Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians' experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS). We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008-2012; n = 154), and Group B (2013-2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p <0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs. 4.1 months, p = 0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs. 11.0 months, p = 0.003) with a sharp increase in the 2-year survival rate (28.1 vs. 18.4%, p = 0.003) in Group B. Multivariate time-dependent Cox regression analysis confirmed later period of treatment (2013-2017) as an independent predictor of survival (HR 0.728; 95%CI 0.581-0.937; p = 0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis. Experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive. Sorafenib has been the standard frontline systemic treatment for hepatocellular carcinoma for over a decade. Its tolerability is limited by different adverse events, which might lead to its permanent discontinuation in a sizeable proportion of patients. After a careful analysis of potential confounders, we demonstrated that the physicians' experience in managing adverse events related to sorafenib has improved over time, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into longer patient survival. Our results have relevant repercussions in clinical practice and in the design of future clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive adult cancers with an unacceptable prognosis. For this reason novel therapies accounting for PDAC peculiarities, such as the relevant stromal reaction, are urgently needed. Here adipose mesenchymal stromal/stem cells (AD-MSC) have been armed to constantly release a soluble trimeric and multimeric variant of the known anti-cancer TNF-related apoptosis-inducing ligand (sTRAIL). This cancer gene therapy strategy was in vitro challenged demonstrating that sTRAIL was thermally stable and able to induce apoptosis in the PDAC lines BxPC-3, MIA PaCa-2 and against primary PDAC cells. sTRAIL released by AD-MSC relocated into the tumor stroma was able to significantly counteract tumor growth in vivo with a significant reduction in tumor size, in cytokeratin-7+ cells and by an anti-angiogenic effect. In parallel, histology on PDAC specimens form patients (n = 19) was performed to investigate the levels of TRAIL DR4, DR5 and OPG receptors generating promising insights on the possible clinical translation of our approach. These results indicate that adipose MSC can very efficiently vehicle a novel TRAIL variant opening unexplored opportunities for PDAC treatment.

The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (¹H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that ¹H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan–Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology.

Cellular therapies based on mesenchymal stromal/stem cells (MSC) are promising strategies in regenerative medicine and oncology. Despite encouraging results, there is still some level of concerns on inoculating MSC in cancer patients. To face this issue, one possibility resides in engineering MSC by incorporating a suicide gene in order to control their fate once infused. Strategies based on Herpes Simplex Virus Thymidine Kinase (HSV-TK) and the Cytosine Deaminase genes have been developed and more recently a novel suicide gene, namely, iCasp9, has been proposed. This approach is based on a variant of human Caspase9 that binds with high affinity to a synthetic, bioinert small molecule (AP20187) leading to cell death. Based on this technology so far marginally applied to MSC, we tested the suitability of iCasp9 suicide strategy in MSC to further increase their safety. MSC have been transfected by a lentiviral vector carrying iCasp9 gene and then tested for viability after AP20187 treatment in comparison with mock-transfected cells. Moreover, accounting our anti-tumor approaches based on MSC expressing potent anti-cancer ligand TNF-Related Apoptosis-Inducing Ligand (TRAIL), we generated adipose MSC co-expressing iCasp9 and TRAIL successfully targeting an aggressive sarcoma type. These data show that anti-cancer and suicide mechanisms can coexist without affecting cells performance and hampering the tumoricidal activity mediated by TRAIL. In conclusion, this study originally indicates the suitability of combining a MSC-based anti-cancer gene approach with iCasp9 demonstrating efficiency and specificity.

Pancreatic cancer represents a very challenging disease, with an increasing incidence and an extremely poor prognosis. Peculiar features of this tumor entity are represented by pancreatic exocrine insufficiency and an early and intense nutritional imbalance, leading to the highly prevalent and multifactorial syndrome known as cancer cachexia. Recently, also the concept of sarcopenic obesity has emerged, making the concept of pancreatic cancer malnutrition even more multifaceted and complex. Overall, these nutritional derangements play a pivotal role in contributing to the dismal course of this malignancy. However, their relevance is often underrated and their assessment is rarely applied in clinical daily practice with relevant negative impact for patients’ outcome in neoadjuvant, surgical, and metastatic settings. The proper detection and management of pancreatic cancer-related malnutrition syndromes are of primary importance and deserve a specific and multidisciplinary (clinical nutrition, oncology, etc.) approach to improve survival, but also the quality of life. In this context, the introduction of a “Nutritional Oncology Board” in routine daily practice, aimed at assessing an early systematic screening of patients and at implementing nutritional support from the time of disease diagnosis onward seems to be the right path to take.

Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset.