modulate epithelial plasticity by inducing transcriptional reprogramming leading to epithelial‐mesenchymal transition (EMT), invasion, and metastases. Though commonly regarded as EMT inducers, sirtuins may also suppress this process, and their functional properties seem to largely depend on the cellular context, stage of cancer development, tissue of origin, and microenvironment architecture. Here, we review the role of sirtuins in cancer biology with particular emphasis on their role in EMT.

Cutaneous melanoma shows a high metastatic potential based on its ability to overcome the immune system’s control. The mechanisms activated for these functions vary extremely and are also represented by the production of a number of extracellular vesicles including exosomes. Other vesicles showing a potential role in the melanoma progression include oncosomes and melanosomes and the majority of them mediate tumor processes including angiogenesis, immune regulation, and modifications of the micro-environment. Moreover, a number of epigenetic modifications have been described in melanoma and abundant production of altered microRNAs (mi-RNAs), non-coding RNAs, histones, and abnormal DNA methylation have been associated with different phases of melanoma progression. In addition, exosomes, miRNAs, and other molecular factors have been used as potential biomarkers reflecting disease evolution while others have been suggested to be potential druggable molecules for therapeutic application.

Background Long‐acting somatostatin analogs (SSAs) are the primary first‐line treatment of well‐differentiated advanced gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki‐67 ≥10% are still limited. Materials and Methods To assess the clinical outcomes of advanced, non‐functioning, well‐differentiated panNETs with Ki‐67 ≥10% receiving first‐line long‐acting SSAs in a real‐world setting, we carried out a retrospective, multi‐center study including patients treated between 2014‐2018 across ten centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression‐free survival (PFS), while overall survival (OS) and treatment safety were secondary endpoints. Results 73 patients were included (68 G2, 5 G3), with liver metastases in 61 cases (84%). After a median follow‐up of 36.4 months (range, 6‐173 months), the median TNT and PFS were 14.2 months (95% CI, 11.6‐16.2 months) and 11.9 months (95% CI, 8.6‐14.1 months) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs lanreotide), while increased tumor grade (HR: 4.4, 95% CI, 1.2‐16.6; p=0.04) and hepatic tumor load (HR: 2, 95% CI, 1‐4; p=0.03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8‐86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR: 3.4, 95% CI, 1.2‐10; p=0.01). Treatment‐related adverse events were reported in 14 patients, most frequently diarrhea. Conclusions SSAs exert antiproliferative activity in PanNETs with Ki‐67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice The results of the study call in the question the anti‐proliferative activity of SSAs in panNETs with Ki‐67 ≥10%. Patients with G2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results, in order to optimize tailored therapeutic strategies for this specific patient population.