Coffee, Green Tea Intake, and the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Observational Studies.

Several studies suggest an inverse relationship between coffee intake and risk of hepatocellular carcinoma (HCC), but the association between green tea intake and the risk of HCC is still inconclusive. We performed a meta-analysis of observational studies to clarify the association. We identified eligible studies published from January 1, 1992, to February 28, 2022, by searching PubMed, Web of Science, and EMBASE. A total of 32 studies were included in the meta-analysis. Among them, 21 studies involving 2,492,625 participants and 5980 cases of HCC reported coffee intake, 18 studies involving 1,481,647 participants and 6985 cases of HCC reported green tea intake, and seven studies reported both coffee intake and green tea intake. The results showed that a higher coffee (RR = 0.53; 95% CI: 0.47-0.59; I2 = 0.0%; Pheterogeneity = 0.634) or green tea (RR = 0.80; 95% CI: 0.67-0.95; I2 = 72.30%; Pheterogeneity < 0.001) intake may be associated with a lower risk of HCC. The same results were observed in both cohort and case-control subgroups. Our findings suggest that drinking coffee or green tea may be a potentially effective approach for the prevention or mitigation of HCC, but this still needs to be confirmed by further well-designed observational studies and clinical experimental research.

Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: The multi-ethnic cohort.

BACKGROUND AND AIMS: Lifestyle factors are well associated with risk of hepatocellular carcinoma (HCC). However, the impact of reducing adverse lifestyle behaviours on population-level burden of HCC is uncertain. METHODS: We conducted prospective analysis of the population-based multi-ethnic cohort (MEC) with linkage to cancer registries. The association of lifestyle factors (smoking, alcohol, diet quality assessed by alternate Mediterranean diet score, coffee drinking, physical activity and body mass index) with HCC incidence was examined using Cox regression. Population-attributable risk (PAR, %) for the overall, lean and overweight/obese populations was determined. RESULTS: A total of 753 incident cases of HCC were identified in 181,346 participants over median follow-up of 23.1 years. Lifestyle factors associated with elevated HCC risk included former/current smoking, heavy alcohol use, poor diet quality, lower coffee intake and obesity, but not physical activity. The lifestyle factor with highest PAR was lower coffee intake (21.3%; 95% CI: 8.9%-33.0%), followed by current smoking (15.1%; 11.1%-19.0%), obesity (14.5%; 9.2%-19.8%), heavy alcohol use (7.1%; 3.5%-10.6%) and lower diet quality (4.1%; 0.1%-8.1%). The combined PAR of all high-risk lifestyle factors was 51.9% (95% CI: 30.1%-68.6%). A higher combined PAR was observed among lean (65.2%, 26.8%-85.7%) compared to overweight/obese (37.4%, 11.7%-58.3%) participants. Adjusting for viral hepatitis status in a linked MEC-Medicare dataset resulted in similar PAR results. CONCLUSIONS: Modifying lifestyle factors, particularly coffee intake, may have a substantial impact on HCC burden in diverse populations, with greater impact among lean adults. Diet and lifestyle counselling should be incorporated into HCC prevention strategies.

Management of Hepatocellular Carcinoma: A Review.

Importance: Hepatocellular carcinoma (HCC) is the sixth most common malignancy and fourth leading cause of cancer-related death worldwide. Recent advances in systemic and locoregional therapies have led to changes in many guidelines regarding systemic therapy, as well as the possibility to downstage patients to undergo resection. This review examines the advances in surgical and medical therapies relative to multidisciplinary treatment strategies for HCC. Observations: HCC is a major health problem worldwide. The obesity epidemic has made nonalcoholic fatty liver disease a major risk factor for the development of HCC. Multiple societies, such as the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Asian Pacific Association for the Study of the Liver, and the National Comprehensive Cancer Network, provide guidelines for screening at-risk patients, as well as define staging systems to guide optimal treatment strategies. The Barcelona Clinic Liver Cancer staging system is widely accepted and has recently undergone updates with the introduction of new systemic therapies and stage migration. Conclusions and Relevance: The treatment of patients with HCC should involve a multidisciplinary approach with collaboration among surgeons, medical oncologists, radiation oncologists, and interventional radiologists to provide optimal care. Treatment paradigms must consider both tumor and patient-related factors such as extent of liver disease, which is a main driver of morbidity and mortality. The advent of more effective systemic and locoregional therapies has prolonged survival among patients with advanced disease and allowed some patients to undergo surgical intervention who would otherwise have disease considered unresectable.

The survival outcomes and prognostic factors of hepatocellular carcinoma among type 2 diabetes patients: a two-centre retrospective cohort study.

BACKGROUND: To determine the survival outcomes and prognostic factors associated with hepatocellular carcinoma (HCC) survival in type 2 diabetes (T2D) patients. METHODS: This was a retrospective cohort study involving two hepatobiliary centres from January 1, 2012, to June 30, 2018. Medical records were analysed for sociodemographic, clinical characteristics, laboratory testing, and HCC treatment information. Survival outcomes were examined using the Kaplan-Meier and log-rank test. Prognostic factors were determined using multivariate Cox regression. RESULTS: A total of 212 patients were included in the study. The median survival time was 22 months. The 1-, 3-, and 5-year survival rates were 64.2%, 34.2%, and 18.0%, respectively. Palliative treatment (adjusted hazard ratio [AHR] = 2.82, 95% confidence interval [CI] 1.75-4.52), tumour size ≥ 5 cm (AHR = 2.02, 95%CI: 1.45-2.82), traditional medication (AHR = 1.94, 95%CI: 1.27-2.98), raised alkaline phosphatase (AHR = 1.74, 95%CI: 1.25-2.42), and metformin (AHR = 1.44, 95%CI: 1.03-2.00) were significantly associated with poor prognosis for HCC survival. Antiviral hepatitis treatment (AHR = 0.54, 95% CI: 0.34-0.87), nonalcoholic fatty liver disease (NAFLD) (AHR = 0.50, 95% CI: 0.30-0.84), and family history of malignancies (AHR = 0.50, 95%CI: 0.26-0.96) were identified as good prognostic factors for HCC survival. DISCUSSION: Traditional medication, metformin treatment, advanced stage and raised alkaline phosphatase were the poor prognostic factors, while antiviral hepatitis treatment, NAFLD, and family history of malignancies were the good prognostic factors for our HCC cases comorbid with T2D.

The Characteristics and Mortality of Chinese Herbal Medicine Users among Newly Diagnosed Inoperable Huge Hepatocellular Carcinoma (≥10 cm) Patients: A Retrospective Cohort Study with Exploration of Core Herbs.

For patients with inoperable huge hepatocellular carcinoma (H-HCC, tumor size ≥10 cm), treatment options are limited. This study aimed to evaluate the characteristics and outcomes of patients with H-HCC who use Chinese herbal medicine (CHM). Multi-institutional cohort data were obtained from the Chang Gung Research Database (CGRD) between 1 January 2002 and 31 December 2018. All patients were followed up for 3 years or until the occurrence of death. Characteristics of CHM users and risk of all-cause mortality were assessed, and core CHMs with potential pharmacologic pathways were explored. Among 1618 patients, clinical features of CHM users (88) and nonusers (1530) were similar except for lower serum α-fetoprotein (AFP) and higher serum albumin levels in CHM users. CHM users had significantly higher 3 year overall survival rates (15.0% vs. 9.7%) and 3 year liver-specific survival rates (13.4% vs. 10.7%), about 3 months longer median survival time, and lower risk of all-cause mortality. Core CHMs were discovered from the prescriptions, including Hedyotis diffusa Willd combined with Scutellaria barbata D.Don, Salvia miltiorrhiza Bunge., Curcuma longa L., Rheum palmatum L., and Astragalus mongholicus Bunge. CHM use appears safe and is possibly beneficial for inoperable H-HCC patients; however, further clinical trials are still required.

The role of dietary factors in nonalcoholic fatty liver disease to hepatocellular carcinoma progression: A systematic review.

BACKGROUND AND AIMS: Dietary factors play an important role in promoting nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) development through regulation of metabolism and inflammation. However, so far there was no evidence regarding how dietary factors may influence different disease outcomes in the NAFLD to HCC progression. Our study aimed to comprehensively evaluate the role of dietary factors on the risk of progression from NAFLD to HCC. METHODS: A comprehensive literature research was conducted in PubMed, Web of Science and Embase databases to identify case-control and cohort studies published up to March 15, 2022 in English. We included studies investigating associations of food and beverage items (excluding alcohol), food groups, dietary patterns, and dietary habits with incidence risk of four main chronic liver diseases involved in the NAFLD-to-HCC progression (i.e., NAFLD, liver fibrosis, liver cirrhosis, and HCC). Three researchers independently performed the literature search, selected eligible articles, performed data abstraction and evaluated study quality. After evaluating adequacy and credibility of the associations reported for each dietary factor and each liver disease outcome, we summarized and evaluated the consistency of associations based on a priori determined criteria considering study design and the proportion of significant associations. RESULTS: There were 109 studies included in this review (47 on NAFLD, 1 on liver fibrosis, 6 on liver cirrhosis, and 55 on HCC). Consistent evidence suggested that higher dietary inflammatory potential was associated with increased risk of both NAFLD and HCC whereas Mediterranean diet was associated with lower risk of both diseases. Additionally, greater conformity to the Healthy Eating Index, Dietary Approaches to Stop Hypertension score, and Mediterranean Diet Score, and dietary patterns with high dietary antioxidant capacity reduced NAFLD risk. Some specific foods including soft drinks and red and/or processed meat were associated with increased NAFLD risk while total vegetables and spinach were associated with reduced NAFLD risk. Coffee and white meat consumption were inversely related to HCC risk. CONCLUSIONS: Dietary patterns or individual foods representing a more anti-inflammatory potential were associated with reduced risk of both NAFLD and HCC, which implied diet-induced inflammation may impact NAFLD progression towards HCC.

Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B.

BACKGROUND & AIMS: Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial. METHODS: After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis. RESULTS: A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results. CONCLUSIONS: ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention. LAY SUMMARY: Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B.

Associations between six dietary habits and risk of hepatocellular carcinoma: A Mendelian randomization study.

Diet is reported to be associated with hepatocellular carcinoma (HCC), but whether there is a causal relationship remains unclear. This study aimed to explore the potential causal associations between dietary habits and HCC risk using Mendelian randomization in an East Asian population. From the BioBank Japan, we obtained summary-level genome-wide association studies data for the following six dietary habits: ever/never drinker (n = 165,084), alcohol consumption (n = 58,610), coffee consumption (n = 152,634), tea consumption (n = 152,653), milk consumption (n = 152,965), and yoghurt consumption (n = 152,097). We also obtained data on HCC (1866 cases and 195,745 controls). Single-nucleotide polymorphisms (SNPs) that were associated with exposures (p < 5 × 10-8 ) were selected as instrumental variables (IVs). Five, two, and six SNPs were identified for ever/never drinkers, alcohol consumption, and coffee consumption. One SNP was used for consumption of tea, milk, and yoghurt. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by inverse variance weighted (for an IV with more than one SNP) or Wald ratio (for an IV with one SNP). Ever/never drinkers (OR, 1.11; 95% CI, 1.05-1.18; p < 0.001) and alcohol consumption (OR, 1.57; 95% CI, 1.32-1.86; p < 0.001) were positively associated with HCC risk. Conversely, coffee consumption was inversely related to HCC risk (OR, 0.69; 95% CI, 0.53-0.90; p = 0.007). Similar inverse associations were observed for consumption of tea, milk, and yoghurt, with ORs (95% CIs) of 0.11 (0.05-0.26), 0.18 (0.09-0.34), and 0.18 (0.09-0.34), respectively (all p < 0.001). Conclusion: There are potential causal associations between six dietary habits and HCC risk. Our findings inform clinical practice by providing evidence on the impact of dietary habits on HCC.

Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: SORAMIC is a previously published randomised controlled trial assessing survival in patients with advanced hepatocellular carcinoma who received sorafenib with or without selective internal radiation therapy (SIRT). Based on the per-protocol (PP) population, we assessed whether the outcome of patients receiving SIRT+sorafenib vs. sorafenib alone was affected by adverse effects of SIRT on liver function. METHODS: The PP population consisted of 109 (SIRT+sorafenib) vs. 173 patients (sorafenib alone). Comparisons were made between subgroups who achieved a significant survival benefit or trend towards improved survival with SIRT and the inverse group without a survival benefit: <65 years-old vs. ≥65 years-old, Child-Pugh 5 vs. 6, no transarterial chemoembolisation (TACE) vs. prior TACE, no cirrhosis vs. cirrhosis, non-alcohol- vs. alcohol-related aetiology. The albumin-bilirubin (ALBI) score was used to monitor liver function over time during follow-up. RESULTS: ALBI scores increased in all patient groups during follow-up. In the PP population, ALBI score increases were higher in the SIRT+sorafenib than the sorafenib arm (p = 0.0021 month 4, p <0.0001 from month 6). SIRT+sorafenib conferred a survival benefit compared to sorafenib alone in patients aged <65 years-old, those without cirrhosis, those with Child-Pugh 5, and those who had not received TACE. A higher increase in ALBI score was observed in the inverse subgroups in whom survival was not improved by adding SIRT (age ≥65 years-old, p <0.05; cirrhosis, p = 0.07; Child-Pugh 6, p <0.05; prior TACE, p = 0.08). CONCLUSION: SIRT frequently has a negative, often subclinical, effect on liver function in patients with hepatocellular carcinoma, which may impair prognosis after treatment. Careful patient selection for SIRT as well as prevention of clinical and subclinical liver damage by selective treatments, high tumour uptake ratio, and medical prophylaxis could translate into better efficacy. CLINICAL TRIAL NUMBER: EudraCT 2009-012576-27, NCT01126645 LAY SUMMARY: This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.

All coffee types decrease the risk of adverse clinical outcomes in chronic liver disease: a UK Biobank study.

BACKGROUND: Chronic liver disease (CLD) is a growing cause of morbidity and mortality worldwide, particularly in low to middle-income countries with high disease burden and limited treatment availability. Coffee consumption has been linked with lower rates of CLD, but little is known about the effects of different coffee types, which vary in chemical composition. This study aimed to investigate associations of coffee consumption, including decaffeinated, instant and ground coffee, with chronic liver disease outcomes. METHODS: A total of 494,585 UK Biobank participants with known coffee consumption and electronic linkage to hospital, death and cancer records were included in this study. Cox regression was used to estimate hazard ratios (HR) of incident CLD, incident CLD or steatosis, incident hepatocellular carcinoma (HCC) and death from CLD according to coffee consumption of any type as well as for decaffeinated, instant and ground coffee individually. RESULTS: Among 384,818 coffee drinkers and 109,767 non-coffee drinkers, there were 3600 cases of CLD, 5439 cases of CLD or steatosis, 184 cases of HCC and 301 deaths from CLD during a median follow-up of 10.7 years. Compared to non-coffee drinkers, coffee drinkers had lower adjusted HRs of CLD (HR 0.79, 95% CI 0.72-0.86), CLD or steatosis (HR 0.80, 95% CI 0.75-0.86), death from CLD (HR 0.51, 95% CI 0.39-0.67) and HCC (HR 0.80, 95% CI 0.54-1.19). The associations for decaffeinated, instant and ground coffee individually were similar to all types combined. CONCLUSION: The finding that all types of coffee are protective against CLD is significant given the increasing incidence of CLD worldwide and the potential of coffee as an intervention to prevent CLD onset or progression.

Twelve-month post-treatment parameters are superior in predicting hepatocellular carcinoma in patients with chronic hepatitis B.

BACKGROUND & AIMS: There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population. METHODS: We included two treatment-naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n = 1480, Korea prospective SAINT cohort) and the validation cohort (n = 426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method. RESULTS: We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-foetoprotein and platelet at 12 months showed the best performance (AUROC = 0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC = 0.844) and better than other existing prediction models including the APA, PAGE-B and GAG models (AUROC = 0.769 to 0.818). CONCLUSIONS: We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487).

Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities.

PURPOSE: This retrospective analysis focuses on treatment stage migration in patients with hepatocellular carcinoma (HCC) to identify successful treatment sequences in a large cohort of real-world patients. METHODS: 1369 HCC patients referred from January 1993 to January 2020 to the tertiary center of the Heidelberg University Hospital, Germany were analyzed for initial and subsequent treatment patterns, and overall survival. RESULTS: The most common initial treatment was transarterial chemoembolization (TACE, n = 455, 39.3%) followed by hepatic resection (n = 303, 26.1%) and systemic therapy (n = 200, 17.3%), whereas the most common 2nd treatment modality was liver transplantation (n = 215, 33.2%) followed by systemic therapy (n = 177, 27.3%) and TACE (n = 85, 13.1%). Kaplan-Meier analysis revealed by far the best prognosis for liver transplantation recipients (median overall survival not reached), followed by patients with hepatic resection (11.1 years). Patients receiving systemic therapy as their first treatment had the shortest median overall survival (1.7 years; P < 0.0001). When three or more treatment sequences preceded liver transplantation, patients had a significant shorter median overall survival (1st seq.: not reached; 2nd seq.: 12.4 years; 3rd seq.: 11.1 years; beyond 3 sequences: 5.5 years; P = 0.01). CONCLUSION: TACE was the most common initial intervention, whereas liver transplantation was the most frequent 2nd treatment. While liver transplantation and hepatic resection were associated with the best median overall survival, the timing of liver transplantation within the treatment sequence strongly affected median survival.

Co-Medication and Nutrition in Hepatocellular Carcinoma: Potentially Preventative Strategies in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with about 841,000 new cases and 782,000 deaths annually. Given the clearly defined population at risk, mostly patients with liver cirrhosis, prevention of HCC could be highly effective. SUMMARY: Besides regular ultrasound surveillance, numerous publications have suggested protective effects of diverse drugs and nutrients. However, none of those preventive options has made it into clinical routine or practice guidelines. We therefore summarize the current status of preventive effects of drugs such as statins, acetylsalicylic acid (ASA), and metformin, but also dietary aspects and nutrients such as coffee, tea, and vitamin D supplementation. A successful implementation of some of these strategies may potentially lead to improved prevention of HCC development in patients with liver cirrhosis. Key Messages: Accumulating data suggest that particularly ASA, antidiabetic therapies, and statins may substantially decrease HCC incidence in patients at risk.

Inverse Association of Coffee with Liver Cancer Development: An Updated Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Coffee consumption has been suggested to reduce the risk for hepatocellular carcinoma (HCC). While several studies report inverse correlation with coffee drinking, others have suggested more than 2 cups of coffee every day decrease the risk of liver cancer or HCC. However, controversy exists about the exact dose that would provide protective benefit. Therefore, we aimed to carry out a systematic review and meta-analysis of all studies that investigated the association of coffee consumption and risk of HCC and/or liver cancer. Our outcomes were the evaluation of the association of coffee with HCC or liver cancer development along with the amount of coffee needed to prevent HCC or liver cancer. METHODS: We performed a PubMed/MEDLINE/EMBASE/Ovid/Google Scholar search of original articles published in English from 1996 to June 2019, on case-control or cohort or prospective studies that associated coffee with liver cancer or HCC. We calculated the relative risk (RR) of the two conditions for coffee drinking and then stratified this into increments of one cup of coffee per day. Twenty studies were identified. The analysis was performed using random effects models from the methods of DerSimonian and Laird with inverse variance weighting. The Cochrane Q and the I 2 statistics were calculated to assess heterogeneity between studies. A p<0.10 value for chi-square test and I 2 <20% were interpreted as low-level heterogeneity. Probability of publication bias was assessed using funnel plots and with the Egger's test. RESULTS: The overall RR was 0.69 (95%CI 0.56-0.85; p<0.001) with significant heterogeneity between the studies. We performed subgroup analysis over the increments of 1 cup of coffee. Higher doses of coffee consumption were associated with a significant decrease in the risk of developing HCC or liver cancer. The funnel plot did not show significant publication bias. CONCLUSIONS: Our systematic review and meta-analysis suggests that drinking coffee provides benefits with a reduction in the risk of HCC or liver cancer. Higher doses of coffee have higher benefits in terms of risk reduction. However, further biological and epidemiological studies are required to determine the exact mechanism and to study specific subgroups such as viral hepatitis B or C related HCC.

Dietary habits and risk of hepatocellular carcinoma among hepatitis B surface antigen carriers: A prospective cohort study in China.

OBJECTIVE: In this prospective cohort study, we aimed to evaluate the association between dietary habits and the risk of developing hepatocellular carcinoma (HCC) in hepatitis B surface antigen (HBsAg)-positive carriers in Qidong, an hepatitis B virus (HBV)-epidemic area in China. METHODS: A total of 3199 HBsAg carriers aged 30-70 years in a prospective cohort in Qidong, China from 2007 to 2011 were included in the study. At baseline, all participants self-reported their dietary habits in a questionnaire interview. A follow-up check-up was performed every 6 months to identify HCC cases until November 2017. Cox's regression analysis and an interaction analysis were performed to estimate the relative risks of HCC in terms of baseline diet. RESULTS: Among 3199 HBsAg-positive participants, 270 developed HCC (143.86/100 000 person-years [PYs]). Compared with participants who rarely consume garlic, the risk of HCC in those who consumed it ≥ once per week decreased along with the increase in frequency (HR = 1.00, 0.90 and 0.62 in those who consumed it rarely vs those who consumed it 1-6 times per week and ≥ 7 times per week, respectively). This study found a synergistic effect between garlic and tea consumption on the risk of HCC (P = 0.039 for a multiplicative interaction). CONCLUSIONS: HBsAg carriers should improve their diet. Regular consumption of garlic and tea drinking may reduce the HCC incidence in HBsAg carriers.

Iron metabolism imbalance at the time of listing increases overall and infectious mortality after liver transplantation.

BACKGROUND: Liver transplantation (LT) is the best treatment for patients with liver cancer or end stage cirrhosis, but it is still associated with a significant mortality. Therefore identifying factors associated with mortality could help improve patient management. The impact of iron metabolism, which could be a relevant therapeutic target, yield discrepant results in this setting. Previous studies suggest that increased serum ferritin is associated with higher mortality. Surprisingly iron deficiency which is a well described risk factor in critically ill patients has not been considered. AIM: To assess the impact of pre-transplant iron metabolism parameters on post-transplant survival. METHODS: From 2001 to 2011, 553 patients who underwent LT with iron metabolism parameters available at LT evaluation were included. Data were prospectively recorded at the time of evaluation and at the time of LT regarding donor and recipient. Serum ferritin (SF) and transferrin saturation (TS) were studied as continuous and categorical variable. Cox regression analysis was used to determine mortality risks factors. Follow-up data were obtained from the local and national database regarding causes of death. RESULTS: At the end of a 95-mo median follow-up, 196 patients were dead, 38 of them because of infections. In multivariate analysis, overall mortality was significantly associated with TS > 75% [HR: 1.73 (1.14; 2.63)], SF < 100 µg/L [HR: 1.62 (1.12; 2.35)], hepatocellular carcinoma [HR: 1.58 (1.15; 2.26)], estimated glomerular filtration rate (CKD EPI Cystatin C) [HR: 0.99 (0.98; 0.99)], and packed red blood cell transfusion [HR: 1.05 (1.03; 1.08)]. Kaplan Meier curves show that patients with low SF (< 100 µg/L) or high SF (> 400 µg/L) have lower survival rates at 36 mo than patients with normal SF (P = 0.008 and P = 0.016 respectively). Patients with TS higher than 75% had higher mortality at 12 mo (91.4% ± 1.4% vs 84.6% ± 3.1%, P = 0.039). TS > 75% was significantly associated with infection related death [HR: 3.06 (1.13; 8.23)]. CONCLUSION: Our results show that iron metabolism imbalance (either deficiency or overload) is associated with post-transplant overall and infectious mortality. Impact of iron supplementation or depletion should be assessed in prospective study.

Integrating Chinese and Western medicines reduced the incidence of hepatocellular carcinoma in patients with diabetes mellitus: A Taiwanese population-based cohort study.

OBJECTIVES: Much epidemiological evidence links diabetes mellitus (DM) to the development of multiple cancers and, in particular, the development of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether Chinese herbal medicine (CHM) reduces the incidence of HCC in patients receiving Western antidiabetic drugs. INTERVENTIONS AND MAIN OUTCOME MEASURES: This retrospective cohort study used data from the National Health Insurance Research Database involving 81,105 diabetic patients, including 5122 CHM users and 25,966 non-CHM users. Analyses of treatment effects were adjusted for covariates including gender, age, comorbidities, antidiabetic drugs and liver medications. NodeXL software performed a network analysis to identify the 50 most commonly used CHM herbs and formulas. RESULTS: In Cox proportional hazards models adjusted for demographic and clinical characteristics, DM patients exposed to adjuvant CHM therapy were significantly less likely to develop HCC compared with non-CHM users (adjusted hazard ratio [aHR] 0.59; 95 % confidence interval [CI], 0.41-0.87; p = 0.01). Kaplan-Meier analysis revealed a lower 10-year cumulative risk of HCC among CHM users compared with non-CHM users. Amongst the 10 individual CHM herbs and herbal formulas most commonly prescribed for DM, the most frequent were Salvia miltiorrhiza (Dan Shen) and Liu Wei Di Huang Wan, respectively. CONCLUSION: This nationwide retrospective cohort study from Taiwan provides some valuable insights into the prescribing characteristics of CHM treatment in patients with DM. Compared with use of Western antidiabetic medications alone, use of adjuvant CHM effectively reduces the incidence of HCC in patients with DM.

The potential mechanism of miR-130b on promotion of the invasion and metastasis of hepatocellular carcinoma by inhibiting Notch-Dll1.

Introduction: This study aimed to elucidate the regulatory role and molecular regulation mechanism of miR-130b gene in the process of invasion and metastasis of hepatocarcinoma, and provide a theoretical basis for seeking of effective prevention and treatment of new targets for hepatocellular carcinoma.Materials and methods: The expression level of miR-130b gene in hepatocarcinoma tissues was determined by qRT-PCR. The biological function and mechanism of miR-130b gene were verified by cell and animal models, and the target gene was verified by double luciferase assay.Results: In the liver cancer tissues of patients with metastasis, the expression level of miR-130b gene was increased, and the difference was significantly significant (p < 0.05). Evaluation of independent risk factors for overall survival showed significant difference (p < 0.01). Up-regulation of miR-130b in MHCC97L- subpopulation cells significantly enhanced the invasion and migration ability, and the difference was statistically significant (p < 0.05). The invasion and migration ability of MHCC97H + subpopulation cells with increased expression of miR-130b was significantly decreased, and the difference was notably significant (p < 0.05). When the expression of miR-130b in MHCC97H + subpopulation cells was inhibited, the expressions of Notch-Dll1 and SOX2, Nanog and E2F3 proteins in transplanted tumor tissues were significantly higher than those in other groups (p < 0.05). When miR-130b in MHCC97L- subpopulation cells was up-regulated, the expressions of Notch-Dll1 and Bcl-2, CCND1, Nanog and MET proteins in transplanted tumor tissues were significantly increased than those in other groups (p < 0.05). The prediction results of bioinformatics data suggest that the target gene of miR-130b may be Notch-Dll1 gene. The experiment of luciferase reporter gene confirmed that miR-130b gene can be inhibited and contains fluorescent reporter gene with complementary binding site, lost activity.Conclusion: The miR-130b gene can inhibit the protein expression of Notch-Dll1, and it can promote the invasion and metastasis of liver cancer cells.

Hepatocellular carcinoma prediction beyond year 5 of oral therapy in a large cohort of Caucasian patients with chronic hepatitis B.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) may develop in patients with chronic hepatitis (CHB) even after 5 years of oral therapy and cannot be easily predicted. We assessed predictors of HCC development and the need for HCC surveillance in this setting. METHODS: Of 1,951 adult Caucasians with CHB included in the PAGE-B cohort, 1,427 (73%) had completed >5 years of follow-up under therapy without developing HCC by year 5. Median follow-up was 8.4 years from treatment onset. Points-based risk scores were developed to predict HCC risk after year 5. RESULTS: In years 5-12, HCC was diagnosed in 33/1,427 (2.3%) patients with cumulative incidences of 2.4%, 3.2% and 3.8% at 8, 10 and 12 years, respectively. Older age or age >50 years, baseline cirrhosis and liver stiffness (LSM) ≥12 kPa at year 5 were independently associated with increased HCC risk. The HCC incidence was lower in non-cirrhotics than cirrhotics at baseline with year-5 LSM <12; among cirrhotics at baseline, it was lower in those with year-5 LSM <12 than ≥12 kPa. CAGE-B score was based on age at year 5 and baseline cirrhosis in relation to LSM at year 5 and SAGE-B score was based only on age and LSM at year 5 (c-index = 0.809-0.814, 0.805-0.806 after bootstrap validation). Both scores offered 100% negative predictive values for HCC development in their low risk groups. CONCLUSIONS: In Caucasians with CHB, the HCC risk after the first 5 years of antiviral therapy depends on age, baseline cirrhosis status and LSM at year 5. CAGE-B and particularly SAGE-B represent simple and reliable risk scores for HCC prediction and surveillance beyond year 5 of therapy. LAY SUMMARY: In Caucasians with chronic hepatitis B, the risk of hepatocellular carcinoma after the first 5 years of entecavir or tenofovir therapy depends on age, baseline cirrhosis status and liver stiffness at year 5, which can provide simple and reliable risk scores for hepatocellular carcinoma prediction and surveillance beyond year 5. In patients with cirrhosis at baseline, liver stiffness <12 kPa at year 5 is associated with lower HCC risk, but surveillance may be still required.