Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.

Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04–2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients’ outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Hepatocellular carcinoma (HCC) is one of the most common human solid malignancies worldwide. Although the MRI is the technique that is best adapted to characterize HCC, there is not an agreement regarding the study protocol and even what the role of Diffusion-weighted imaging (DWI). The possibility that imaging study can correlate to histologic grade to selecting the therapeutic strategy would be valuable in helping to direct the proper management of HCC. Apparent Diffusion Coefficient (ADC) and IVIM-derived perfusion fraction (fp) and tissue diffusivity (Dt) values of HCC showed significantly better diagnostic performance in differentiating high-grade HCC from low-grade HCC, and significant correlation was observed between ADC, fp, Dt and histological grade.

Objective. To assess local disease control rates (LDCR) and overall survival (OS) in locally advanced pancreatic cancer (LAPC) treated with electrochemotherapy (ECT). Methods. Electrochemotherapy with bleomycin was performed in 25 LAPC patients who underwent baseline Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and Position Emission Tomography (PET) scans before ECT and 1 and 6 months post ECT. LDCR were assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Choi criteria. Needle electrodes with fixed linear (N-30-4B) or fixed hexagonal configurations (N-30-HG or I-40-HG or H-30-ST) or variable geometry (VGD1230 or VGD1240) (IGEA S.p.A., Carpi, Italy) were used to apply electric pulses. Pain evaluation was performed pre-ECT, after 1 month and after 6 months with ECT. Overall survival estimates were calculated by means of a Kaplan-Meier analysis. Results. At 1 month after ECT, 76% of patients were in partial response (PR) and 20% in stable disease (SD). Six months after ECT, 44.0% patients were still in PR and 12.0% in SD. A LDCR of 56.0% was reached six months after ECT: 13 patients treated with fixed geometry had a LDCR of 46.1%, while for the 12 patients treated with variable geometry, the LDCR was 66.7%. The overall survival median value was 11.5 months: for patients treated with fixed geometry the OS was 6 months, while for patients treated with variable geometry it was 12 months. Electrochemotherapy was well-tolerated and abdominal pain was rapidly resolved. Conclusions. Electrochemotherapy obtained good results in terms of LDCR and OS in LAPC. Multiple needle insertion in a variable geometry configuration optimized by pre-treatment planning determined an increase in LDCR and OS compared to a fixed geometry configuration.

Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target.