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Background: The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes., Data Synthesis: A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms. A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%-23%;I 2  = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%-31%;I 2  = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH., Conclusion: This study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Data on survival and safety of sorafenib for hepatocellular carcinoma recurrence after liver transplant are still equivocal., Aim: We performed a meta-analysis of published studies, with the aim of estimating the 1-year rates of survival, analysing the variability in survival rates and, finally, identifying the factors associated with a longer survival., Methods: Data from 8 of the 17 selected studies were pooled, while the other 9 were excluded because survival rates were missing. All included studies were retrospective., Results: Overall, the 1-year survival ranged from 18% to 90%. Tumour progression was the main cause of death. The second cause was bleeding, reported only in patients undergoing m-Tor inhibitor therapy. The pooled estimate of 1-year survival was 63%. There was a significant heterogeneity among studies (P < 0.0001). Among the 34 variables assessed by univariate meta-regression, 5 were associated with an increase in the 1-year survival rate: (1) male gender (P = 0.001); (2) Time to progression (P = 0.038); and adverse drug events, divided in (3) gastrointestinal (P = 0.038), (4) cardiovascular (P = 0.029), and (5) dermatological (P = 0.014)., Conclusions: Additional data from multicentre prospective studies are required to clearly determine if sorafenib is a safe and acceptable treatment in hepatocellular carcinoma recurrence after liver transplant. Nevertheless, its association with m-Tor inhibitors should be discouraged., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: We assessed the cost-effectiveness of boceprevir-based triple therapy compared to peginterferon alpha and ribavirin dual therapy in untreated patients with genotype 1 chronic hepatitis C; patients were discriminated according to the combination of baseline plus on-treatment predictors of boceprevir-based triple therapy., Methods: Cost-effectiveness analysis performed according to data from the available published literature. The target population was composed of untreated Caucasian patients, aged 50 years, with genotype 1 chronic hepatitis C, and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro, at 2013 value), life-years gained, quality-adjusted life year, and incremental cost-effectiveness ratio. The robustness of the results was evaluated by multivariable probabilistic sensitivity analyses., Results: According to the baseline predictors of sustained virological response (genotype 1b, low viral load, fibrosis F0-F3, and body mass index) and the 1Log drop of HCV-RNA after the dual therapy lead-in period, boceprevir was cost-effective in different patient profiles., Conclusions: In untreated genotype 1b chronic hepatitis C patients, the cost-effectiveness of boceprevir-based triple therapy widely ranges according to different profiles of sustained virological response predictors, allowing optimization and personalization of triple therapy., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Randomised controlled trials (RCTs) show that triple therapy (TT) with peginterferon alfa, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ribavirin dual therapy (DT) in the treatment of genotype 1 (G1) chronic hepatitis C (CHC) patients with previous relapse (RR), partial response (PAR), and null-response (NR). We assess the cost-effectiveness of TT compared to no therapy in the treatment of patients previously treated with G1 CHC., Methods: The available published literature provided the data source. The target population was made up of previously treated Caucasian patients with G1 CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro at 2012 value), life years gained (LYG), quality adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER).The robustness of the results was evaluated by one-way deterministic and multivariable probabilistic sensitivity analyses., Results: In RR patients, ICER per LYG compared to no therapy was €9555 for BOC-LEAD-IN-RR and €7910 for TVR-LEAD-IN-RR, being BOC dominated by TVR. In PAR patients, ICER for LYG was €11,947 for BOC-LEAD-IN-PAR and €14,931 for TVR-PAR, being TVR cost-effective compared to BOC (ICER for QALY €22,258). In NR patients, ICER for LYG was €26,499 for TVR-LEAD-IN-NR. The models were sensitive to likelihood of sustained virological response and to BOC/TVR prices., Conclusions: 1st generation HCV PI is highly cost-effective compared to no therapy in RR and PAR G1 CHC patients. TVR dominated BOC in RR, and was cost-effective compared to BOC in PAR patients. In NR patients an assessment of the response after a lead-in period should be performed to improve safety and cost-effectiveness., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: There is clear evidence from two systematic reviews that radiotherapy (RT) reduces the risk of local recurrence in patients with resectable rectal cancer, though the data on survival are still equivocal., Objective: To assess the effects of chemotherapy combined concomitantly with radiotherapy (CRT) on the increase of overall survival, and on the prevention of local recurrence and distant metastases., Data Sources: Computerized bibliographic searches of MEDLINE and CANCERLIT (1970-2008) were supplemented with hand searches of reference lists., Study Selection: Studies were included if they were randomized controlled trials (RCTs) comparing preoperative or postoperative CRT to preoperative or postoperative RT alone, and if they included patients with resectable, histologically-proven, rectal adenocarcinoma without metastases. Thirteen RCTs, seven of preoperative CRT vs. preoperative RT (2787 patients), four of postoperative CRT vs. postoperative RT (726 patients) and two of postoperative CRT vs. preoperative RT (1400 patients), were analyzed., Data Extraction: Data on population, intervention, and outcomes were extracted from each RCT, in accordance with the intention-to-treat method, by three independent observers, and combined using the DerSimonian method and Laird method., Results: Preoperative CRT compared to preoperative RT alone significantly reduces the 5-year local recurrence rate (RR 1.05; 95%CI 1.01-1.10). No increase was observed in 5-year overall survival rate (RR 0.94; 95%CI 0.94-1.09), and in the occurrence of distant metastases (RR 0.97; 95%CI 0.93-1.02). Instead, postoperative CRT did not reduce local recurrence (RR 0.96; 95%CI 0.80-1.16), distant metastases (RR 1.11; 95%CI 0.94-1.31) and overall mortality (RR 1.09; 95%CI 0.83-1.41). By pooling data on postoperative CRT vs. preoperative RT a significant reduction of local recurrence was found for the preoperative approach (RR 0.93; 95%CI 0.90-0.96), though no difference was found in distant metastases rates and overall survival. Finally, the risk of mortality related to toxic events was significantly higher when adding chemotherapy to radiotherapy (RR 2.86; 95%CI 0.99-8.26)., Conclusions: In patients with resectable rectal cancer, CRT does not increase overall survival, despite the fact that preoperative CRT significantly reduces the risk of the local recurrence. No reduction in the distant metastases rate was found. Toxicity-related mortality is significantly increased by the concomitant approach, emphasizing the need for safer treatment combinations., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background/aims: Efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin of non-responders to standard or pegylated IFN plus ribavirin has been assessed in various studies, but sustained virologic response (SVR) rates are variable and factors influencing efficacy and tolerability still remain incompletely defined. We aimed to focus on SVR rates and to identify factors influencing them in this meta-analysis., Methods: MEDLINE as well as a manual search were used. Studies were included if they were controlled or uncontrolled trials, if they had been published as full-length papers and if they included non-responders to standard or pegylated IFN and ribavirin therapy. Fourteen trials were included in the meta-analysis. Data on study populations, interventions, and outcomes were extracted from trials using a random-effects model. Primary outcome was the SVR rate., Results: The pooled estimate of SVR rate was 16.3% (95% Confidence Interval - 95% CI, 8.3-29.6%). There was a significant heterogeneity among studies (p<0.0001). Heterogeneity was less apparent in studies that included fewer patients with cirrhosis or overweight. By meta-regression, higher SVR rate was observed in trials with a lower prevalence of subjects with genotype 1 infection and with fewer overweight patients. The use of a 24-week retreatment stopping rule did not affect SVR rate., Conclusions: The overall modest efficacy argues against an indiscriminate retreatment with PEG-IFN and ribavirin of all non-responders. Restricting retreatment to non-overweight patients or to those with genotype 2 or 3 infection, using a 24-week retreatment stopping rule, would optimize the potential benefit with a scarce likelihood of missing a curative response.

Background: The benefit of external radiotherapy for gastric carcinoma has been extensively studied, but data on survival are still equivocal., Objective: To assess the effectiveness of surgery combined with preoperative radiotherapy or postoperative chemoradiotherapy in the reduction of all-cause mortality in patients with resectable gastric carcinoma., Methods: Computerised bibliographic searches of MEDLINE and CANCERLIT (1970-2006) were supplemented with hand searches of reference lists., Study Selection: Studies were included if they were randomised controlled trials (RCTs) comparing mortality of surgery combined with preoperative radiotherapy or postoperative chemoradiotherapy to surgery alone, and if they included patients with histologically-proven gastric adenocarcinoma without metastases. Nine eligible RCTs, 4 of preoperative radiotherapy (832 patients) and 5 of postoperative chemoradiotherapy (869 patients), were identified and included in the meta-analysis., Data Extraction: Data on study populations, interventions, and outcomes were extracted from each RCT according to the intention to treat method by three independent observers and combined using the DerSimonian and Laird method., Results: Surgery combined with preoperative radiotherapy compared to surgery alone significantly reduced the 3-year (OR 0.57; 95% CI 0.43-0.76: p=0.0001) and 5-year (OR 0.62; 95% CI 0.46-0.84; p=0.002) mortality rate. A significant reduction of the 5-year (OR 0.45; 95% CI 0.32-0.64; p<0.00001) mortality rate was observed when surgery followed by chemoradiotherapy was compared to surgery alone., Conclusions: In patients with resectable gastric carcinoma, adjuvant radiotherapy significantly reduces 3-year and 5-year all-cause mortality, but the magnitude of the benefit is relatively small. Available evidence is inadequate to determine whether postoperative chemoradiotherapy is superior to preoperative radiotherapy.