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Aims: This work was designed to identify the subgroup of advanced hepatocellular carcinoma (HCC) patients for whom treatments containing immune checkpoint blockers (ICBs) were most effective. Materials & methods: A meta-analysis was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs. Results: A total of 2228 patients from four randomized control trials were included. Treatments containing ICBs had better overall survival, progression-free survival and higher objective response rate over treatment without ICBs. Subgroup analysis revealed that treatments containing ICBs were highly effective in improving the overall survival of males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients. Conclusion: Treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Fatty liver (FL) is reportedly a risk factor for hepatocellular carcinoma (HCC) in individuals affected with Hepatitis C (HCV) or B (HBV) virus. However, the results are contradictory, necessitating a meta-analysis. Sixteen relevant studies involving 88,618 individuals were retrieved from the Cochrane Library, PubMed, MEDLINE, Embase, and Scopus databases from their inception to 10 December 2022. The hazard ratios (HR) and 95% confidence intervals (CI) were analyzed. Liver biopsy-proven FL may be a significant risk factor for HCC in individuals affected with HBV (univariate analyses: HR = 3.13, 95% CI = 1.69–5.79; multivariate analyses: HR = 3.42, 95% CI = 0.83–14.09) as well as HCV (univariate analyses: HR = 1.64, 95% CI = 0.93–2.90; multivariate analyses: HR = 1.75, 95% CI = 1.02–3.00). However, the presence of FL confirmed using reasonable methods other than liver biopsy may not indicate a risk for HCC in HBV-infected individuals (univariate analyses: HR = 0.90, 95% CI = 0.44–1.81; multivariate analyses: HR = 0.69, 95% CI = 0.45–1.08). Biopsy-proven FL may be a significant risk factor for HCC in HCV/HBV-infected individuals. Thus, such individuals should receive suitable interventions to prevent HCC formation or at least attenuate the risk of HCC.

The prognostic value of alpha-fetoprotein (AFP) response for efficacy of targeted therapy or immune checkpoint inhibitors (ICIs) has not been established. The purpose of this meta-analysis is to elucidate the relationship between AFP response and survival outcomes in hepatocellular carcinoma (HCC) patients who received targeted therapy or ICIs. The hazard ratio (HR) with 95% confidence interval (CI) was used to evaluate the relationship between AFP response and overall survival (OS)/progression-free survival (PFS). Twenty-six articles containing 3056 HCC patients were finally included in the study. The pooled results showed that after targeted therapy or ICIs, patients with decrease in AFP had better prognosis (OS:HR = 0.48, 95%CI:0.40–0.56; PFS:HR = 0.39, 95%CI:0.33–0.46), while patients with increase in AFP had worse prognosis (OS:HR = 2.30, 95%CI:1.82–2.89; PFS:HR = 2.34, 95%CI = 1.69–3.24). Subgroup analysis revealed that compared to AFP decrease >50%, AFP decrease >20% can better predict the prognosis of patients who received targeted therapy (OS:HR = 0.51, 95%CI:0.41–0.62; PFS:HR = 0.39, 95%CI:0.30–0.51) or ICIs treatment (OS:HR = 0.34, 95%CI:0.16–0.71; PFS:HR = 0.22, 95%CI:0.10–0.47), and 8 weeks after targeted therapy may be the appropriate time point for AFP assessment. AFP decrease >20% within 8 weeks may be the appropriate definition for early AFP response which probably works best in predicting the efficacy of therapy. The review was not registered.

Objective: This meta-analysis was designed to explore the association between the systemic immune–inflammation index (SII) and the therapeutic effect of immune checkpoint inhibitors. Materials & methods: The authors retrieved relevant studies published before May 25, 2022. Hazard ratio (HR) with 95% CI was used to evaluate the relationship between SII and overall survival (OS) and progression-free survival (PFS). Results: 14 articles comprising 2721 patients were included in this study. The pooled results proved that high SII levels were closely related to poor prognosis in cancer patients receiving immune checkpoint inhibitors (OS HR = 2.40; 95% CI: 2.04–2.82; PFS HR = 1.57; 95% CI: 1.33–1.86) and that an SII value of 750 was appropriate as a cut-off value (OS HR = 2.20; 95% CI: 1.83–2.63; PFS HR = 1.54; 95% CI: 1.33–1.80). Conclusion: High SII levels (>750) may be an indicator of worse OS and PFS in cancer patients treated with immune checkpoint inhibitors.

Background The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumor development, while its precise contribution to immune checkpoint inhibitors (ICIs) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICIs therapy.Method We analyzed the role of RET mutations in predicting the prognosis of patient receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumor inflamed anti-tumor immune response and tumor antigenicity.Results Our study revealed that RET mutation is associated with better clinical outcomes for ICIs therapy in 606 cases across five types of cancer, including elevated response rate, longer PFS and OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of ICIs-treated patients after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICI immunotherapy was further validated in the validation cohort (n = 1683). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS and PFS between RET- wildtype tumors and RET- mutant tumors. Multi-omics data analysis revealed potential anti-tumor immunity mechanisms of RET mutations, suggesting that RET-mutant tumors have enhanced immunogenicity, higher expression of immune checkpoints, chemokines, and immune cell infiltration than RET-wildtype tumors, potentially indicating a more favorable response to immunotherapy.Conclusions RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive molecular mechanism investigation and prospective studies are needed in the future.

Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy.A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs).A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection.Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.

Tumor vaccines for hepatocellular carcinoma (HCC) is an area of intense interest. Tremendous clinical trials have been conducted globally, but the efficacy and security of tumor vaccines are elusive. The aim of our study was to evaluate the efficacy and security of tumor vaccines.All relevant studies were identified in PubMed, EMBASE, Web of science and Cochrane Library databases. Objective response rate (ORR), median overall survival (OS), or median progression-free survival (PFS) and 95% CI were meta-analyzed based on the random-effects model. The individual-level data of OS, PFS were pooled by conducting survival analysis. All observed adverse events were collected.31 studies containing 35 eligible cohorts with 932 HCC patients were included. The pooled ORR were 7% (95% CI 3-14%), while ORR of dendritic cell (DC) vaccine (19%, 95% CI 11-29%) were highly significant than ORR of peptide vaccine (1%, 95% CI 0-5%). The pooled median OS and PFS were 13.67 months (95% CI 8.20-22.80) and 6.19 months (95% CI 2.97-12.91), respectively. The pooled median OS (DC vaccine: median OS = 21.77 months, 95% CI 18.33-25.86; Peptide vaccine: median OS = 10.08 months, 95% CI 5.23-19.44) and PFS (DC vaccine: median PFS = 11.01 months, 95% CI 5.25-23.09; Peptide vaccine: median PFS = 1.97 months, 95% CI 1.53-2.54) of DC vaccine were also longer than that of peptide vaccine. HBV-related HCC may acquire more benefits from tumor vaccines than HCV-related HCC. In almost all studies, the observed toxicities were moderate even tiny.Tumor vaccines for HCC, especially DC vaccine, are safe and worth exploring. More high-quality prospective studies are warranted.

To evaluate and predict liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), several non-invasive scoring systems were built and widely used in the progress of diagnosis and treatment, which showed great diagnostic efficiency, such as aspartate aminotransferase to platelet ratio index, fibrosis-4 index, body mass index, aspartate aminotransferase to alanine aminotransferase ratio, diabetes score and NAFLD fibrosis score. Since the new concept of metabolic associated fatty liver disease (MAFLD) was proposed, the clinical application value of the non-invasive scoring systems mentioned above has not been assessed in MAFLD. The evaluation of the diagnostic performance of these non-invasive scoring systems will provide references for clinicians in the diagnosis of MAFLD.

Preliminary studies have suggested that soluble programmed death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) have prognostic implications in many malignant tumors. However, the correlation between sPD-1/sPD-L1 level and prognosis of hepatocellular carcinoma (HCC) is still unclear. We searched several electronic databases from database inception to October 7, 2021. Meta-analyses were performed separately for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), time to progression (TTP), and tumor-free survival (TFS). Random effects were introduced to this meta-analysis. The correlation between sPD-1/sPD-L1 level and prognosis was evaluated using hazard ratios (HRs) with 95% confidence intervals (95%CIs). A total of 11 studies (1291 patients) were incorporated into this meta-analysis, including seven on sPD-L1, two on sPD-1, and two about both factors. The pooled results showed that high sPD-L1 level was associated with worse OS (HR = 2.46, 95%CI 1.74–3.49, P

The introduction of immune checkpoint inhibitors (ICIs) has reshaped the therapy of hepatocellular carcinoma (HCC). ICIs are a novel therapy with frequent adverse events (AEs), including treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). However, no comprehensive overview of the toxicity spectrum of ICIs in HCC patients has been provided. Electronic databases were searched to identify eligible studies. A meta-analysis of the incidence rate of AEs in HCC patients treated with ICIs was performed. Lastly, the prognostic value of irAEs in HCC patients treated with ICIs was verified. Forty-seven studies with 6472 participations met the inclusion criteria. The pooled all-grade trAEs incidence rate was 83.4% (95% confidence interval [95% CI] 77.0-89.1%), ≥ grade 3 trAEs incidence rate was 33.0% (95% CI 26.9-39.5%), all-grade irAEs incidence rate was 34% (95% CI 22-47%), and ≥ grade 3 irAEs incidence rate was 9% (95% CI 5-14%). Aspartate aminotransferase (AST) increase (38%, 95% CI 35-40%) is the most common trAEs. Fatigue (14%, 95% CI 7-23%) is the most common irAEs. The pooled results also showed that 18.8% (95% CI 13.2-25.2%) of patients required systemic steroid therapy due to AEs, while 6.6% (95% CI 4.6-9.0%) of patients withdrew from treatment due to AEs. Additionally, patients experiencing irAEs may have a better progression-free survival (PFS) (multivariate analysis: hazard ratio [HR] = 0.41, 95% CI 0.27-0.61, I

Recent studies have identified an increased risk of hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH). Sex and regional disparities in incidence of HCC in AIH continue to be reported worldwide. Nevertheless, the magnitude of this gap remains unknown. We searched several databases including PubMed, Embase, Web of Science, Cochrane Library, Wanfang Data, CNKI and SinoMed. Incidence rates of HCC in AIH were combined and analyzed following the EBayes method. Incidence rate ratios were pooled to assess the sex differences. The impact of population difference, sex, age, cirrhotic condition was further analyzed with subgroup analysis and linear regression analysis. 39 studies meeting our eligibility criteria were chosen for the analysis. The pooled incidence rate of HCC in AIH was 3.54 per 1000 person years (95% CI 2.76–4.55). Pooled IRR for the risk of HCC in male AIH patients compared to female was 2.16 (95% CI 1.25–3.75), with mild heterogeneity among studies. The pooled HCC incidence rate in AIH by continents was as follows: Europe 2.37 per 1000 person-years (95% CI 1.45–3.88), Asia 6.18 per 1000 person-years (95%CI 5.51–6.93), North America 2.97 per 1000 person-years (95%CI 2.40–3.68), Oceania 2.60 (95%CI 0.54–7.58). The pooled HCC incidence rate in AIH-related cirrhosis by continent was as follows: Europe 6.35 per 1000 person-years (95%CI 3.94–10.22), Asia 17.02 per 1000 person-years (95%CI 11.18–25.91), North America 10.89 per 1000 person-years (95%CI 6.69–17.74). A higher HCC incidence in AIH was observed among male and in Asian populations. Cirrhosis status at AIH diagnosis is significantly associated with an increased incidence rate for HCC, and routine HCC surveillance is recommended for patients with AIH cirrhosis, especially for those in Asia.

Most patients with hepatocellular carcinoma (HCC) have underlying cirrhosis and a compromised liver function. Immune checkpoint inhibitors (ICIs) have emerged as an important approach for HCC treatment. The purpose of our study was to explore the prognostic significance of liver function in HCC patients receiving ICIs.Hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the relationship between liver function and overall survival (OS)/progression-free survival (PFS).41 articles with 4483 patients with HCC were included. The pooled results revealed that either Child-Pugh score (OS:HR = 2.01,95 %CI:1.69-2.38; PFS:HR = 1.39,95 %CI:1.15-1.68) or albumin-bilirubin (ALBI) score (OS:HR = 2.04,95 %CI:1.55-2.69; PFS:HR = 1.42,95 %CI:1.21-1.67) can predict the patient prognosis. The Child-Pugh score has some degree of subjectivity, and the ALBI score can better stratify patients. Therefore, the ALBI score was used to evaluate patients' liver function and determine treatment options. Further subgroup analysis found that the results of prospective studies were statistically significant only for the ALBI score with regards to OS (HR = 1.69,95 %CI:1.26-2.26). Meanwhile, the effect of liver function on the efficacy of ICIs in the large-sample studies was not as obvious as that in small-sample studies. Moreover, the incidence of adverse events did not significantly increase in patients with impaired liver function.Poor liver function is associated with a poor prognosis in patients with HCC receiving ICIs. The ALBI score is simpler and reliable for patient stratification than the Child-Pugh score. Although the survival time of patients with impaired liver function may be relatively short, ICIs still have great potential for therapeutic applications.

Angiogenesis and immunosuppression have been described as closely related processes that can occur in parallel. As an inhibitor of matrix metalloproteinase, whether the level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in hepatocellular carcinoma (HCC) reflects a link between angiogenesis and immunosuppression is still unknown. We analyzed RNA expression, immune infiltration and survival of HCC from The Cancer Genome Atlas databases. Immune scores and stromal scores were calculated based on the ESTIMATE algorithm to quantify the immune and stromal components in HCC. The association between RECK and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high RECK expression was significantly better than that of patients with low RECK expression. High RECK expression was associated with high ESTIMATE Score, recruitment of more tumor-infiltrating lymphocytes, low tumor purity, and high PD-L1 expression. In addition, positive RECK expression was associated with a lower incidence of vascular invasion and recurrence, a lower level of alpha fetoprotein (AFP) and microvessel density and a better tumor differentiation. Multivariate analyses revealed that reduced RECK expression was an independent prognostic factor for recurrence and poor prognosis. In conclusion, high RECK expression reflects an immunogenic and hypovascularity status in HCC. RECK is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive anti-angiogenic therapy or immunotherapy.

Background Glycemic index (GI), glycemic load (GL), and carbohydrates have been shown to be associated with a variety of cancers, but their correlation with hepatocellular carcinoma (HCC) remains controversial. The purpose of our study was to investigate the correlation of GI, GL and carbohydrate with risk of HCC.Methods Systematic searches were conducted in PubMed, Embase and Web of Science until November 2020. According to the size of heterogeneity, the random effect model or the fixed effect model was performed to calculate the pooled relative risks (RRs) and 95% confidence intervals (CIs) for the correlation of GI, GL, and carbohydrates with the risk of HCC.Results Seven cohort studies involving 1,193,523 participants and 1,004 cases, and 3 case-control studies involving 827 cases and 5,502 controls were eventually included. The pooled results showed no significant correlation of GI (RR=1.11, 95%CI 0.80-1.53, I2= 62.2%), GL (RR=1.09, 95%CI 0.76-1.55, I2 = 66%), and carbohydrate (RR=1.09, 95%CI 0.84-1.32, I2=0%) with the risk of HCC in general population. Subgroup analysis revealed that in hepatitis B virus (HBV) or/and hepatitis C virus (HCV)-positive group, GI was not correlated with the risk of HCC (RR=0.65, 95%CI 0.32-1.32, p=0.475, I2=0.0%), while GL was significantly correlated with the risk of HCC (RR=1.52, 95%CI 1.04-2.23, p=0.016, I2=70.9%). In contrast, in HBV and HCV-negative group, both GI (RR=1.23, 95%CI 0.88-1.70, p=0.222, I2=33.6%) and GL (RR=1.17, 95% CI 0.83-1.64, p=0.648, I2=0%) were not correlated with the risk of HCC. Conclusion A high GL diet is correlated with a higher risk of HCC in people with hepatitis virus. A low GL diet may be recommended for patients with viral hepatitis to reduce the risk of HCC.

BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.

Previous meta-analyses have shown that aspirin use may reduce the risk of hepatocellular carcinoma (HCC). However, the optimal dose, frequency, and duration of aspirin use or the safety and efficacy of aspirin in target populations for HCC prevention remain unclear. The study aim was to investigate the efficacy and safety of aspirin for prevention of HCC.Publications were retrieved by a comprehensive literature research of several databases. Based on a random-effects model, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship between aspirin use and HCC risk was assessed with a restricted cubic spline model.Twenty-two studies were included in the meta-analysis. Aspirin use was associated with a reduced risk of HCC (HR=0.64, 95% CI: 0.56-0.75). The effect was robust across sex and age; however, women and the non-elderly had the greatest benefit from aspirin use. The preventive effect was well reproduced in those with comorbidities. Daily use and long-term use of aspirin appeared to offer greater benefits. Aspirin 100 mg/d was associated with maximum reduction of HCC risk. Aspirin use did slightly increase the risk of bleeding (HR=1.14, 95% CI: 1.02-1.27).Our meta-analysis confirmed that use of aspirin significantly reduced the incident risk of HCC. Regular and long-term aspirin use offers a greater advantage. Aspirin use was associated with an increased risk of bleeding. We recommend 100 mg/d aspirin as a feasible dose for further research on primary prevention of HCC in a broad at-risk population.

Background: Recent studies have identified an increased risk of hepatocellular carcinoma (HCC) among individuals diagnosed with autoimmune hepatis (AIH). Nevertheless, the gender differences and global disparities in HCC risk among AIH patients have not been studied yet. Method: We did a systematic review and meta-analysis of HCC incidence in AIH patients and further explored the gender differences and regional disparities. We searched several databases including PubMed, Embase, Web of Science, Cochrane Library, Wangfang Data, CNKI and Sinomed from the inception of the databases through December 23, 2020. Observational studies which reported incidence rates of HCC in AIH patients or provided sufficient raw data to calculate incidence rates were included in our analysis. Incidence rates of HCC in AIH patients were combined and analyzed following the Ebayes method. Incidence rate ratios were pooled to assess the gender differences. The impact of population difference, gender, age, cirrhotic condition was further analyzed with subgroup analysis and liner regression. Our study protocol was registered in the PROSPERO database (CRD42020157000). Findings: We found 1,350 studies from the literature search, of which 39 studies meeting our eligibility criteria were chosen for the analysis, including a total of 14,597 AIH patients. The pooled incidence rate of HCC in AIH patients was 3.54 per 1,000 person-years (95%CI = 2.76–4.55). Pooled IRR for the risk of HCC in male AIH patients compared to female was 2.16 (95%CI = 1.25-3.75), with mild heterogeneity among studies. The pooled HCC incidence rate in AIH patients according to continents was as follows: Europe 2.37 per 1,000 person-years (95%CI = 1.45-3.88), Asia 6.18 per 1,000 person-years (95%CI = 5.51-6.93), North America 2.97 per 1,000 person-years (95%CI = 2.40-3.68), Oceania 2.60 (95%CI 0.54-7.58). The pooled HCC incidence rate in AIH-cirrhosis patients by continent was as follows: Europe 6.35 per 1,000 person-years (95%CI = 3.94-10.22), Asia 17.02 per 1,000 person-years (95%CI = 11.18-25.91), North America 10.89 per 1,000 person-years (95%CI = 6.69-17.74). Interpretation: It is more risky for male AIH patients to develop HCC. AIH patients in Asia were at an increased risk for HCC. Routine HCC surveillance is cost effective for patients with AIH cirrhosis, especially for those in Asia. Registration : Our study protocol was registered in the PROSPERO database (CRD42020157000). Funding Statement: This work was supported by the grants from the Taishan Scholars Program for Young Expert of Shandong Province (Grant No. tsqn20161064) and National Natural Science Foundation of China (Grant No. 82073200 & 81874178). Declaration of Interests: There are no conflicts of interest to declare.

BACKGROUND AND AIM The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.

Background: Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the most common liver malignant tumors worldwide. Investigating the molecular basis of these malignancies is vital to the development of new treatments. Recent studies have found that mutation and abnormal expression of ARID1A, are frequently shown in HCC and cholangiocarcinoma. Herein, we aimed to estimate the effects of ARID1A mutation and expression on prognosis of HCC and cholangiocarcinoma.Methods: We searched PubMed, EMBASE, Web of Science, the Cochrane Library for studies evaluating the relationship between ARID1A mutations or expression and the survival of HCC or cholangiocarcinoma patients. Meta-analysis was performed to generate a combined HR with a 95% confidence interval (CI) for overall survival (OS).Results: We identified 12 articles that evaluated the impact of ARID1A mutation or expression on the prognosis of patients with HCC or cholangiocarcinoma. Six studies provided data on HCC survival and 6 studies examined cholangiocarcinoma survival. For HCC, ARID1A mutation carriers or patients with low ARID1A expression had worse OS (HR = 1.75; 95% CI = 1.22–2.51) than non-carriers or patients with high ARID1A expression. For cholangiocarcinoma, ARID1A mutation carriers or patients with low ARID1A expression also had significantly shorter OS (HR = 3.70, 95% CI = 2.88–4.76).Conclusions: Our study suggests that ARIDIA mutation or low expression is strongly associated with poor prognosis of patients with HCC or cholangiocarcinoma, and may be considered as a potential prognostic biomarker for these patients.

Background and aims Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB-EGF to promote angiogenesis and HCC progression. Approach and results A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB-EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia-inducible factor 1 α signaling pathway. In addition, HB-EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3-kinase/Akt signaling pathway. The level of HB-EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence-free survival, which suggests that HB-EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB-EGF inhibitor cross-reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. Conclusions HB-EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB-EGF inhibitor cross-reacting material 197 with sorafenib might be used for individualized treatment of HCC.