Enhanced prognosis of HCC patients undergoing radical treatments with tenofovir versus entecavir: A meta-analysis based on propensity score matching studies.

The selection of postoperative antiviral therapy for hepatocellular carcinoma (HCC) patients with HBV infection undergoing radical treatments (HPHR) is a topic of ongoing debate and controversy. The primary aim of this study was to compare the prognostic impact of selecting entecavir (ETV) or tenofovir disoproxil fumarate (TDF) as antiviral therapy options in HPHR. All the studies included in this analysis were implemented propensity score matching (PSM) methodology. Meta-analysis was performed using R statistical software (version 4.3.0). The primary outcome measures, overall survival (OS) and recurrence-free survival (RFS), were quantified using hazard ratios (HR) and 95% confidence intervals (CI). This study analyzed 13 studies involving 6961 patients (2394 in the TDF group and 4567 in the ETV group). We conducted a meta-analysis of 8 studies that included a total of 5289 patients using the PSM analysis method. In comparison to the ETV group, the TDF group demonstrated significantly better RFS (HR = 0.81; 95% CI, 0.70-0.93; p = 0.0034) and OS (HR = 0.61; 95% CI, 0.42-0.88; p = 0.0085). Furthermore, the disparity between the two drugs was particularly evident in the prognosis of patients undergoing hepatectomy. Regional disparities were observed, with mainland China studies favoring RFS benefits and Taiwan or Korea studies favoring OS benefits. In conclusion, TDF has demonstrated significant superiority over ETV in terms of RFS and OS outcomes for HPHR. The findings hold significant implications for informing clinical decision-making and guiding the selection of postoperative antiviral therapy drugs in HCC patients.

The effect of switch therapy to tenofovir versus entecavir maintenance on recurrence of hepatocellular carcinoma after surgery (SWITE): study protocol for a randomized controlled trial.

BACKGROUND: Antiviral therapy has been reported to be associated with lower recurrence rate of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV) infection. While entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were both recommended as first-line therapies for HBV patients, recent retrospective studies proposed a lower incidence rate of HCC occurrence or recurrence in those receiving TDF compared ETV. However, the survival benefits of switching to TDF therapy after prolonged ETV treatment before surgery remain uncertain. We delineate the rationale and design of SWITE, a randomized, open-label, phase III trial contrasting TDF switch therapy versus ETV maintenance in HBV-related HCC patients. METHODS AND ANALYSIS: This is a prospective, randomized, controlled, single-center study with two parallel groups of patients with HBV-related HCC who have received long-term ETV therapy before surgery. West China Hospital will enroll 238 patients, randomized in a 1:1 ratio to TDF switch therapy or ETV maintenance after surgery. The primary endpoint of this study is 3-year recurrence free survival (RFS), with the secondary endpoint being 3-year overall survival (OS) after curative surgery of HCC. Safety events will be diligently recorded. ETHICS AND DISSEMINATION: The study protocol aligns with the ethical guidelines of the 1975 Declaration of Helsinki. It was approved by ethics committee of West China Hospital (approval number: 2022-074) and was registered with chictr.org.cn (chiCTR2200057867). Informed consent will be obtained from all participants. The results of this trial will be published in peer-reviewed journals and presentations at national and international conferences relevant to this topic. TRIAL REGISTRATION: chiCTR2200057867 . Date of registration is March 20 2022.

Sarcopenia Imperils Postoperative Long-Term Survival in HCC Patients with Metabolic Dysfunction-Associated Fatty Liver Disease: A Propensity Score Matching Analysis.

Background: Recent research has suggested that sarcopenia may have an impact on postoperative outcomes. The number of hepatocellular carcinoma (HCC) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) has increased significantly over time. The main objective of this study was to investigate the impact of sarcopenia on the prognosis of HCC patients with MAFLD after hepatectomy. Methods: A multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were conducted to ensure that the baseline characteristics were similar. Kaplan‒Meier survival curves were used to compare the prognosis of the two groups. Results: This study involved 112 HCC patients with MAFLD undergoing hepatectomy. Sarcopenia was indicated as a risk factor for both recurrence-free survival (RFS) and overall survival (OS) in HCC patients with MAFLD after multivariate analysis (p=0.002 and 0.022, respectively). After conducting PSM analysis, Kaplan‒Meier survival curve analysis revealed significant differences in both the RFS and OS between the two groups (p=0.0002 and p=0.0047, respectively). All results showed that sarcopenia had a poor prognosis for HCC patients with MAFLD undergoing hepatectomy. Conclusion: In summary, our study suggests that sarcopenia might be a risk factor for OS and RFS in HCC patients with MAFLD who underwent hepatectomy through multivariate analysis and PSM analysis. Sarcopenia imperils postoperative survival rates and this finding can guide clinical decision-making. For postoperative patients, preventing or treating sarcopenia can potentially improve survival outcomes for patients with HCC and MAFLD.

The role of noninvasive scoring systems for predicting cardiovascular disease risk in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.

BACKGROUNDS: Cardiovascular disease (CVD) is suggested as a leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). The aim of this work was to clarify the role of noninvasive scoring systems (NSSs) in predicting CVD risk among this population. METHODS: The PubMed, Web of Science, and Cochrane databases were searched until 23 March 2022. Meta-analysis was performed for three most commonly used NSS separately, that is, fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and AST/platelet ratio index (APRI). RESULTS: Totally, nine studies including 155 382 patients with NAFLD were enrolled. Patients with NAFLD had a higher risk of CVD with increasing FIB-4 score (1.94, 1.52-2.46), the association remained significant after adjustment for age, sex, body mass index, hypertension, and diabetes (2.44, 1.85-3.22). Similarly, a higher risk of CVD was also observed in patients with increasing NFS (2.17, 1.58-2.98) and APRI scores (1.36, 1.04-1.79) in the unadjusted model. However, in the adjusted model, the association was significant only for NFS (3.83, 1.40-10.43), but not for APRI (1.41, 0.79-2.51). Additionally, the increment in CVD risk was most noticeable in subgroup of FIB > 2.67 vs. FIB ≤ 1.3 (6.52, 3.07-13.86) and subgroup of NFS > 0.676 vs. NFS ≤ -1.455 (16.88, 5.68-50.23). All subgroup analyses showed significant associations between FIB-4, NFS, and risk of CVD. Sensitivity analyses did not modify these results. CONCLUSIONS: FIB-4 and NFS might be useful in identifying those who are at higher risk of CVD among patients with NAFLD. However, APRI was not recommended for this use.

Extrahepatic morbidities and mortality of NAFLD: an umbrella review of meta-analyses.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions currently and may contribute to multiple extrahepatic outcomes. AIM: To comprehensively summarise evidence of associations between NAFLD and risk of extrahepatic outcomes. METHODS: We conducted an umbrella review. We searched PubMed, Web of Science and Cochrane database from inception to 27 November 2021. RESULTS: We included 22 meta-analyses with 374 original studies in our analysis. Subjects with NAFLD had an increased risk of mortality, multiple cardiovascular complications, extrahepatic cancers, diabetes and chronic kidney disease (CKD) than those without NAFLD. Excess risks of several other extrahepatic outcomes including hypothyroidism, urolithiasis, gastro-oesophageal reflux disease, gallstones, depression and worse maternal and foetal outcomes were also observed in this population. However, associations were not significant for prostate cancer, female organ genital cancer, haematological cancer, diabetic retinopathy or osteoporotic fracture. The risks of CVD, diabetes and CKD were similar in obese and non-obese patients. Most associations were heterogeneous across regions; significantly, Europeans with NAFLD were more prone to all-cause mortality than North Americans. The certainty of evidence was graded from only very low to moderate as all included studies were observational. CONCLUSIONS: Patients with NAFLD are at heightened risk of extrahepatic outcomes. However, the certainty of evidence is only from very low to moderate. Further studies at low risk of bias are required to support the evidence and elucidate any causal associations.

Aspirin for the prevention of hepatocellular carcinoma: an updated meta-analysis with particular focus on patients with chronic liver disease.

BACKGROUND: Previous studies have suggested a chemoprotective effect of aspirin in hepatocellular carcinoma (HCC), but evidence is limited for patients with chronic liver disease (CLD). Thus, we performed a meta-analysis of all observational studies, and aimed to provide a comprehensive and quantitative understanding of this topic. METHODS: The PubMed/MEDLINE, Scopus, Cochrane, and Web of Science databases were systematically searched until September 2021. We pooled the hazard ratio (HR) of HCC for aspirin use versus non-use and investigated the possible dose-risk and duration-risk associations. RESULTS: Ten studies involving 202,567 CLD patients were enrolled in this study. The pooled results showed a significant reduction in HCC risk in aspirin users than in non-users (HR = 0.64; 95% CI = 0.54-0.77; pheterogeneity < 0.001; I2 = 84.9%). In subgroup analyses, an aspirin dose of 100 mg/day (0.56, 0.44-0.72) showed a significant protective effect against HCC than 160 mg/day. The linear model showed a significant inverse association between the duration of aspirin use and HCC risk (exb(b) = 0.92; 95% CI = 0.90-0.94); also, a non-linear model revealed a comparable association (coef1 = 0.80, p1 < 0.001; coef2 = 1.13, p2 = 0.001). No significantly higher risk of gastrointestinal bleeding of the aspirin-treated group was detected. CONCLUSIONS: The present meta-analysis suggested a significant and duration-related association between reduced HCC risk and aspirin use in a broad at-risk population. Nevertheless, aspirin therapy applied to CLD patients should be carefully monitored, although there was no significantly higher risk of gastrointestinal bleeding. REGISTRATION: PROSPERO, CRD42021229892.

Green leafy vegetable and lutein intake and multiple health outcomes.

Green leafy vegetables (GLVs) are a key element of healthy eating patterns and are an important source of lutein. To clarify the evidence for associations between GLVs and lutein intake and multiple health outcomes, we performed a review. A total of 24 meta-analyses with 29 health outcomes were identified by eligibility criteria. Dose-response analyses revealed that, per 100 g/d GLV intake was associated with a decreased risk (ca. 25%) of all-cause mortality, coronary heart disease and stroke. Beneficial effects of GLV intake were found for cardiovascular disease and bladder and oral cancer. Dietary lutein intake was inversely associated with age-related macular degeneration, age-related cataracts, coronary heart disease, stroke, oesophageal cancer, non-Hodgkin lymphoma, metabolic syndrome, and amyotrophic lateral sclerosis. Caution was warranted for contamination with potentially pathogenic organisms, specifically Escherichia coli. GLV consumption and lutein intake therein are generally safe and beneficial for multiple health outcomes in humans.

Tomato and lycopene and multiple health outcomes: Umbrella review.

Lycopene is a potent lipophilic antioxidant in tomato. We aim to clarify the evidence for associations between tomato and lycopene and multiple health outcomes. Umbrella review of meta-analyses and systematic reviews was performed in humans. A total of 174 articles were searched, 17 articles with 20 health outcomes were identified by eligibility criteria. Tomato intake was inversely associated with all-cause mortality, coronary heart disease mortality, cerebrovascular disease mortality, prostate cancer, and gastric cancer. Dietary lycopene intake or serum lycopene was inversely associated with all-cause mortality, prostate cancer, stroke, cardiovascular disease, metabolic syndrome, and male infertility. Caution was warranted for potential allergy and pollution. The quality of the vast majority of evidence by GRADE was low or very low with the remaining six as moderate. The intake of tomato or lycopene was generally safe and beneficial for multiple health outcomes in humans. But the quality of the evidence was not high.

Soy and Isoflavone Consumption and Multiple Health Outcomes: Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies and Randomized Trials in Humans.

SCOPE: To assess the existing evidence of associations between consumption of soy and isoflavone and multiple health outcomes. METHODS AND RESULTS: This is an umbrella review of meta-analyses and systematic reviews of randomized trials and observational studies in humans. 114 Meta-analyses and systematic reviews are identified with 43 unique outcomes. Soy and isoflavone consumption seems more beneficial than harmful for a series of health outcomes. Beneficial associations are identified for cancers, cardiovascular disease, gynecological, metabolic, musculoskeletal, endocrine, neurological, and renal outcomes, particularly in perimenopausal women. Harmful association is only found for gastric cancer (RR: 1.17, 95% CI: 1.02-1.36) for high intake of miso soup (1-5 cups per day) in male. CONCLUSION: Generally, soy and isoflavone consumption is more beneficial than harmful. The results herein support promoting soy intake as part of a healthy diet. Randomized controlled trials are necessary to confirm this finding.

Allium vegetable consumption and health: An umbrella review of meta-analyses of multiple health outcomes.

Previously, our meta-analysis and other studies have suggested that allium vegetable consumption is beneficial for health, but no umbrella review has been conducted to assess the evidence of the various health benefits of allium vegetable consumption. Therefore, we conducted this umbrella review on this topic. This umbrella review included a total of 16 meta-analyses with 50 unique outcomes. The most beneficial cancer-related outcome was shown for gastric cancer (risk ratio 0.78; 95% confidence interval [CI] 0.67-0.91). In addition, only 8 weeks of garlic consumption significantly decreased serum total cholesterol (weighted mean differences -17.20 mg/dl; 95% CI -23.10 to -11.30), and patients with dyslipidemia who consumed garlic experienced more benefits than the whole population. Diabetic patients with longer durations of garlic intake experienced more benefits in terms of fasting blood glucose (FBG), HbA1c, and serum fructosamine than healthy participants, and garlic intake was associated with blood pressure reduction in hypertensive patients but not in normotensive participants. Limited side effects of garlic, such as garlic odor and gastrointestinal complaints, were reported among the included meta-analyses. Our results suggested that allium vegetables might be beneficial for cancer prevention. In particular, garlic was comparatively safe and is recommended as a long-term dietary component for patients with dyslipidemia, diabetes, and hypertension.

Tea Consumption and Health Outcomes: Umbrella Review of Meta-Analyses of Observational Studies in Humans.

SCOPE: The aim of this article is to conduct an umbrella review to study the strength and validity of associations between tea consumption and diverse health outcomes. METHODS AND RESULTS: Meta-analyses of observational studies examining associations between tea consumption and health outcomes in all human populations and settings are screened. The umbrella review identifies 96 meta-analyses with 40 unique health outcomes. Tea consumption shows greater benefits than harm to health in this review. Dose-response analyses of tea consumption indicates reduced risks of total mortality, cardiac death, coronary artery disease, stroke, and type 2 diabetes mellitus with increment of two to three cups per day. Beneficial associations are also found for several cancers, skeletal, cognitive, and maternal outcomes. Harmful associations are found for esophageal and gastric cancer when the temperature of intake is more than 55-60 °C. CONCLUSION: Tea consumption, except for very hot tea, seems generally safe at usual levels of intake, with summary estimates indicating the largest reduction for diverse health outcomes at two to three cups per day. Generally, tea consumption seems more beneficial than harmful in this umbrella review. Randomized controlled trials are further needed to understand whether the observed associations are causal.

Prognostic value of tumor necrosis in gastrointestinal stromal tumor: A meta-analysis.

BACKGROUND AND AIMS: There is currently no consensus regarding the influence of tumor necrosis on the prognosis of gastrointestinal stromal tumors (GISTs). Therefore, we conducted a meta-analysis to determine the prognostic role of tumor necrosis in patients with GIST. METHODS: PubMed, Embase, and Web of Science electronic databases were searched from their inception to March 2018. Studies reporting data on the relationship between tumor necrosis and GIST prognosis were eligible. The measure of the effect of interest was the odds ratios (ORs) with 95% confidence intervals (CIs). This study has been registered in the Prospero (number CRD42018096036). RESULTS: In total, 18 studies including 2320 patients were identified. The total odds of tumor necrosis were associated with a poor GIST prognosis (OR = 5.54, 95% CI = 4.39-6.99). Subgroup analysis of different observed outcomes indicated that tumor necrosis was associated with a decreased disease-free survival (OR = 7.08, 95% CI = 4.78-10.49), recurrence-free survival (OR = 3.96, 95% CI = 2.48-6.32), and overall survival (OR = 4.29, 95% CI = 2.02-9.13). In addition, any tumor site, tumor size, follow-up time, ethnicity, different outcomes of GIST, and different degrees of positive staining of immunohistochemical markers subgroups showed a significantly increased risk of a poor prognosis. CONCLUSIONS: Tumor necrosis may likely predict a poorer prognosis for GIST. However, further well-designed prospective studies with large sample size are required in the future.

PD-1/PD-L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway.

OBJECTIVES: Although targeted therapy has revolutionized the treatment of gastrointestinal stromal tumours (GIST), it is almost never curative in GIST, and resistance commonly develops. One potential strategy is to combine targeted therapy with immunotherapy. MATERIALS AND METHODS: We first studied Programmed cell death 1 ligand 1 (PD-L1) expression and tumour-infiltrating T cells (TILs) in GIST. IFN-γ was used to induce the upregulation of PD-L1 expression in GIST-882 cells, a well-known GIST cell line. CD8+ T-cell apoptosis was determined by flow cytometry. The PI3K/Akt/mTOR levels in CD8+ T cells were examined by Western blotting. RESULTS: PD-L1 expression was an independent factor of poor prognosis in GIST and resulted in exhausted T cells in the TILs population or the blood. Then, we found that PD-L1 blockade alone could not increase tumour cell apoptosis in GIST. The apoptosis rate of CD8+ T cells was higher when T cells were cultured with PD-L1+ GIST-882 cells (GIST-882 cells with high PD-L1 expression) than when T cells were cultured with control GIST-882 cells. However, when the PD-L1 blockade was used, the apoptosis rates of the CD8+ T cells in the two groups became similar. Then, Western blotting showed the PI3K/Akt/mTOR levels of the CD8+ T cells rescued by the PD-1/PD-L1 blockade were higher than those of the CD8+ T cells not treated with the PD-1/PD-L1 blockade. CONCLUSIONS: PD-L1 expression was an independent poor prognosis factor in GIST. PD-1/PD-L1 blockade rescued exhausted CD8+ T cells in GIST via the PI3K/Akt/mTOR signalling pathway. In GIST, PD-1/PD-L1 not only function as predictive biomarkers but also improve current therapies as treatment targets.