As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

Objective Artificial dermal substitutes (DSs) are fundamental in physiological wound healing to ensure consistent and enduring wound closure and provide a suitable scaffold to repair tissue. We compared the clinical and histological features of two DSs, Pelnac and Integra, in the treatment of traumatic and iatrogenic skin defects. Methods This prospective observational study involved 71 randomly selected patients from our hospital. Wound healing was analyzed using the Wound Surface Area Assessment, the Vancouver Scar Scale, and a visual analog scale. Histological and immunohistochemical evaluations were also performed. Results At 2 weeks, greater regeneration with respect to proliferation of the epidermis and renewal of the dermis was observed with Pelnac than with Integra. At 4 weeks, the dermis had regenerated with both DSs. Both templates induced renewed collagen and revascularization. Differences in the Vancouver Scar Scale score were statistically significant at 4 weeks and 1 year. Pelnac produced a significant increase in contraction at 2 weeks with increasing effectiveness at 4 weeks. Integra produced a higher percentage reduction in the wound surface area and a shorter healing time than Pelnac for wounds >1.5 cm deep. Conclusion Our observational data indicate that both DSs are effective and applicable in different clinical contexts.

: Immunotherapy based on anti PD-1/PD-L1 inhibitors has proven to be more effective than sunitinib in the first-line setting of advanced renal cell carcinoma (RCC). RCC patients with sarcomatoid histology (sRCC) have a poor prognosis and limited therapeutic options. We performed a systematic review and a meta-analysis of randomized-controlled trials (RCTs) of first-line anti PD-1/PDL-1 agents vs. sunitinib, presenting efficacy data in the sub-group of sRCC patients. The systematic research was conducted on Google Scholar, Cochrane Library, PubMed and Embase and updated until 31th January, 2020. Abstracts from ESMO and ASCO (2010–2019) were also reviewed. Full texts and abstracts reporting about RCTs testing first-line anti-PD-1/ PD-L1 agents vs. sunitinib in RCC were included if sRCC sub-group analyses of either PFS (progression-free survival), OS (overall survival) or radiological response rate were available. Pooled data from 3814 RCC patients in the ITT (intention-to-treat) population and from 512 sRCC patients were included in the quantitative synthesis. In the sRCC sub-group vs. the ITT population, pooled estimates of the PFS-HRs were 0.57 (95%: 0.45–0.74) vs. 0.79 (95% CI: 0.70–0.89), respectively, with a statistically meaningful interaction favoring the sRCC sub-group (pooled ratio of the PFS-HRs = 0.64; 95% CI: 0.50–0.82; p < 0.001). Pooled estimates of the difference in CR-R (complete response-rate) achieved with anti-PD-1/PDL-1 agents vs. sunitinib were + 0.10 (95% CI: 0.04–0.16) vs. + 0.04 (95% CI: 0.00–0.07) in the sRCC vs. the non-sRCC sub groups, with a statistically meaningful difference of + 0.06 (95% CI: 0.02–0.10; p = 0.007) favoring the sRCC sub-group. Sarcomatoid histology may be associated with improved efficacy of anti PD-1/PDL-1 agents vs. sunitinib in terms of PFS and CR-R.

The stromal vascular fraction (SVF) consists of a heterogeneous population of stem and stromal cells, generally obtained from adipose tissue by enzymatic digestion. For human cell-based therapies, mechanical process methods to obtain SVF represent an advantageous approach because they have fewer regulatory restrictions for their clinical use. The aim of this study was to characterize a novel commercial system for obtaining SVF from adipose tissue by a mechanical approach without substantial manipulations. Lipoaspirate samples collected from 27 informed patients were processed by a simple and fast mechanical system (by means of Hy-Tissue SVF). The Hy-Tissue SVF product contained a free cell fraction and micro-fragments of stromal connective tissue. The enzymatic digestion of the micro-fragments increased the yield of free cells (3.2 times) and CFU-F (2.4 times). Additionally, 10% of free cells from SVF were positive for CD34+, suggesting the presence of endothelial cells, pericytes, and potential adipose-derived stem cells (ADSC). Moreover, the SVF cells were able to proliferate and differentiate in vitro toward adipocytes, osteocytes, and chondrocytes. The immunophenotypic analysis of expanded cells showed positivity for typical mesenchymal stem cell markers. The Hy-Tissue SVF system allows the isolation of stromal vascular fraction, making this product of potential interest in regenerative medicine.

Autologous fat grafting is a surgical technique in which adipose tissue is transferred from one area of the body to another, in order to reconstruct or regenerate damaged or injured tissues. Before reinjection, adipose tissue needs to be purified from blood and cellular debris to avoid inflammation and preserve the graft viability. To perform this purification, different enzymatic and mechanical methods can be used. In this study, we characterized in vitro the product of a closed automatic device based on mechanical disaggregation, named Rigenera®, focusing on two sites of adipose tissue harvesting. At first, we optimized the Rigenera® operating timing, demonstrating that 60 s of treatment allows a higher cellular yield, in terms of the cell number and growth rate. This result optimizes the mechanical disaggregation and it can increase the clinical efficiency of the final product. When comparing the extracted adipose samples from the thigh and abdomen, our results showed that the thigh provides a higher number of mesenchymal-like cells, with a faster replication rate and a higher ability to form colonies. We can conclude that by collecting adipose tissue from the thigh and treating it with the Rigenera® device for 60 s, it is possible to obtain the most efficient product.