Extrahepatic Malignancies and Antiviral Drugs for Chronic Hepatitis B: A Nationwide Cohort Study.

Background/Aims: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment. Methods: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders. Results: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.1, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30). Conclusions: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Gamma-glutamyl transferase and the risk of all-cause and disease-specific mortality in patients with diabetes: A nationwide cohort study.

BACKGROUND: There exists a paucity of data regarding whether gamma-glutamyl transferase is associated with disease-specific mortality in patients with type 2 diabetes mellitus. This study aimed to investigate the association of serum gamma-glutamyl transferase levels with all-cause and disease-specific mortality in patients with diabetes mellitus using a Korean nationwide health-screening database. METHODS: A total of 9 687 066 patients without viral hepatitis or liver cirrhosis who underwent health examination in 2009 were included. These patients were divided into four groups according to sex-specific quartiles of serum gamma-glutamyl transferase levels. RESULTS: During a median follow-up period of 8.1 years, 222 242 deaths were identified. The all-cause mortality rate increased as the serum gamma-glutamyl transferase levels became higher (highest quartile vs lowest quartile: hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.55-1.59; p for trend <.001). Similar trends were observed for cardiovascular disease (HR, 1.57; 95% CI, 1.53-1.62), ischemic heart disease (HR, 1.40; 95% CI, 1.33-1.48), and stroke (HR, 1.72; 95% CI, 1.60-1.85) in the highest quartile, as compared with the lowest quartile (p for trend <.001). As the gamma-glutamyl transferase quartiles became higher, mortality rates related to cancer (HR, 1.56; 95% CI, 1.52-1.60), liver disease (HR, 9.42; 95% CI, 8.81-10.07), respiratory disease (HR, 1.55; 95% CI, 1.49-1.62), and infectious disease (HR, 1.73; 95% CI, 1.59-1.87) also increased in the highest quartile, compared with the lowest quartile (p for trend <.001). CONCLUSIONS: Serum gamma-glutamyl transferase levels may be useful for the risk assessment of all-cause and disease-specific mortality among patients with type 2 diabetes mellitus.

No-Touch Radiofrequency Ablation Using Twin Cooled Wet Electrodes for Recurrent Hepatocellular Carcinoma Following Locoregional Treatments.

OBJECTIVE: To evaluate the therapeutic outcomes of no-touch radiofrequency ablation (NT-RFA) using twin cooled wet (TCW) electrodes in patients experiencing recurrent hepatocellular carcinoma (HCC) after undergoing locoregional treatments. MATERIALS AND METHODS: We conducted a prospective, single-arm study of NT-RFA involving 102 patients, with a total of 112 recurrent HCCs (each ≤ 3 cm). NT-RFA with TCW electrodes was implemented under the guidance of ultrasonography (US)-MR/CT fusion imaging. If NT-RFA application proved technically challenging, conversion to conventional tumor puncture RFA was permitted. The primary metric for evaluation was the mid-term cumulative incidence of local tumor progression (LTP) observed post-RFA. Cumulative LTP rates were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard regression was used to explore factors associated with LTP. Considering conversion cases from NT-RFA to conventional RFA, intention-to-treat (ITT; including all patients) and per-protocol (PP; including patients not requiring conversion to conventional RFA alone) analyses were performed. RESULTS: Conversion from NT-RFA to conventional RFA was necessary for 24 (21.4%) out of 112 tumors. Successful treatment was noted in 111 (99.1%) out of them. No major complications were reported among the patients. According to ITT analysis, the estimated cumulative incidences of LTP were 1.9%, 6.0%, and 6.0% at 1, 2, and 3 years post-RFA, respectively. In PP analysis, the cumulative incidence of LTP was 0.0%, 1.3%, and 1.3% at 1, 2, and 3 years, respectively. The number of previous locoregional HCC treatments (adjusted hazard ratio [aHR], 1.265 per 1 treatment increase; P = 0.004), total bilirubin (aHR, 7.477 per 1 mg/dL increase; P = 0.012), and safety margin ≤ 5 mm (aHR, 9.029; P = 0.016) were independently associated with LTP in ITT analysis. CONCLUSION: NT-RFA using TCW electrodes is a safe and effective treatment for recurrent HCC, with 6.0% (ITT analysis) and 1.3% (PP analysis) cumulative incidence of LTP at 2 and 3-year follow-ups.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

Risk of hepatocellular carcinoma after curative treatment when switching from tenofovir disoproxil fumarate or entecavir to tenofovir alafenamide: A real-world multicenter cohort study.

AIM: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high-quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence. METHODS: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time-varying effect of NA use on HCC recurrence was analyzed using various statistical methods. RESULTS: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68-1.47; p = 1.00) by time-varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67-1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51-2.33; p = 0.82 for ETV). Kaplan-Meier analysis showed comparable HCC recurrence-free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time-varying Cox analyses in various subgroups confirmed the primary findings. CONCLUSIONS: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment.

Urinary microbiome-based metagenomic signature for the noninvasive diagnosis of hepatocellular carcinoma.

BACKGROUND: Gut microbial dysbiosis is implicated in chronic liver disease and hepatocellular carcinoma (HCC), but the role of microbiomes from various body sites remains unexplored. We assessed disease-specific alterations in the urinary microbiome in HCC patients, investigating their potential as diagnostic biomarkers. METHODS: We performed cross-sectional analyses of urine samples from 471 HCC patients and 397 healthy controls and validated the results in an independent cohort of 164 HCC patients and 164 healthy controls. Urinary microbiomes were analyzed by 16S rRNA gene sequencing. A microbial marker-based model distinguishing HCC from controls was built based on logistic regression, and its performance was tested. RESULTS: Microbial diversity was significantly reduced in the HCC patients compared with the controls. There were significant differences in the abundances of various bacteria correlated with HCC, thus defining a urinary microbiome-derived signature of HCC. We developed nine HCC-associated genera-based models with robust diagnostic accuracy (area under the curve [AUC], 0.89; balanced accuracy, 81.2%). In the validation, this model detected HCC with an AUC of 0.94 and an accuracy of 88.4%. CONCLUSIONS: The urinary microbiome might be a potential biomarker for the detection of HCC. Further clinical testing and validation of these results are needed in prospective studies.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND/AIM: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). METHODS: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. RESULTS: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). CONCLUSION: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Extrahepatic malignancies in metabolic dysfunction-associated fatty liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. METHODS: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality. RESULTS: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001). CONCLUSION: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required.

Machine learning-based clinical decision support system for treatment recommendation and overall survival prediction of hepatocellular carcinoma: a multi-center study.

The treatment decisions for patients with hepatocellular carcinoma are determined by a wide range of factors, and there is a significant difference between the recommendations of widely used staging systems and the actual initial treatment choices. Herein, we propose a machine learning-based clinical decision support system suitable for use in multi-center settings. We collected data from nine institutions in South Korea for training and validation datasets. The internal and external datasets included 935 and 1750 patients, respectively. We developed a model with 20 clinical variables consisting of two stages: the first stage which recommends initial treatment using an ensemble voting machine, and the second stage, which predicts post-treatment survival using a random survival forest algorithm. We derived the first and second treatment options from the results with the highest and the second-highest probabilities given by the ensemble model and predicted their post-treatment survival. When only the first treatment option was accepted, the mean accuracy of treatment recommendation in the internal and external datasets was 67.27% and 55.34%, respectively. The accuracy increased to 87.27% and 86.06%, respectively, when the second option was included as the correct answer. Harrell's C index, integrated time-dependent AUC curve, and integrated Brier score of survival prediction in the internal and external datasets were 0.8381 and 0.7767, 91.89 and 86.48, 0.12, and 0.14, respectively. The proposed system can assist physicians by providing data-driven predictions for reference from other larger institutions or other physicians within the same institution when making treatment decisions.

Demographic, clinical and psychological predictors of malnutrition among people with liver cancer.

PURPOSE: This study aimed to explore the nutritional status and examine the demographic, clinical, nutritional, and psychosocial characteristics associated with malnutrition among people with liver cancer. METHODS: A descriptive cross-sectional design was used. Data were collected from a convenience sample of 162 liver cancer outpatients at a tertiary university hospital. Nutritional status was evaluated using the Patient-Generated Subjective Global Assessment (PG-SGA). Self-administered structured questionnaires were administered, and medical records were reviewed for demographic, clinical, nutritional, and psychosocial characteristics. RESULTS: Based on PG-SGA scores, 27 patients (16.7%) were classified into the malnutrition group. The stages of liver cancer, chemotherapy, physical and psychological symptom distress, global distress index, levels of alpha-fetoprotein and protein induced by vitamin K absence or antagonists, body mass index, appetite, hemoglobin and albumin levels, and depression were statistically significantly associated with malnutrition. Logistic regression model revealed that physical symptom distress, liver cancer stage, depression, and body mass index influenced statistically significantly malnutrition. CONCLUSIONS: In this study, clinical, nutritional, and psychosocial characteristics predicted malnutrition among people with liver cancer. Nurses should consider these characteristics when evaluating the nutritional status of people with liver cancer.

Reappraisal of Portal Vein Tumor Thrombosis as a Prognostic Factor for Patients with Hepatocellular Carcinoma.

Background/Aims: : This study aimed to assess whether hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) could have favorable prognoses with proper treatment under selective conditions. Methods: : This retrospective, single-center study involved 1,168 patients diagnosed with HCC between January 2005 and December 2006, before the introduction of sorafenib. Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox proportional hazards model was used to identify and adjust the variables associated with OS. Results: : In nodular-type HCC, the OS differed significantly according to the presence of PVTT (log-rank p<0.001), and the level of PVTT, not only its presence, was a major independent factor affecting OS. PVTT at the Vp1-3 branch was associated with significantly longer OS than was PVTT at the Vp4 level (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21). In multivariate analysis, the OS was further stratified according to the PVTT level and tumor type, representing that nodular HCC without PVTT exhibited the best OS, whereas nodular HCC with Vp4 PVTT (adjusted HR, 2.59; 95% CI, 1.57 to 4.28) showed a poor prognosis similar to that of infiltrative HCC. The PVTT level was consistently correlated with OS in patients treated with transarterial chemoembolization. Nodular HCC without PVTT showed the best prognosis, while nodular HCC with Vp1-3 PVTT also exhibited a favorable OS, although inferior to that without PVTT (adjusted HR, 1.47, 95% CI, 0.92 to 2.36). Conclusions: : Active treatment such as transarterial chemoembolization can be considered for selected PVTT cases. The level of PVTT and type of HCC were independent prognostic factors.

A circulating cell-free DNA methylation signature for the detection of hepatocellular carcinoma.

To address the shortcomings of current hepatocellular carcinoma (HCC) surveillance tests, we set out to find HCC-specific methylation markers and develop a highly sensitive polymerase chain reaction (PCR)-based method to detect them in circulating cell-free DNA (cfDNA). The analysis of large methylome data revealed that Ring Finger Protein 135 (RNF135) and Lactate Dehydrogenase B (LDHB) are universally applicable HCC methylation markers with no discernible methylation level detected in any other tissue types. These markers were used to develop Methylation Sensitive High-Resolution Analysis (MS-HRM), and their diagnostic accuracy was tested using cfDNA from healthy, at-risk, and HCC patients. The combined MS-HRM RNF135 and LDHB analysis detected 57% of HCC, outperforming the alpha-fetoprotein (AFP) test's sensitivity of 45% at comparable specificity. Furthermore, when used with the AFP test, the methylation assay can detect 70% of HCC. Our findings suggest that the cfDNA methylation assay could be used for HCC liquid biopsy.

Anatomical ablation for small hepatocellular carcinomas using multiple applicators: a preliminary study.

BACKGROUND: Anatomical ablation, defined as thermal ablation of tumor-bearing small portal territories, may provide excellent local tumor control in peripherally-located small hepatocellular carcinomas (HCC), which has been a major concern with percutaneous ablation alone. PURPOSE: To evaluate the technical feasibility and therapeutic outcomes of anatomical ablation using multiple radiofrequency (RF) applicators for the ablation of tumor-bearing small portal territories of peripherally-located small (≤ 4 cm) HCCs. MATERIALS AND METHODS: Patients with peripherally-located single HCCs (≤ 4 cm) to be treated with anatomical ablation using multiple RF applicators between January 2020 and March 2022 were enrolled in this prospective study. Anatomical ablation was performed for the index tumor under real-time US-CT/MR fusion imaging guidance, with one or two clustered electrode needles placed across the tumor-bearing portal vein branches. Technical success and complications of anatomical ablations were assessed. Cumulative incidence of local tumor progression (LTP) and recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Fifty-five HCCs (mean size, 1.77 ± 0.59 cm) in 55 participants (mean age, 66.4 ± 7.7 years; 39 men, 16 women) were treated with anatomical ablation; 98.2% (54/55) technical success was achieved. No major complications were noted. Among the 55 participants, LTP occurred in only one patient who had experienced technical failure of anatomical ablation. Estimated 1- and 2-year cumulative incidences of LTP were 0% and 3.7%, respectively. Five patients developed intrahepatic remote recurrence during the median follow-up period of 19.2 months (range, 3.7-28.8 months); therefore, estimated 1- and 2-year recurrence-free survival was 91.7% and 85.0%, respectively. CONCLUSION: Anatomical ablation using multiple RF applicators provided the excellent results of local tumor control in patients with peripherally-located small (≤ 4 cm) HCCs. TRIAL REGISTRATION: clinicaltrial.gov identifier: NCT05397860.

A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma.

PURPOSE: Synergistic effect of radiotherapy and immunotherapy for the treatment of hepatocellular carcinoma (HCC) has been reported. This phase I/IIa pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) and durvalumab in patients with locally advanced unresectable HCC. PATIENTS AND METHODS: Patients with Child-Pugh score ≤ 7 and locally advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B HCC or BCLC-C disease without extrahepatic metastases, received Y90-radioembolization followed by intravenous durvalumab 1,500 mg 7 to 14 days after Y90-radioembolization and every 4 weeks thereafter. Primary endpoint was time to progression (TTP) assessed by modified RECIST (mRECIST). Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) determined by mRECIST, and safety. RESULTS: All 24 patients enrolled received Y90-radioembolization and 23 received at least one dose of durvalumab. Median follow-up duration was 19.0 months (range, 2.2-24.2). Median TTP was 15.2 months [95% confidence interval (CI), 6.1-not estimated]. Median OS was not reached and 18-month OS rate was 58.3% (95% CI, 36.4-75.0). Median PFS was 6.9 months (95% CI, 5.4-15.2). Seven (29.2%) patients had a complete response and 13 (54.2%) had a partial response; ORR was 83.3% (95% CI, 62.6-95.3). Eleven (47.8%) patients experienced any-grade treatment-related adverse events. Two (8.7%) patients had grade 3 treatment-related adverse events (neutropenia and fever). None experienced any treatment-related serious adverse events. CONCLUSIONS: In patients with locally advanced unresectable HCC, the combination of Y90-radioembolization and durvalumab demonstrated promising efficacy and safety, warranting further evaluation in large-scale controlled trials.

Association between daily aspirin therapy and risk of hepatocellular carcinoma according to metabolic risk factor burden in non-cirrhotic patients with chronic hepatitis B.

BACKGROUND: Several studies have demonstrated chemopreventive effects of aspirin against hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). AIMS: To investigate the associations of aspirin use with risks of HCC, liver-related mortality, and major bleeding according to metabolic risk factor burden among non-cirrhotic patients with CHB METHODS: Using the Korean National Health Insurance Service database, we identified 282,611 non-cirrhotic adults with CHB. Data on obesity, diabetes, high blood pressure, and hypercholesterolemia were collected. Subjects were stratified into lower and higher metabolic risk groups (≤2 and ≥3 risk factors, respectively). Propensity score-matched cohorts of aspirin users and non-users were generated. Risks of HCC, liver-related death and major bleeding were analyzed. RESULTS: During the median follow-up of 7.4 years, positive associations between metabolic risk factor burden and outcomes were verified (all ptrend < 0.001). In the lower metabolic risk group (13,104 pairs), the association between aspirin use and HCC risk was not significant after multivariable adjustment (adjusted subdistribution hazard ratio [aSHR]: 0.93; 95% CI: 0.84-1.03); however, aspirin use was associated with elevated major bleeding risk (aSHR: 1.22; 95% CI: 1.08-1.39). In the higher metabolic risk group (2984 pairs), aspirin use was associated with reduced risks of HCC (aSHR: 0.72; 95% CI: 0.57-0.91) and liver-related mortality (aSHR: 0.69; 95% CI: 0.50-0.96) without an increase in risk of major bleeding (aSHR: 1.02; 95% CI: 0.79-1.32). CONCLUSIONS: Aspirin therapy was associated with reduced risks of HCC and liver-related death without excess risk of major bleeding, in non-cirrhotic patients with CHB who had a higher metabolic risk factor burden.

Efficacy of Antiviral Prophylaxis up to 6 or 12 Months From Completion of Rituximab in Resolved Hepatitis B Patients: A Multicenter, Randomized Study.

BACKGROUND: Rituximab occasionally induces reactivation of hepatitis B virus (HBV) in patients with resolved HBV, at times with fatal consequences. The optimal duration of prophylactic antiviral therapy in this situation is unclear. We aimed to investigate the difference in HBV reactivation according to the duration of prophylactic tenofovir disoproxil fumarate (TDF) in patients with resolved HBV and receiving rituximab. METHODS: A multicenter, randomized, open-label, prospective study was conducted in hepatitis B surface antigen-negative and anti-HBc-positive non-Hodgkin's lymphoma patients treated with rituximab-based chemotherapy. A total of 90 patients were randomized and received prophylactic TDF from the initiation of rituximab until 6 months (the 6-month group) or 12 months (the 12-month group) after the completion of rituximab. The primary outcome was the difference in HBV reactivation and the secondary outcomes were the difference in hepatitis flare and adverse events between the two groups. RESULTS: In an intention to treat (ITT) analysis, HBV reactivation occurred in 1 of 43 patients (2.3%; 95% confidence interval [CI], 0.41-12%) at a median of 13.3 months in the 6-month group and 2 of 41 patients (4.9%; 95% CI, 1.4-16%) at a median of 13.7 months in the 12-month group. In a per protocol (PP) analysis, HBV reactivation occurred in 1 of 18 patients (5.6%; 95% CI, 0.99-26%) at 13.3 months in the 6-month group and 1 of 13 patients (7.7%; 95% CI, 1.4-33%) at 9.7 months in the 12-month group. The cumulative incidence of HBV reactivation was not significantly different between the two groups in ITT and PP analyses (P = 0.502 and 0.795, respectively). The occurrence of adverse events was not significantly different between the two groups in ITT (9.3% in the 6-month group, 22.0% in the 12-month group, P = 0.193) and PP analyses (5.6% in the 6-month group, 7.7% in the 12-month group, P > 0.999). CONCLUSION: Prophylactic TDF up to 6 months after completion of rituximab-based chemotherapy is sufficient in terms of the efficacy and safety of reducing HBV reactivation in patients with resolved HBV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02585947.

Association between the fatty liver index and the risk of fracture among individuals over the age of 50 years: a nationwide population-based study.

Background and purpose: The association between fatty liver and fracture risk has not been firmly established. In this study, we investigated the relationship between the fatty liver index (FLI) and the incidence of fractures among individuals ≥50 years of age, using a nationwide population-based cohort. Methods: Data from the Korean National Health Insurance System between January 2009 and December 2019 were analyzed using the Cox proportional hazards model. Fatty liver status was defined using FLI. Newly diagnosed fractures were identified based on insurance claim data. Results: Among the 3,384,457 individuals who met our inclusion criteria over the study period, 444,203 cases of incident fractures were identified over a median follow-up of 10.3 years. On multivariate analysis, the risk of fracture was significantly higher among individuals with a higher FLI score compared to those with an FLI<30, with adjusted hazard ratio [aHR] and 95% confidence interval [CI] as follows: FLI 30-59 group, aHR 1.04 and 95% CI 1.03-1.05; and FLI ≥60 group, aHR 1.12 and 95% CI 1.10-1.13. A higher FLI was associated with a greater risk of hip (aHR 1.23 and 1.52 for the FLI 30-59 and FLI ≥60 group, respectively) and vertebral fracture (aHR 1.08 and 1.16 for the FLI 30-59 and FLI≥60 group, respectively). The association between the risk for fracture and FLI ≥60 was prominent for non-obese than obese individuals (aHR 1.25 and 95% CI, 1.22-1.27 versus 1.06 and 1.05-1.08, respectively). Conclusions: A high FLI is associated with an increased risk of hip and vertebral fractures among individuals ≥50 years of age, suggestive of an association between a higher FLI and osteoporotic fractures.

The association between alcohol consumption and the risk of hepatocellular carcinoma according to glycemic status in Korea: A nationwide population-based study.

BACKGROUND: Alcohol and diabetes are known risk factors for hepatocellular carcinoma (HCC); however, it is unclear whether the association between alcohol consumption and HCC risk differs by fasting serum glucose level and diabetes. We investigated the dose-response relationship between alcohol consumption and the risk of HCC according to glycemic status. METHODS AND FINDINGS: This population-based observational cohort study included patients who underwent general health checkups in 2009 using the Korean National Health Insurance Service Database. The primary outcome was HCC incidence, and Cox proportional hazard regression analysis was performed to estimate the relationship between alcohol consumption and HCC risk according to glycemic status. A total of 34,321 patients newly diagnosed with HCC were observed in the median follow-up period of 8.3 years. In the multivariable model, we adjusted for age, sex, smoking, regular exercise, income, hypertension, dyslipidemia, and body mass index. Mild-to-moderate alcohol consumption increased the risk of HCC in all glycemic statuses (normoglycemia: hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.02 to 1.10; prediabetes: HR, 1.19; 95% CI, 1.14 to 1.24; and diabetes: HR, 2.02; 95% CI, 1.93 to 2.11) compared to normoglycemic nondrinking. Heavy alcohol consumption also increased the risk of HCC in all glycemic statuses (normoglycemia: HR, 1.39; 95% CI, 1.32 to 1.46; prediabetes: HR, 1.67; 95% CI, 1.58 to 1.77; and diabetes: HR, 3.29; 95% CI, 3.11 to 3.49) compared to normoglycemic nondrinking. Since alcohol consumption information in this study was based on a self-administered questionnaire, there may be a possibility of underestimation. Although we excluded patients with a history of viral hepatitis using diagnosis codes, we could not obtain information on hepatitis B or hepatitis C serum markers. CONCLUSIONS: Both mild-to-moderate and heavy alcohol consumption was associated with an increased risk of HCC in all glycemic statuses. The increased risk of HCC according to alcohol consumption was the highest in the diabetes group, suggesting that more intensive alcohol abstinence is required for patients with diabetes.

Differential risk of 23 site-specific incident cancers and cancer-related mortality among patients with metabolic dysfunction-associated fatty liver disease: a population-based cohort study with 9.7 million Korean subjects.

INTRODUCTION: Although an association between metabolic dysfunction-associated fatty liver disease (MAFLD) and cardiovascular disease or overall mortality has been reported, it is unclear whether there is an association between MAFLD and cancer incidence or mortality. We aimed to investigate the differential risk of all- and site-specific cancer incidence and mortality according to MAFLD subgroups categorized by additional etiologies of liver disease. METHODS: Using the Korean National Health Insurance Service database, we stratified the participants into three groups: (1) single-etiology MAFLD (S-MAFLD) or MAFLD of pure metabolic origin; (2) mixed-etiology MAFLD (M-MAFLD) or MAFLD with additional etiological factor(s) (i.e., concomitant liver diseases and/or heavy alcohol consumption); and (3) non-MAFLD. Hepatic steatosis and fibrosis were defined using the fatty liver index and the BARD score, respectively. Cox proportional hazards regression was performed to estimate the risk of cancer events. RESULTS: Among the 9,718,182 participants, the prevalence of S-MAFLD and M-MAFLD was 29.2% and 6.7%, respectively. During the median 8.3 years of follow-up, 510,330 (5.3%) individuals were newly diagnosed with cancer, and 122,774 (1.3%) cancer-related deaths occurred among the entire cohort. Compared with the non-MAFLD group, the risk of all-cancer incidence and mortality was slightly higher among patients in the S-MAFLD group (incidence, adjusted hazard ratio [aHR] = 1.03; 95% confidence interval [CI]: 1.02-1.04; mortality, aHR = 1.06; 95% CI: 1.04-1.08) and highest among patients with M-MAFLD group (incidence, aHR = 1.31; 95% CI: 1.29-1.32; mortality, aHR = 1.45; 95% CI: 1.42-1.48, respectively). The M-MAFLD with fibrosis group (BARD score ≥ 2) showed the highest relative risk of all-cancer incidence (aHR = 1.38, 95% CI = 1.36-1.39), followed by the M-MAFLD without fibrosis group (aHR = 1.09, 95% CI = 1.06-1.11). Similar trends were observed for cancer-related mortality. CONCLUSIONS: MAFLD classification, by applying additional etiologies other than pure metabolic origin, can be used to identify a subgroup of patients with poor cancer-related outcomes.

Use of doxorubicin-eluting bead transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein invasion: a prospective study.

Background/Aim: To evaluate the applicability of transarterial chemoembolization (TACE) treatment with doxorubicin drug-eluting beads (DEBs) in advanced hepatocellular carcinoma (HCC) patients with portal vein invasion (PVI). Methods: This prospective study was approved by the institutional review board and informed consent was obtained from all participants. A total of 30 HCC patients with PVI received DEB-TACE between 2015 and 2018. The following parameters were evaluated: complications during DEB-TACE, abdominal pain, fever, and laboratory outcomes, including liver function change. Overall survival (OS), time to progression (TTP), and adverse events were also analyzed and assessed. Results: DEBs measuring 100-300 µm in diameter were loaded with doxorubicin (150 mg per procedure). There were no complications during DEB-TACE and no significant differences in the levels of prothrombin time, serum albumin, or total bilirubin at follow-up compared to baseline. The median TTP was 102 days (95% confidence interval [CI], 42-207 days) and the median OS was 216 days (95% CI, 160-336 days). Three patients (10%) had severe adverse reactions, including transient acute cholangitis (n=1), cerebellar infarction (n=1), and pulmonary embolism (n=1), but no treatment-related death occurred. Conclusions: DEB-TACE may be a therapeutic option for advanced HCC patients with PVI.