Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria:a meta-analysis of 18,421 patients

Background:Outcomes after liver resection(LR)and liver transplantation(LT)for hepatocellular carcinoma(HCC)are heterogenous and may vary by region,over time periods and disease burden.We aimed to compare overall survival(OS)and disease-free survival(DFS)between LT versus LR for HCC within the Milan criteria.Methods:Two authors independently searched Medline and Embase databases for studies comparing survival after LT and LR for patients with HCC meeting the Milan criteria.Meta-analyses and meta-regression were conducted using random-effects models.Results:We screened 2,278 studies and included 35 studies with 18,421 patients.LR was associated with poorer OS[hazard ratio(HR)=1.44;95%confidence interval(CI):1.14-1.81;P<0.01]and DFS(HR=2.71;95%CI:2.23-3.28;P<0.01)compared to LT,with similar findings among intention-to-treat(ITT)studies.In uninodular disease,OS in LR was comparable to LT(P=0.13)but DFS remained poorer(HR=2.95;95%CI:2.30-3.79;P<0.01).By region,LR had poorer OS versus LT in North America and Europe(P≤0.01),but not Asia(P=0.25).LR had inferior survival versus LT in studies completed before 2010(P=0.01),but not after 2010(P=0.12).Cohorts that underwent enhanced surveillance had comparable OS after LT and LR(P=0.33),but cohorts undergoing usual surveillance had worse OS after LR(HR=1.95;95%CI:1.24-3.07;P<0.01).Conclusions:Mortality after LR for HCC is nearly 50%higher compared to LT.Survival between LR and LT were similar in uninodular disease.The risk of recurrence after LR is threefold that of LT.

Foregut bypass vs.restrictive bariatric procedures for nonalcoholic fatty liver disease:a meta-analysis of 3,355 individuals

Background:Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease(NAFLD).However,there remains inadequate data regarding the effects of different bariatric procedures on various NAFLD parameters,especially for histological outcomes.Thus,this meta-analysis aimed to compare the effects of restrictive bariatric procedures and foregut bypass on the metabolic,biochemical,and histological parameters for patients with NAFLD.Methods:Medline and Embase were searched for articles relating to bariatric procedures and NAFLD.Pairwise meta-analysis was conducted to compare efficacy of bariatric procedures pre-vs.post-procedure with subgroup analysis to further compare restrictive against foregut bypass procedures.Results:Thirty-one articles involving 3,355 patients who underwent restrictive bariatric procedures(n=1,460)and foregut bypass(n=1,895)were included.Both foregut bypass(P<0.01)and restrictive procedures(P=0.03)significantly increased odds of fibrosis resolution.Compared to restrictive procedures,foregut bypass resulted in a borderline non-significant decrease in fibrosis score(P=0.06)and significantly lower steatosis score(P<0.001).For metabolic parameters,foregut bypass significantly lowered body mass index(P=0.003)and low-density lipoprotein(P=0.008)compared to restrictive procedures.No significant differences were observed between both procedures for aspartate aminotransferase(P=0.17)and alkaline phosphatase(P=0.61).However,foregut bypass resulted in significantly lower gamma-glutamyl transferase than restrictive procedures(P=0.01)while restrictive procedures resulted in significantly lower alanine transaminase than foregut bypass(P=0.02).Conclusions:The significant histological and metabolic advantages and comparable improvements in biochemical outcomes support the choice of foregut bypass over restrictive bariatric procedures in NAFLD management.

Factors early in life associated with hepatic steatosis

BACKGROUND The rise in prevalence of non-alcoholic fatty liver disease(NAFLD)mirrors the obesity epidemic.NAFLD is insidious but may gradually progress from simple steatosis to steatohepatitis,fibrosis and cirrhosis and/or hepatocellular carcinoma.Intervention strategies to ameliorate developmental programming of NAFLD may be more efficacious during critical windows of developmental plasticity.AIM To review the early developmental factors associated with NAFLD.METHODS Databases MEDLINE via PubMed,and EMBASE and Reference Citation Analysis were searched and relevant publications up to April 30,2021 were assessed.Original research studies that included risk factors associated with early development of NAFLD in human subjects were included.These factors include:Maternal factors,intrauterine and prenatal factors,post-natal factors,genetic and ethnic predisposition,childhood and adolescence environmental factors.Studies were excluded if they were review articles or animal studies,case reports or conference abstracts,or if NAFLD was not clearly defined and assessed radiologically.RESULTS Of 1530 citations identified by electronic search,420 duplicates were removed.Of the 1110 citations screened from title and abstract,80 articles were included in the final analysis.Genetic polymorphisms such as patatin-like phospholipase domain-containing protein 3(PNPLA3)and membrane-bound O-acyltransferase domain-containing protein 7(MBOAT7)were associated with increased risk of NAFLD.Familial factors such as maternal obesogenic environment and parental history of hepatic steatosis was associated with offspring NAFLD.Longer duration of exclusive breastfeeding in infancy was associated with a lower risk of developing NAFLD later in life while metabolic dysfunction and/or obesity in adolescence was associated with increased risk of NAFLD.Studies relating to socioeconomic factors and its association with NAFLD reported confounding results.CONCLUSION Maternal metabolic dysfunction during pregnancy,being exclusively breastfed for a longer time postnatally,diet and physical activity in childhood and adolescence are potential areas of intervention to decrease risk of NAFLD.

Engineering immunosuppressive drug-resistant armored(IDRA)SARS-CoV-2 T cells for cell therapy

Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different ISDs.We demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response.Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection.To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron variants.This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.

Clinical utility of non-invasive tests to predict clinical outcomes in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is the leading cause of chronic liver disease,and the fastest-growing cause of hepatocellular carcinoma(HCC)worldwide(1,2).As the number of people with NAFLD is too great to perform surveillance in all,risk-stratification strategies are increasingly important to identify those at the highest risk of decompensation and HCC(3,4).