BackgroundForkhead box G1 (FOXG1) is a member of the Fox transcription factor family involved in regulation of many cancers. However, the role of FOXG1 in hepatocellular carcinogenesisis largely unclear. The present study aimed at examining the biological function and underlying mechanism of FOXG1 on hepatocellular carcinoma (HCC) tumor metastasis as well as its clinical significance.MethodsLevels of FOXG1 were determined by immunohistochemical and real-time PCR analysis in HCC cell lines and human HCC samples. The effect of FOXG1 on cancer cell invasion and metastasis was investigated in vitro and in vivo in either FOXG1-silenced or overexpressing human HCC cell lines. Immunoprecipitation and chromatin immunoprecipitation assays were performed to investigate the interaction of FOXG1, β-catenin, TCF4 and the effect on Wnt target-gene promoters.ResultsIn human HCC, the level of FOXG1 progressively increased from surrounding non tumorous livers to HCC, reaching the highest levels in metastatic HCC. Furthermore, expression levels of FOXG1 directly correlated with cancer cell epithelial-mesenchymal transition (EMT) phenotype. In FOXG1-overexpressing cells, FOXG1 promotes the stabilization and nuclear accumulation of β-catenin by directly binding to β-catenin and it associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) on Wnt responsive enhancers (WREs) in chromatin.ConclusionsThe results show that FOXG1 plays a key role in mediating cancer cell metastasis through the Wnt/β-catenin pathway in HCC cells and predicts HCC prognosis after surgery. Targeting FOXG1 may provide a new approach for therapeutic treatment in the future.

Background : Tumor mutation burden (TMB) was associated with prognosis in various malignancies, but it remains to be elucidated in hepatocellular carcinoma (HCC). We aimed to investigate the prognostic effects of TMB and its relationship with immune infiltration so as to establish a panel model capable of predicting prognosis. Methods : TMB was calculated in all 374 HCC patients from the Cancer Genome Atlas, and high TMB and low TMB groups were determined based on propensity score matching and X-tile analysis. WCGNA was utilized to screen out genes related to immune cells and TMB, followed by multivariate analysis to generated the final TMB-Infiltration (TMB-IF) panel. 453 HCC patients from ICGC-LIRI-JP, GSE76427 and GSE20017 verified the robustness and extensibility of TMB-IF. Additionally, whole-exome sequencing (WES) was performed in 8 follow-up patients to investigate the relationship between HCC recurrence and TMB. Results : Patients in high TMB group had worse prognosis than those in low TMB group, with a cutoff TMB value of 4.9. Enrichment analysis demonstrated that differentially expressed genes were mainly related to T cell activation, cell membrane localization and matrix composition. Tumor immune infiltration analysis revealed the infiltrations of Th2, Th17, and Tgd were up-regulated in high TMB group, while those of Tr1, MAIT, and DC were up-regulated in low TMB group. And TMB-IF fit well with the actual survival observation, with a C-index 0.785 (0.700-0.870), which verified in ICGC-LIRI-JP was 0.670 (0.573-0.767), and 0.774 (0.670-0.877) in GSE76427. In addition, TMB-IF showed a good performance in predicting tumor vascular invasion with a C-index of 0.847 (0.778-0.916). Conclusions : Higher TMB means worse prognosis in HCC patients. Patients with higher frequency of immunerelated gene mutations and TMB are prone to relapse after radical treatment.

Hepatocellular carcinoma (HCC) is a severe disease with high mortality and global incidence. However, the interaction between the gut microbiome and combined immunotherapy for HCC is yet unclear. In this prospective clinical study, patients with unresectable HCC who had not received systemic treatment previously were recruited. Fecal and serum samples were collected at the baseline point and before each subsequent administration as specified. Between 20 October 2019 and 2 February 2021, 61 patients were screened for eligibility, of whom 35 patients were finally included in this study. Alpha diversity of fecal samples from patients who responded to immunotherapy was higher than that of nonresponders at baseline. However, the prominent alpha‐diversity between responders and nonresponders became similar as early as week 6 after treatment. The beta diversity of intergroup did not show significant difference at the ninth week after treatment. Alpha‐d‐Glucose was the only serum metabolite that differed between the responders and nonresponders after 3 months. Responder‐enriched Ruminococcus showed a positive correlation with serum galactaric acid, while Klebsiella was positively associated with 3‐methylindole and lenticin (all P < .01). The machine learning classifier based on serum metabolites were more able to discriminate HCC patients who potentially benefited from immunotherapy at baseline (AUC 0.793, 95% CI: 0.632‐0.954) than the classifier of gut microbiome. In conclusion, gut microbiome biomarkers are associated with the response to anti‐PD‐1 based immunotherapy in HCC patients. Classifiers based on gut microbiota and serum metabolites are feasible.

Background/aims In patients with acute-on-chronic liver failure (ACLF), type 1 hepatorenal syndrome (HRS) is a critical organ failure complication that resulted in rapid mortality. There are no efficient parameters to predict HRS in hepatitis B virus (HBV)-related ACLF. To assess HBV-ACLF risk factors and evaluate the association between mean arterial pressures (MAP), HRS and survival in patients with HBV-ACLF. Methods A total of 420 ACLF patients were screened from June 2015 to June 2016, and 57 HBV-ACLF patients were included in the study. Clinical data and MAP measurements of these patients were collected. Multivariate analyses, Cox proportional hazards regression and receiver operator characteristic (ROC) curves were used to analyze. Results In a 30-day study period, 43 (75.44%) patients survived. Patients in the HRS group were older and had higher Model for End-Stage Liver Disease (MELD) scores than patients in the non-HRS group. A MAP drop of ≥9.5 mmHg was an independent predictor of HRS with a sensitivity and specificity of 92.86 and 69.77%, respectively. The baseline MELD score was also an independent risk factor of HRS. MAP drop (OR, 1.582; P = 0.000), prothrombin time, HRS, MELD and FIB were independent prognostic factors for 30-day mortality. The area under the ROC curve of MAP drop was 0.808 (P = 0.001). Conclusion A decrease in MAP was a valuable predictor of HRS in patients with HBV-related ACLF. MAP drop ≥9.5 mmHg may be useful for predicting patient prognosis and exploring new treatment measures in patients with HBV-related ACLF. Eur

Background : Tumor mutation burden (TMB) was associated with prognosis in various malignancies, but it remains to be elucidated in hepatocellular carcinoma (HCC). We aimed to investigate the prognostic effects of TMB and its relationship with immune infiltration so as to establish a panel model capable of predicting prognosis. Methods : TMB was calculated in all 374 HCC patients from the Cancer Genome Atlas, and high TMB and low TMB groups were determined based on propensity score matching and X-tile analysis. WCGNA was utilized to screen out genes related to immune cells and TMB, followed by multivariate analysis to generated the final TMB-Infiltration (TMB-IF) panel. 453 HCC patients from ICGC-LIRI-JP, GSE76427 and GSE20017 verified the robustness and extensibility of TMB-IF. Additionally, whole-exome sequencing (WES) was performed in 8 follow-up patients to investigate the relationship between HCC recurrence and TMB. Results : Patients in high TMB group had worse prognosis than those in low TMB group, with a cutoff TMB value of 4.9. Enrichment analysis demonstrated that differentially expressed genes were mainly related to T cell activation, cell membrane localization and matrix composition. Tumor immune infiltration analysis revealed the infiltrations of Th2, Th17, and Tgd were up-regulated in high TMB group, while those of Tr1, MAIT, and DC were up-regulated in low TMB group. And TMB-IF fit well with the actual survival observation, with a C-index 0.785 (0.700-0.870), which verified in ICGC-LIRI-JP was 0.670 (0.573-0.767), and 0.774 (0.670-0.877) in GSE76427. In addition, TMB-IF showed a good performance in predicting tumor vascular invasion with a C-index of 0.847 (0.778-0.916). Conclusions : Higher TMB means worse prognosis in HCC patients. Patients with higher frequency of immune-related gene mutations and TMB are prone to relapse after radical treatment.

Background. Chronic hepatitis B (CHB) patients with normal or minimally increased levels of alanine aminotransferase (ALT) are still at the risk of hepatocellular carcinoma, cirrhotic events, and mortality. However, there is a debate over the initiation of antiviral treatment for these patients. This systematic review and mate-analysis aimed to explore this problem. Methods. MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases were systematically searched for retrieving relevant studies with risk ratios (RRs) or risk differences (RDs) for virological changes between antivirus-treated and no antivirus-treated CHB patients with ALT levels less than two-fold of the upper limit of normal. Retrieved data ranged from January 1990 to October 2020. Results. Of 6783 abstracts screened, 9 studies met the criteria for inclusion in the systematic review and had a low risk of bias. Among studies that were involved in the meta-analyses, it was found that the rates of HBsAg loss (RR = 12.22, 95% confidence interval (CI): 4.28–34.95, P < 0.001 ), HBsAg seroconversion (RR = 19.90, 95% CI: 2.75–144.09, P = 0.003 ), and undetectable HBV DNA (RR = 11.89, 95% CI: 2.44–57.89, P = 0.002 ) were both higher in the antiviral treatment group compared with placebo or no treatment group. Subgroup analysis suggested that patients who received interferon (IFN)-based therapy were more inclined to achieve HBsAg loss ( P = 0.010 ), HBsAg seroconversion ( P = 0.020 ), and HBeAg loss ( P = 0.002 ). Conclusion. From a sizable population, it was revealed that CHB patients with normal or minimally increased levels of ALT could benefit from the antiviral therapy, especially those who received IFN-based treatment.

An amendment to this paper has been published and can be accessed via the original article.

No abstract