Background/Aims: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS). Methods: Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features. Results: With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. ≥55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index ≥55% (type C). Conclusions: The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index.

There are limited and discordant results on the comparison between microwave ablation (MWA) and radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC). This meta-analysis aims to compare the two treatments in terms of efficacy and safety, based on a meta-analysis of randomized-controlled trials (RCTs). A computerized bibliographic search was performed on the main databases throughout August 2020. The primary outcome was the complete response rate, while survival rate (at 1-, 2-, 3-, and 5-year), disease-free survival rate (at 1-, 2-, 3-, and 5-year), local and distant recurrence rate, adverse event rate, and number of treatment sessions were the secondary outcomes. Seven RCTs enrolling 921 patients were included. No difference in terms of complete response between the two treatments was observed (risk ratio (RR) 1.01, 95% CI 0.99–1.02). Survival rates were constantly similar, with RRs ranging from 1.05 (0.96–1.15) at 1 year to 0.91 (0.81–1.03) at 5 years. While local recurrence rate was similar between MWA and RFA (RR 0.70, 0.43–1.14), distant recurrence rate was significantly lower with MWA (RR 0.60, 0.39–0.92). Disease-free survival at 1, 2, and 3 years was similar between the two groups with RR 1.00 (0.96–1.04), 0.94 (0.84–1.06), and 1.06 (0.93–1.21), respectively. On the other hand, RR for disease-free survival at 5 years was significantly in favor of MWA (3.66, 1.32–42.27). Adverse event rate was similar between the two treatments (RR 1.06, 0.48–2.34), with bleeding and hematoma representing the most frequent complications. Our results indicate a similar efficacy and safety profile between the two techniques. MWA seems to decrease the rate of long-term recurrences, but this finding needs to be confirmed in further trials.

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08–2.22, p = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84–1.16; p = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71–1.1; p = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3–4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized “real world” studies to date has not provided evidence of a major benefit of one regimen over the other.

Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50–0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32–0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34–0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means of the DerSimonian and Laird test. Primary endpoint was the time-dependent correlation between statin use and HCC incidence expressed as hazard ratio (HR), both crude and adjusted. The crude and adjusted odds ratios (OR) for HCC occurrence between statin users and non-users were analyzed. Twenty-five studies with 1,925,964 patients were included. Crude OR for HCC incidence was 0.59 (95% CI: 0.47–0.74), confirmed in adjusted analysis (OR: 0.74, 95% CI: 0.70–0.78). Adjusted HR was 0.73 (95% CI: 0.69–0.76). This effect was more pronounced in HBV patients (HR: 0.46, 95% CI: 0.36–0.60) and with a cumulative daily dose beyond 365 (HR: 0.27, 95% CI: 0.11–0.67). Lipophilic statins were associated with reduced HCC incidence (HR: 0.49, 95% CI: 0.39–0.62). Atorvastatin determined the greater magnitude of effect (HR: 0.43, 95% CI: 0.28–0.65). This meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins.