Viral Load-Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B : A Multinational Study for the Development and External Validation of a New Prognostic Model.

BACKGROUND: A nonlinear association between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma (HCC) risk has been suggested in patients with chronic hepatitis B (CHB). OBJECTIVE: To develop and externally validate a prognostic model for HCC risk in noncirrhotic adult patients with CHB and no notable alanine aminotransferase (ALT) elevation. DESIGN: Multinational cohort study. SETTING: A community-based cohort in Taiwan (REVEAL-HBV [Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus]; REACH-B [Risk Estimation for HCC in CHB] model cohort) and 8 hospital-based cohorts from Korea and Hong Kong (GAG-HCC [Guide with Age, Gender, HBV DNA-HCC] and CU-HCC [Chinese University-HCC] cohorts). PARTICIPANTS: Model development: 6949 patients with CHB from a Korean hospital-based cohort. External validation: 7429 patients with CHB combined from the Taiwanese cohort and 7 cohorts from Korea and Hong Kong. MEASUREMENTS: Incidence of HCC. RESULTS: Over median follow-up periods of 10.0 and 12.2 years, the derivation and validation cohorts identified 435 and 467 incident HCC cases, respectively. Baseline HBV DNA level was one of the strongest predictors of HCC development, demonstrating a nonlinear parabolic association in both cohorts, with moderate viral loads (around 6 log10 IU/mL) showing the highest HCC risk. Additional predictors included in the new model (Revised REACH-B) were age, sex, platelet count, ALT levels, and positive hepatitis B e antigen result. The model exhibited satisfactory discrimination and calibration, with c-statistics of 0.844 and 0.813 in the derivation and validation cohorts with multiple imputation, respectively. The model yielded a greater positive net benefit compared with other strategies in the 0% to 18% threshold. LIMITATION: Validation in cohorts of other races and receiving antiviral treatment was lacking. CONCLUSION: Our new prognostic model, based on the nonlinear association between HBV viral loads and HCC risk, provides a valuable tool for predicting and stratifying HCC risk in noncirrhotic patients with CHB who are not currently indicated for antiviral treatment. PRIMARY FUNDING SOURCE: Korean government.

A risk prediction model for hepatocellular carcinoma in non-alcoholic fatty liver disease without cirrhosis: HCC prediction for non-cirrhotic NAFLD.

BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC), HCC risk in non-cirrhotic NAFLD received little attention. We aimed to develop and validate an HCC risk prediction model for non-cirrhotic NAFLD. METHODS: A nationwide cohort of non-cirrhotic NAFLD patients in Korea was recruited to develop a risk prediction model and validate it internally (n = 409 088). A model using a simplified point system was developed by Cox proportional hazard model. K-fold cross-validation assessed the accuracy, discrimination and calibration. The model was validated externally using a hospital cohort from Asan Medical Center (n = 8721). RESULTS: An 11-point HCC risk prediction model for non-cirrhotic NAFLD was developed using six independent factors of age, sex, diabetes, obesity, serum alanine aminotransferase level and gamma-glutamyl transferase level (c-index 0.75). The average area under receiver operating curves (AUROCs) of the model was 0.72 at 5 years and 0.75 at 10 years. In the external validation cohort, the AUROCs were 0.79 [95% confidence interval [CI], 0.59-0.95] at 5 years and 0.84 (95% CI, 0.73-0.94) at 10 years. The calibration plots showed the expected risks corresponded well with the observed risks. Risk stratification categorized patients into the low (score 0-6), moderate (7, 8) and high (9-11; estimated incidence rate >0.2%/year) risk groups. CONCLUSIONS: A novel HCC risk prediction model for non-cirrhotic NAFLD patients was developed and validated with fair performance. The model is expected to serve as a simple and reliable tool to assess HCC risk and assist precision screening of HCC.

Five-year on-treatment variables-based PPACS model predicts subsequent hepatocellular carcinoma in entecavir/tenofovir-treated patients.

Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term potent antiviral therapy, models predicting HCC after 5 years of therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4-fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore, Platelet counts and Prothrombin time at 5 years, Age at baseline and Sex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time-dependent area under the curve of 0.80 (95% confidence interval, 0.75-0.85) at 8-year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (https://ppacs.shinyapps.io/shiny_app_up/).

A model for predicting poor survival in patients with cirrhosis undergoing portosystemic shunt embolization.

BACKGROUND AND AIM: Portosystemic shunt embolization (PSSE) is a promising treatment for hepatic encephalopathy (HEP) and gastric varix (GV) in cirrhotic patients with a spontaneous portosystemic shunt. However, PSSE may worsen portal hypertension causing hepatorenal syndrome, liver failure, and mortality. This study aimed to develop and validate a prognostic model that helps identify patients with a risk of poor short-term survival after PSSE. METHODS: We included 188 patients who underwent PSSE for recurrent HEP or GV at a tertiary center in Korea. To develop a prediction model for 6-month survival after PSSE, Cox proportional-hazard model was used. The developed model was validated in a separate cohort of 184 patients from two other tertiary centers. RESULTS: In multivariable analysis, the 1-year overall survival after PSSE was significantly associated with baseline levels of serum albumin, total bilirubin, and international normalized ratio (INR). We therefore developed the albumin-bilirubin-INR (ABI) score by assigning 1 point each for albumin < 3.0 g/dL, total bilirubin ≥ 1.5 mg/dL, and INR ≥ 1.5. Time-dependent areas under the curve of the ABI score for predicting 3-month and 6-month survival were 0.85 and 0.85 in the development cohort and 0.83 and 0.78 in the validation cohort, indicating good discrimination performance. The ABI score showed a better discrimination and calibration performance than the model for end-stage liver disease and the Child-Pugh scores, especially in high-risk patients. CONCLUSIONS: The ABI score is a simple prognostic model that helps decide whether to proceed with PSSE for the prevention of HEP or GV bleeding in patients with spontaneous portosystemic shunt.

Effectiveness and Safety of COVID-19 Vaccination During Preconceptional and Preclinical Pregnancy Period: A National Population Study.

BACKGROUND: We aimed to assess the risk of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and early abortive outcomes after the association between coronavirus disease 2019 (COVID-19) vaccination during the preconceptional period and preclinical pregnancy, which are likely to be inadvertent vaccination. METHODS: We used data from the Korea Disease Control and Prevention Agency-COVID19-National Health Insurance Service cohort from December 2020 to December 2021. The vaccinated pregnant women were matched to unvaccinated pregnant controls at a 1:4 ratio. The risks of SARS-CoV-2 infection and intensive care unit (ICU) admission within 14 days of infection were analyzed to assess its effectiveness. For safety measures, the adjusted relative risks (aRRs) of early abortive outcomes for the first COVID-19 vaccination during the preconceptional and preclinical periods were calculated considering covariates. We compared the risk of early abortion between mRNA and viral vector vaccines. RESULTS: The overall COVID-19 vaccination rates during the preconceptional period and preclinical pregnancy were 3.1% (6,662/215,211) and 2.6% (5,702/215,211), respectively. The cumulative incidence of ICU admission within 14 days of SARS-CoV-2 infection was 6/100,000 in the unvaccinated group, whereas there were no ICU admissions in the vaccinated groups. The risks of early abortive outcomes were not significantly different between the preconceptional vaccination group and the unvaccinated group (aRR, 1.04; 95% confidence interval [CI],0.99-1.10) or between preclinical pregnancy vaccination and their matched controls (1.02; 95% CI, 0.96-1.08). mRNA and viral vector vaccines have shown similar risks for early abortive outcomes and miscarriages. CONCLUSION: Our findings have provided compelling evidence regarding the effectiveness and safety of COVID-19 vaccination prior to and during early pregnancy. Further research is required to extend the safety and efficacy profiles of COVID-19 vaccines to pregnant women and their babies.

Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-ß and tau in a mouse model of Alzheimer's disease.

The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-ß (Aß) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aß and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aß, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aß, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.

Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.

BACKGROUND & AIMS: It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma (HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection, with a focus on late recurrence. METHODS: This study comprised 2,520 consecutive patients who received curative liver resection for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection), time-dependent Cox and multistate modeling. RESULTS: The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence in the 2-, 5-, and 8-year landmark analysis (p = 0.04, p = 0.02 and p = 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted hazard ratio 0.62; p = 0.005). Based on a 3-state unidirectional illness-death model, patients without HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who experienced HBsAg seroclearance. CONCLUSIONS: HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related HCC among Korean patients who undergo curative liver resection. LAY SUMMARY: Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the risk of HCC recurrence after liver resection (a procedure used to treat and in some cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B surface antigen or HBsAg) has an impact on recurrence after liver resection remains unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late recurrence of HCC after liver resection in patients with HBV-related HCC.

A risk scoring system to predict clinical events in chronic hepatitis B virus infection: A nationwide cohort study.

Many patients with chronic hepatitis B do not receive adequate follow-up. This study aimed to develop a risk score to predict clinical events in patients with chronic hepatitis B virus (HBV) infection at the population level for identifying patients at high risk to warrant regular follow-up. This study analysed population-based data from the nationwide claims database of South Korea obtained between 2005 and 2015. We identified 507,239 non-cirrhotic patients with chronic HBV infection who are not under antiviral treatment. A risk score for predicting clinical events (hepatocellular carcinoma, death or liver transplantation) was developed based on multivariable Cox proportional hazard model in a development cohort (n = 401,745) and validated in a validation cohort (n = 105,494). The cumulative incidence rates of clinical events at 5 years were 2.56% and 2.44% in the development and validation cohorts, respectively. Clinical events in asymptomatic patients with chronic HBV infection (CAP-B) score ranging from 0 to 7.5 points based on age, sex, socioeconomic status, chronic hepatitis C co-infection, diabetes mellitus, statin or antiplatelet exposure, smoking, alcohol consumption, alanine aminotransferase and gamma-glutamyltransferase had good discriminatory accuracy in both the development and validation cohorts (c-indices for 3-, 5- and 10-year risk prediction: all 0.786). The predicted and observed probabilities of clinical events were calibrated in both cohorts. A score of >3.5 points identified subjects at distinctly high risk. The CAP-B score using easily accessible variables can predict clinical events and may allow selection of patients with chronic HBV infection for priority of regular follow-up.

Association of aspirin and statin use with the risk of liver cancer in chronic hepatitis B: A nationwide population-based study.

BACKGROUND & AIMS: Aspirin and statins have been suggested to prevent hepatocellular carcinoma (HCC). However, the combined effects of aspirin and statins on HCC risk in patients with chronic hepatitis B (CHB) are not clear. METHODS: A nationwide nested case-control study was performed with data from the National Health Insurance Service gathered between 2005 and 2015 in Korea. In a cohort of 538,135 treatment-naïve, non-cirrhotic patients with CHB, 6,539 HCC cases were matched to 26,156 controls and were analysed by conditional logistic regression. Separate historical cohort studies for each drug were analysed by time-dependent Cox regression as a sensitivity analysis. RESULTS: In the nested case-control study, statins (OR 0.34; 95% CI 0.32-0.37) and aspirin (OR 0.92; 95% CI 0.85-0.99) were significantly associated with a HCC risk reduction. However, dose-dependent risk reduction was observed only with statins. By sensitivity analysis in the historical cohorts, statin users (n = 244,455; HR 0.67; 95% CI 0.66-0.68) and aspirin users (n = 288,777; HR 0.81; 95% CI 0.80-0.82) had significantly lower HCC risk. In the drug-stratified analyses, statins were associated with significantly reduced risk of HCC regardless of aspirin, whereas aspirin did not show such associations. CONCLUSIONS: In this nationwide population-based study of patients with CHB, statin use was consistently associated with a significant and dose-dependent reduction in HCC risk. In contrast, the association between aspirin use and HCC risk reduction was not dose-dependent and was suggested to be confounded by statins.

Angiotensin-Converting Enzyme Inhibitor-based Versus Angiotensin Receptor Blocker-based Optimal Medical Therapy After Percutaneous Coronary Intervention: A Nationwide Cohort Study.

ABSTRACT: Optimal medical therapy (OMT) plays a crucial role in the secondary prevention of established coronary artery disease. The renin-angiotensin system (RAS) is an important target of OMT. However, there is limited evidence on whether there is any difference in the combined effect of OMT according to the classes of RAS blockade [angiotensin-converting enzyme inhibitor (ACEI) vs. angiotensin receptor blocker (ARB)]. Based on the nationwide National Health Insurance database in South Korea, 39,096 patients who received OMT after percutaneous coronary intervention between July 2013 and June 2017 were enrolled. Patients were stratified into either acute myocardial infarction (AMI) or angina cohort and analyzed according to the class of RAS blockade included in OMT at discharge (ACEI vs. ARB). The primary end point was all-cause mortality. The study population had a median follow-up of 2.3 years (interquartile range, 1.3-3.3 years). In the propensity score-matched AMI cohort (8219 pairs), the risk for all-cause mortality was significantly lower in patients with ACEI-based OMT than in those with ARB-based OMT (hazard ratio 0.83 of ACEI, 95% confidence interval 0.73-0.94, P = 0.003). However, in the propensity score-matched angina cohort (6693 pairs), the mortality risk was comparable, regardless of the class of RAS blockade (hazard ratio 1.13, 95 confidence interval 0.99-1.29, P = 0.08). In conclusion, in this nationwide cohort study involving patients receiving OMT after percutaneous coronary intervention, ACEI-based OMT was associated with a significantly lower risk of all-cause mortality in patients with AMI in comparison with ARB, but not in those with angina.

Randomized Trial Evaluating Percutaneous Coronary Intervention for the Treatment of Chronic Total Occlusion.

BACKGROUND: Procedural results for percutaneous coronary intervention (PCI) in coronary vessels with chronic total occlusion (CTO) have improved in recent years, and PCI strategies have moved toward more complete revascularization with more liberal use of CTO-PCI. However, evidence evaluating CTO-PCI is limited to observational studies and small clinical trials. METHODS: In this open-label, multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either 1 of 2 strategies: PCI or no PCI for the qualifying de novo CTO lesion with the option for PCI of obstructive non-CTO lesions at the discretion of the operator. The primary end point was a composite of death, myocardial infarction, stroke, or any revascularization. Health-related quality of life was assessed at baseline and at 1, 6, 12, 24, and 36 months. Because of slow recruitment, the trial was stopped before completion of the 1284 planned enrollments. RESULTS: Between March 2010 and September 2016, 834 patients were randomly assigned to the CTO-PCI (n=417) or no CTO-PCI (n=398) strategy. Among the patients assigned to the no CTO-PCI strategy, 78 (19.6%) crossed over to receive staged CTO-PCI within 3 days of randomization. The overall CTO-PCI success rate was 90.6%. Serious nonfatal complications associated with CTO-PCI occurred in 3 patients (1 stroke, 1 cardiac tamponade, and 1 patient with recurrent episodes of ventricular tachyarrhythmia induced by intracoronary thrombus). Approximately half of the patients in each group underwent PCI for an average of 1.3 non-CTO lesions, resulting in a comparable residual SYNTAX score (Synergy Between PCI With TAXUS and Cardiac Surgery; 3.7±5.4 versus 4.0±5.9, P=0.42) confined to non-CTO vessels. During a median follow-up of 4.0 years (interquartile range, 2.4 to 5.1 years), there was no significant difference between the CTO-PCI and the no CTO-PCI strategies in the incidence of the primary end point (22.3% versus 22.4%, hazard ratio, 1.03; 95% CI, 0.77 to 1.37; P=0.86). Both CTO-PCI and no CTO-PCI strategy were associated with significant improvements but without between-group differences in disease-specific health status that was sustained through 36 months. CONCLUSIONS: CTO-PCI was feasible with high success rates. There was no difference in the incidence of major adverse cardiovascular events with CTO-PCI versus no CTO-PCI, but the study was limited by low power for clinical end points and high crossover rates between groups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01078051.

Earlier Alanine Aminotransferase Normalization During Antiviral Treatment Is Independently Associated With Lower Risk of Hepatocellular Carcinoma in Chronic Hepatitis B.

OBJECTIVES: It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB. METHODS: We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as ≤35 U/L (men) and ≤25 U/L (women) and VR as serum hepatitis B virus DNA <15 IU/mL. RESULTS: During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P < 0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P < 0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6-12, 12-24, and >24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P < 0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P = 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P = 0.31) was associated with a significantly lower HCC risk. DISCUSSION: In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR.

Longitudinal Assessment of Three Serum Biomarkers to Detect Very Early-Stage Hepatocellular Carcinoma.

We aimed to determine the surveillance performance of alpha-fetoprotein (AFP), lectin-reactive AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), and their combinations for the early detection of hepatocellular carcinoma (HCC) by using prospectively collected longitudinal samples in patients at risk. Among 689 patients with cirrhosis and/or chronic hepatitis B who participated in four prospective studies, 42 HCC cases were diagnosed, selected, and matched with 168 controls for age, sex, etiology, cirrhosis, and duration of follow-up in a 1:4 ratio. Levels of AFP, AFP-L3, and DCP at the time of HCC diagnosis, month -6, and month -12 were compared between cases and controls. Of 42 HCC cases, 39 (93%) had cirrhosis, 36 (85.7%) had normal alanine aminotransferase levels, and 31 (73.8%) had very early-stage HCC (single <2 cm). AFP and AFP-L3 began to increase from 6 months before diagnosis of HCC in cases (P < 0.05), while they remained unchanged in controls. At HCC diagnosis, the area under the receiver operator characteristic curves (AUROCs) for AFP, AFP-L3, and DCP were 0.77, 0.73, and 0.71, respectively. Combining AFP and AFP-L3 showed a higher AUROC (0.83), while adding DCP did not further improve the AUROC (0.86). With the optimal cutoff values (AFP, 5 ng/mL; AFP-L3, 4%), the sensitivity and specificity of AFP and AFP-L3 combination were 79% and 87%, respectively. The sensitivity of ultrasonography was 48.6%, which was increased to 88.6% and 94.3% by adding AFP and AFP + AFP-L3, respectively. Conclusion: Among three biomarkers, AFP showed the best performance in discriminating HCC cases from controls; the AFP and AFP-L3 combination, adopting cutoff values (5 ng/mL and 4%, respectively), significantly improved the sensitivity for detecting HCC at a very early stage.

High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B.

OBJECTIVE: High serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality. DESIGN: This historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females, <19 IU/mL; males, <30 IU/mL) were compared with those of 1497 immune-active (IA)-phase patients (ALT ≥80 IU/mL) treated with nucleos(t)ide analogues. RESULTS: The IT group was significantly younger than the IA group (mean age, 38 vs 40 years at baseline, p=0.04). The 10-year estimated cumulative incidences of HCC (12.7% vs 6.1%; p=0.001) and death/transplantation (9.7% vs 3.4%; p<0.001) were significantly higher in the IT group than the IA group. In multivariable analyses, the IT group showed a significantly higher risk of HCC (HR 2.54; 95% CI 1.54 to 4.18) and death/transplantation (HR 3.38; 95% CI 1.85 to 6.16) than the IA group, which was consistently identified through inverse probability treatment weighting, propensity score-matched and competing risks analyses. CONCLUSIONS: Untreated IT-phase patients with CHB had higher risks of HCC and death/transplantation than treated IA-phase patients. Unnecessary deaths could be prevented through earlier antiviral intervention in select IT-phase patients.

Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B virus-endemic population.

Most mortalities from liver disease and liver cancer worldwide are attributable to hepatitis B virus (HBV) and hepatitis C virus. Despite remarkable advances in the treatment of HBV over past decades, limited population-level data are available regarding its impact on burden of liver disease and liver cancer. Mortality data from liver disease and liver cancer were obtained from the national death certificate database of Korea, an HBV-endemic country, between 1999 and 2013, and were analyzed by Joinpoint analysis. For liver disease, number of annual deaths decreased by 62.3% (95% confidence interval [CI], 62.0-62.6), crude death rate (CDR) decreased by 64.6% (95% CI, 64.3-64.9) from 21.2 to 7.5 per 100,000 population, and age-standardized death rate (ADR) declined by 75.0% (95% CI, 74.7-75.3), between 1999 and 2013. In contrast, for liver cancer, number of annual deaths increased by 17.8% (95% CI, 17.6-18.0) and CDR increased by 10.2% (95% CI, 10.0-10.4) from 20.5 to 22.6, although ADR decreased by 26.9% (95% CI, 26.6-27.2). The annual number of patients receiving oral antiviral agents against HBV increased from 1,716 to 187,226 during the study period. The increase in mean age at death from liver disease was significantly greater than that from liver cancer (8.8 vs. 6.1 years: P = 0.02). CONCLUSION: Marked reduction in liver disease mortality by widespread use of antiviral treatments against HBV may increase the life expectancy and number of patients at risk of developing liver cancer, inadvertently leading to increased burden of liver cancer in an HBV-endemic population. The competing nature between death from liver disease and that from liver cancer should be carefully considered in establishing a health care policy. (Hepatology 2017;66:1454-1463).

Coronary CT angiography characteristics of OCT-defined thin-cap fibroatheroma: a section-to-section comparison study.

OBJECTIVES: To evaluate whether plaque characteristics as assessed by coronary computed tomography angiography (CCTA) were associated with the presence of a thin-cap fibroatheroma (TCFA)-a precursor of plaque rupture-defined by optical coherence tomography (OCT) in a section-to-section-level comparison. METHODS: From 28 symptomatic patients, 31 coronary lesions were evaluated on 727 cross-sections co-registered by both CCTA and OCT. CCTA plaque characteristics included low attenuation plaque (LAP, <30 HU), napkin ring sign (NRS), positive remodelling (PR, remodelling index ≥1.10), and spotty calcification and plaque area and plaque burden. By OCT, presence of TCFA, lumen area and arc of lipid were determined. RESULTS: OCT revealed a TCFA in 69 (9.4%) sections from 19 (61.2 %) lesions. In per-section analysis, OCT-TCFA showed higher frequency of CCTA-detected LAP (58.0% vs. 18.5%), NRS (31.9% vs. 8.8%) and PR (68.1% vs. 48.0%) and greater plaque burden (70.6% vs. 61.9%) as compared to sections without OCT-TCFA (all p < 0.05). In multivariable analysis, LAP (odds ratio [OR] 4.05, p < 0.001) and NRS (OR 2.47, p = 0.005) were associated with OCT-TCFA. CCTA-measured lumen area correlated well with OCT-measured lumen area (R = 0.859, limits of agreement -0.5 ± 3.7 mm2). CONCLUSIONS: LAP and NRS in CCTA were associated with the presence of OCT-defined TCFA in a section-to-section comparison. KEY POINTS: • CT-defined LAP and NRS were associated with OCT-defined TCFA • OCT-TCFA showed higher frequency of LAP, NRS, PR and greater plaque burden • Non-calcified plaque area was correlated with OCT-measured lipid arc.

Metabolic Syndrome and the Risk of New-Onset Atrial Fibrillation in Middle-Aged East Asian Men.

BACKGROUND: Although the prevalence of both atrial fibrillation (AF) and metabolic syndrome (MetS) has been increasing in East Asia, the association between them is uncertain.Methods and Results:A total of 24,741 middle-aged Korean men without baseline AF were enrolled in a health screening program from January 2003 to December 2008. Among them, 21,981 subjects were evaluated to determine the risk of AF based on baseline MetS status through December 2016. At every visit, the subjects were evaluated for AF using ECG. MetS was defined using the criteria of the International Diabetes Federation and was present in 2,529 subjects (11.5%). Mean (±standard deviation) age was 45.9±5.3 years. During a mean follow-up of 8.7 years, 168 subjects (0.8%) were diagnosed with AF. The age-adjusted and multivariate-adjusted hazard ratios (HR) for MetS with AF were 1.62 (P=0.02) and 1.57 (P=0.03), respectively. Among the components of MetS, central obesity (age-adjusted HR 1.62, P<0.01) and raised blood pressure (age-adjusted HR 1.43, P=0.02) were associated with an increased risk of AF. CONCLUSIONS: MetS is associated with an increased risk of AF in middle-aged East Asian men. Of the components of MetS, central obesity is the most potent risk factor for the development of AF in this population.

Temporal improvement in survival of patients with hepatocellular carcinoma in a hepatitis B virus-endemic population.

BACKGROUND AND AIM: Over the past decade, the management of hepatocellular carcinoma (HCC) and viral hepatitis has been improved. We explored survival trends and factors affecting survival of HCC in a hepatitis B virus (HBV)-endemic population. METHODS: From 31 521 and 38 167 HCC registrants to the population-based national cancer registry in Korea, an HBV-endemic country, in the period of 2003-2005 and 2008-2010, we randomly sampled cohorts of 4515 and 4582 patients, respectively, for the investigation of clinical characteristics and survival. RESULTS: Compared with Cohort 2003-2005, Cohort 2008-2010 had significantly better liver function (Child-Turcotte-Pugh class A, 64.2% vs 71.6%; P < 0.001) and had more advanced tumor stages (Barcelona Clinic Liver Cancer stage B-D, 45.8% vs 50.4%; P < 0.001). HBV was the predominant cause of HCC in both cohorts (62.5% vs 62.2%; P = 0.70). Cohort 2008-2010 had significantly better overall survival than Cohort 2003-2005 by age-adjusted univariate, multivariable, and propensity score-matched analyses (median survival time, 17.2 vs 28.4 months; P < 0.001). In a subcohort analysis, a consistently significant inter-cohort improvement in survival was observed only in patients with HBV-related HCC (median survival, 16.1 vs 30.4 months; P < 0.001). The annual number of patients with HCC receiving oral antiviral agents for HBV precipitously increased from 93 in 2005 to 28 520 in 2010 in the country. CONCLUSIONS: The consistent improvement in survival of patients with HCC was confined to HBV-related HCC subcohort over the last decade in an HBV-endemic population. The survival improvement coincided with the exponential use of oral antiviral agents for HBV in the patients.

Efficacy and Safety of Fully Covered Self-Expanding Metal Stents for Malignant Esophageal Obstruction.

BACKGROUND: Malignant dysphagia can result in poor nutritional status with severe weight loss. Rapid relief from dysphagia can be achieved with esophageal self-expanding metal stents (SEMSs), a minimally invasive method. In this study, we evaluated the usefulness of SEMSs for malignant dysphagia. METHODS: Between 2012 and 2015, 119 patients with malignant dysphagia underwent esophageal SEMS insertion with endoscopic assistance. Their demographics and clinical outcomes were collected. Factors associated with stent-related complications and patient survival were evaluated. All data were retrospectively analyzed. RESULTS: The mean age of the 119 patients was 64.9 ± 11.6 years, and 25 (21%) were female. Seventy-five patients (63.0%) had squamous carcinoma, majority of which were located in the lower thoracic esophagus (n = 42), followed by middle thoracic esophagus (n = 19) and upper esophagus (n = 10). Eighty patients (67.2%) underwent SEMS insertion at diagnosis. Technical and clinical success rates were 99.2 and 89.9%, respectively. Complications occurred in 47 patients (39.5%); the most common complication was migration (36.3%), followed by pain and obstruction. The median stent patency time was 145 days (95% confidence interval 55.19-234.81 days). Gastric cancer (odds ratio 3.51, 95% confidence interval 1.21-10.15; p = 0.021) and a 20-mm-wide stent (odds ratio 2.922, 95% confidence interval 1.237-6.904; p = 0.015) were risk factors for complications. CONCLUSIONS: SEMSs are effective in palliation of malignant dysphagia. However, stent-related complications should be borne in mind, particularly in patients with gastric cancer with esophageal invasion and with larger width stents.

Long-term outcomes of bypass grafting versus drug-eluting stenting for left main coronary artery disease: Results from the IRIS-MAIN registry.

There are limited data on comparative outcomes and its determinants following coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for left main coronary artery disease (LMCAD) in a real-world setting. METHODS: A total of 3,504 consecutive patients with LMCAD treated with CABG (n=1,301) or PCI with DES (n=2,203) from the IRIS-MAIN registry were analyzed. The relative treatment effect of one strategy over another was assessed by propensity-score matching method. The primary outcome was a composite of death, myocardial infarction, or stroke. RESULTS: Median follow-up duration was 4.7 years. In the matched cohort, both groups demonstrated a similar risk for the primary outcome (adjusted hazard ratio [HR]: 0.94; 95% CI: 0.77-1.15; P=.54). Compared with CABG, PCI exhibited higher risks of myocardial infarction (HR: 2.11; 95% CI: 1.16-3.83; P=.01) and repeated revascularization (HR: 5.95; 95% CI: 3.94-8.98; P<.001). In the overall population, age, presence of chronic kidney disease, and low ejection fraction (<40%) were key clinical predictors of primary outcome regardless of the treatment strategy. However, factors deemed to be associated with perioperative morbidity were determinants of primary outcome in the CABG group, whereas those generally associated with the severity of atherosclerotic coronary artery disease were strong predictors in the PCI group. CONCLUSIONS: Among patients with significant LMCAD, the long-term risk of the composite outcome of death, myocardial infarction, or stroke was similar between CABG and PCI. Clinical variables that differentially predict adverse outcomes might be useful in triaging appropriate revascularization strategy.