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The anticancer effect of statins is drawing attention. However, it is unclear whether statin use reduces the risk of hepatocellular carcinoma (HCC) recurrence in patients who undergo liver transplantation (LT) for HCC. Consecutive patients who underwent LT for HCC between 1995 and 2019 were enrolled. The effects of statins on HCC recurrence and mortality were compared between statin user and statin nonuser groups. We performed the analyses in a variety of ways, including inverse probability treatment weighting (IPTW) methods to balance any confounders and the landmark method to avoid immortal time bias. A total of 430 patients were enrolled, among whom 323 (75.1%) were statin nonusers and 107 (24.9%) were statin users. During a median of 64.9 months (IQR, 26.1-122.6 months) of follow-up, 79 patients (18.4%) had HCC recurrence and 111 (25.8%) died. Among those who died, 53 (47.7%) were identified as HCC-related mortalities. Statin use was a predictor of HCC recurrence (adjusted hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.1-0.6; P = 0.002), all-cause mortality (adjusted HR, 0.3; 95% CI, 0.2-0.5; P

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the world. It is linked mainly to insulin resistance and metabolic syndrome including obesity and dyslipidemia. In addition, various endocrine dysfunctions including polycystic ovary syndrome (PCOS) and hypogonadism are involved in the development and progression of NAFLD. We need to know the disease pathophysiology more accurately due to the heterogeneity of clinical presentation of fatty liver disease. The liver is the major metabolic organ with sexual dimorphism. Sexual dimorphism is associated not only with behavioral differences between men and women, but also with physiological differences reflected in liver metabolism. In men, normal androgen levels prevent hepatic fat accumulation, whereas androgen deficiency induce hepatic steatosis. In women, higher androgens can increase the risk of NAFLD in PCOS. Sex hormone binding globulin (SHBG) is involved in androgen regulation. Recently, SHBG may be reported as a surrogate marker for NAFLD. Therefore, this review will focus on the mechanism of androgen dysfunction in the regulation of hepatic metabolism, the risk of developing NAFLD, and the potential role of SHBG in the course of NAFLD.; Keywords: Non-alcoholic fatty liver disease, insulin resistance, sexual dimorphism, androgen, sex hormone binding globulin

LT, liver transplantation; HCC, hepatocellular carcinoma; IS, immunosuppressants; DC, dendritic cells; Treg, regulatory T; Th17, T helper 17; AST, aspartate transaminase; ALT, alanine transaminase; OUT, operational taxonomic unit; LEfSe, linear discriminant analysis effect size; LDA, linear discriminant analysis; IL, interleukin; TGF, transforming growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; TNF-α, tumor necrosis factor-α; MIP-1α, macrophage inflammatory protein-1α; IP-10, interferon γ-induced protein; MCP-1, monocyte chemoattractant protein-1; ACR, acute cellular rejection; NF-κB, nuclear factor κB; PT INR, prothrombin time; QC, quality check; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay.

Background Current guidelines recommend rules for stopping nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB), but off-therapy relapse is still high. This study aimed to identify predictors of off-therapy relapse and improve existing stopping rules. Methods This retrospective study included 488 patients with CHB (262 hepatitis B e antigen [HBeAg]–positive and 226 HBeAg-negative) who discontinued NAs. Posttreatment relapse was investigated. Results During the median follow-up period of 73.3 months, the cumulative 5-year and 10-year virologic relapse (VR) rates were 73.5% and 76.1%, respectively. In HBeAg-positive patients, end-of-therapy hepatitis B surface antigen (HBsAg) levels (hazard ratio [HR], 1.93 [95% confidence interval {CI}, 1.42–2.61]) and consolidation duration ≥2 years (HR, 0.31 [95% CI: .17–.58]) were independent predictors of VR. Consolidation ≥2 years and low HBsAg levels (≤560 IU/mL) significantly lowered VR rates. In HBeAg-negative patients, only the HBsAg level (HR, 1.61 [95% CI: 1.24–2.11]) was independently predictive of VR. Cirrhosis was significantly associated with higher VR rates in HBeAg-negative patients with low HBsAg levels (≤800 IU/mL). Combining end-of-therapy HBsAg levels with current stopping rules or consolidation duration further reduced off-therapy relapse, with 2-year VR rates of approximately 15%–25% in HBeAg-positive patients and 35% in HBeAg-negative patients. Conclusions End-of-therapy HBsAg levels, consolidation duration, and cirrhosis are key determinants of off-therapy relapse. Together with low HBsAg levels, extended consolidation therapy for ≥2 years should be ensured, and cirrhotic patients should continue NAs even if low HBsAg levels are achieved. A combination of these parameters will help identify individuals at low risk of relapse and significantly improve the predictive ability of the existing stopping rules.

Background/Aims: The role of hepatitis B virus (HBV) integration into the host genome in hepatocarcinogenesis following hepatitis B surface antigen (HBsAg) seroclearance remains unknown. Our study aimed to investigate and characterize HBV integration events in chronic hepatitis B (CHB) patients who developed hepatocellular carcinoma (HCC) after HBsAg seroclearance.Methods: Using probe-based HBV capturing followed by next-generation sequencing technology, HBV integration was examined in 10 samples (seven tumors and three non-tumor tissues) from seven chronic carriers who developed HCC after HBsAg loss. Genomic locations and patterns of HBV integration were investigated.Results: HBV integration was observed in six patients (85.7%) and eight (80.0%) of 10 tested samples. HBV integration breakpoints were detected in all of the non-tumor (3/3, 100%) and five of the seven (71.4%) tumor samples, with an average number of breakpoints of 4.00 and 2.43, respectively. Despite the lower total number of tumoral integration breakpoints, HBV integration sites in the tumors were more enriched within the genic area. In contrast, non-tumor tissues more often showed intergenic integration. Regarding functions of the affected genes, tumoral genes with HBV integration were mostly associated with carcinogenesis. At enrollment, patients who did not remain under regular HCC surveillance after HBsAg seroclearance had a large HCC, while those on regular surveillance had a small HCC.Conclusions: The biological functions of HBV integration are almost comparable between HBsAg-positive and HBsAgserocleared HCCs, with continuing pro-oncogenic effects of HBV integration. Thus, ongoing HCC surveillance and clinical management should continue even after HBsAg seroclearance in patients with CHB.

Controlling adverse events (AEs) through dose reduction can enhance drug adherence and treatment response. Currently, there is no guide for sorafenib dosing. The aim of this study was to evaluate whether sorafenib dosing could affect treatment outcomes. A total of 782 hepatocellular carcinoma (HCC) patients treated with sorafenib were evaluated for sorafenib dosing and its modifications via medical records at baseline and regular follow-up. Study outcomes included progression-free survival (PFS), overall survival (OS), sorafenib duration, cumulative dose, AEs and drug discontinuation. The median patient survival was 7.7 months. Overall, 242 (30.9%) patients underwent dose reduction and 121 (17.5%) discontinued sorafenib due to AEs. In multivariate analysis, dose reduction was identified to be independently predictive of PFS and OS. The 800-to-400 mg/day group provided significantly better PFS than the 800 mg/day-maintained group or the 800-to-600 mg/day group. Likewise, the 800-to-400 mg/day group resulted in a significantly better OS than other dosing. However, dose reduction to 200 mg/day led to significantly worse PFS and OS. Hand-foot skin reaction and drug discontinuation due to AEs were higher in the 800-to-600 mg/day group than the 800-to-400 mg/day group. The 800-to-400 mg/day group had significantly longer treatment duration and higher cumulative dose than the 800 mg/day-maintained group. Sorafenib dose reduction can improve HCC survival and increase patient tolerance and adherence coupled with longer duration and higher cumulative dose. Dose reduction from 800 to 400 mg/day than to 600 mg/day is recommended when clinically warranted. However, dose reduction to 200 mg/day is not recommendable.

IgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepatic inflammatory IgAPatient cohorts including steatohepatitis cohort (n=61) and HCC cohort (n=271) were established. Patients' surgical and biopsy specimens were analyzed using immunohistochemistry. Multicolor flow cytometry was performed with a subset of patient samples. Single-cell RNA-Seq analysis was performed using Gene Expression Omnibus (GEO) datasets. Additionally, we performed in vitro differentiation of macrophages, stimulation with coated IgA, and RNA sequencing. Hepa1-6 cells and C57BL/6N mice were used to obtain HCC syngeneic mouse models.Serum IgA levels were associated (p0.001) with fibrosis progression and HCC development in patients with chronic liver diseases. Additionally, immunohistochemical staining of inflamed livers or HCC revealed IgA positivity in monocytes, with a correlation between IgAOverall, the findings of this study showed that serum IgA levels was correlated with intrahepatic and intratumoral infiltration of inflammatory IgA

Background/Aims: To evaluate the efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) therapy in hepatitis C virus (HCV)-infected Korean patients in a real clinical setting.Methods: A total of 273 patients who received LDV/SOF therapy between May 2016 and February 2021 were consecutively enrolled and analyzed. A per-protocol analysis was performed to evaluate the virologic response.Results: Seventy-five percent were infected with genotype 1, and 25% were infected with genotype 2. A hundred eightyone (66.3%) patients had chronic hepatitis, 74 (27.1%) had compensated cirrhosis, eight (2.9%) had decompensated cirrhosis, and 10 (3.7%) had undergone liver transplantation. Undetectable HCV RNA at week 4 was achieved in 90.2% (231/256) of patients, 99.2% (250/252) achieved the end of treatment response, and 98.1% (202/206) achieved sustained virologic response at 12 weeks post-treatment (SVR12). According to liver function, the SVR12 rates were 99.3% (135/136) in chronic hepatitis, 96.4% (53/55) in compensated cirrhosis, and 100% (6/6) in decompensated cirrhosis. The SVR12 rates according to the genotype were 98.2% (167/170) for genotype 1 and 97.2% (35/36) for genotype 2. An 8-week LDV/SOF treatment in treatment-naïve chronic hepatitis patients with HCV RNA < 6,000,000 IU/mL at baseline resulted in 100% (23/23) SVR12 rates. Overall, LDV/SOF was tolerated well, with a 0.7% (2/273) discontinuation rate due to adverse events that were unrelated to LDV/SOF.Conclusions: LDV/SOF is effective and safe for treating HCV-infected Korean patients with high SVR12 rates.

Although rejection or tolerance can occur in liver transplantation (LT) patients, there are no reliable non-invasive methods for predicting immune homeostasis. In this study, we developed a humanized mouse model to predict liver immune homeostasis in patients who underwent LT. The patient-derived avatar model was developed by injecting peripheral blood mononuclear cells from healthy controls (HCs) or LT patients with stable, rejection, or tolerance into NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice, followed by injection of human hepatic stellate cells and Carbone tetrachloride (CCl4). After 7 weeks, the patient’s T-cell engraftment and liver inflammation in the avatar model were evaluated and compared with the liver histology of LT patients. Changes in liver inflammation following treatment with tacrolimus and/or biguanide derivatives were also examined. The C-X-C Motif Chemokine Receptor 3 (CXCR3)-dependently engrafted patient T cells led to differences in liver inflammation in our model according to the status of LT patients. The livers of avatar models from rejection patients had severe inflammation with more T helper 17 cells and fewer regulatory T cells compared to those of models from tolerance and HCs showing only mild inflammation. Moreover, our model classified stable post-LT patients into severe and mild inflammation groups, which correlated well with liver immunity in these patients. Our models revealed alleviation of inflammation after combination treatment with tacrolimus and biguanide derivatives or monotherapy. Consequently, using our new patient-derived avatar model, we predicted liver immune homeostasis in patients with stable LT without biopsy. Moreover, our avatar model may be useful for preclinical analysis to evaluate treatment responses while reducing risks to patients.

Background/Aims: To evaluate the effectiveness and safety of direct acting antivirals (DAAs) available in chronic kidney disease (CKD) patients with hepatitis C virus (HCV) infection in Korea.Methods: In a retrospective, multicenter cohort study, 362 patients were enrolled from 2015 to 2019. The effectiveness and safety of DAAs including glecaprevir/pibrentasvir, sofosubvir/ribavirin, ledipasvir/sofosbuvir, and daclatasvir/asunaprevir were analyzed for patients according to CKD stage. We evaluated sustained virologic response at week 12 after treatment (SVR12) as primary endpoint. The effectiveness and safety were also evaluated according to CKD stage.Results: Among 362 patients, 307 patients completed DAAs treatment and follow-up period after end of treatment. The subjects comprised 87 patients (62 with CKD stage 3 and 25 with CKD stage (4–5), of whom 22 were undergoing hemodialysis). HCV patients with CKD stage 1 and 2 (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2) showed SVR12 of 97.2% and 95.4% respectively. SVR12 of CKD stage 3 and 4–5 (eGFR < 60 mL/min/1.73 m2) patients was 91.9% and 91.6% respectively. Patients undergoing hemodialysis achieved SVR12 (90.9%). Treatment failure of DAAs in stage 1, 2, 3, and 4–5 was 2.8%, 2.7%, 1.6%, and 4%. DAAs showed good safety profile and did not affect deterioration of renal function.Conclusions: DAAs shows comparable SVR12 and safety in CKD patients (stage 3, 4, and 5) with HCV compared with patients with stage 1 and 2. The effectiveness and safety of DAAs may be related to the treatment duration. Therefore, it is important to select adequate regimens of DAAs and to increase treatment adherence.

Background and Aims This retrospective study aimed to investigate the impact of positive hepatitis B core antibody (anti-HBc) and metabolic disorders on clinical characteristics of hepatocellular carcinoma (HCC) patients in an HBV-endemic area. Methods A total of 1950 consecutive patients newly diagnosed with HCC between 2002 and 2015 were included. Patient records were reviewed. We compared non-viral and non-alcoholic HCC patients with other etiological groups for HCC. In addition, we compared HCC patients with negative hepatitis B surface antigen (HBsAg) and positive anti-HBc to those with negative HBsAg and negative anti-HBc, and to those with HBV. Results The prevalence of non-viral and non-alcoholic HCC increased from 7% in 2002–2011 to 12% in 2012–2015. The proportion of non-viral and non-alcoholic HCC gradually increased with age. Patients with non-viral and non-alcoholic HCC exhibited higher rates of metabolic disorders and preserved liver function. The rate of anti-HBc positivity was similarly high in all HCC etiological groups. The clinical features of HCC patients with negative HBsAg and positive anti-HBc were similar to those with negative HBsAg and negative anti-HBc, but significantly different from those with HBV HCC. Regarding tumor characteristics, patients in the non-viral and non-alcoholic HCC group had more advanced stages of tumors (mUICC stage III–V and BCLC stage C/D). There was no significant difference in overall survival among the patient groups. The presence of anti-HBc did not affect patient survival. Conclusion Patients with non-viral and non-alcoholic HCC had a relatively high prevalence of metabolic disorders and preserved liver function. However, they had advanced tumor stage compared to patients from other etiological groups. Anti-HBc positivity did not affect the clinical characteristics or prognosis of non-HBV HCC patients in this study.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70–80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.

ObjectiveThe use of tenofovir (TDF) and entecavir (ETV) in patients with chronic hepatitis B (CHB) has led to a decrease in the incidence of hepatocellular carcinoma (HCC) and liver-related events. However, whether there is a difference between the two agents in the extent of improving such outcomes has not been clarified thus far. Therefore, we aimed to compare TDF and ETV on the risk of HCC and mortality.DesignA total of 7015 consecutive patients with CHB who were treated with TDF or ETV between February 2007 and January 2018 at the liver units of the Catholic University of Korea were screened for study eligibility and 3022 patients were finally analysed. Study end points were HCC and all-cause mortality or liver transplantation (LT) within 5 years after the initiation of antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting methods were used.ResultsNo difference was observed between TDF and ETV in the incidence rates of HCC in the entire cohort (HR 1.030; 95% CI 0.703 to 1.509, PSM model, p=0.880) and subgroups of patients with chronic hepatitis and cirrhosis. Also, no difference was observed between TDF and ETV in the incidence rates of all-cause mortality or LT in the entire cohort (HR 1.090; 95% CI 0.622 to 1.911, PSM model, p=0.763), and patients with chronic hepatitis and cirrhosis.ConclusionThis study has demonstrated the clinical outcomes in patients with CHB who received TDF or ETV treatment. There was no difference in the intermediate-term risk of HCC and mortality or LT between the two drugs.

Background Enterococcus species are a common cause of bacteremia in liver transplant recipients. Vancomycin-resistant enterococci (VRE) have become an important cause of nosocomial infection. In this study, we analyzed the incidence, antibiotic resistance, and outcomes of enterococcal bacteremia in living donor liver transplant recipients and the risk factors for VRE. Patients and Methods This single-center, retrospective review included 536 patients who underwent liver transplant between January 2008 and December 2017. Results Among 536 patients, 42 (7.8%) experienced a total of 58 enterococcal bacteremic episodes (37 Enterococcus faecium, 17 Enterococcus faecalis, 2 Enterococcus casseliflavus, 1 Enterococcus. avium, and 1 Enterococcus raffinosus). Most cases of enterococcal bacteremia (46/58, 79.3%) occurred within 6 months after transplant; among the 26 cases of VRE bacteremia, 50% occurred within 1 month after transplant. E. faecium isolates had the highest rate of vancomycin resistance (25/37, 67.5%), whereas all E. faecalis isolates were susceptible to vancomycin. According to multivariate analysis, post-transplant dialysis (odds ratio, 3.95; 95% CI, 1.51–10.34; P = .005) and length of post-transplant hospital stay (odds ratio, 1.03; 95% CI, 1.009–1.04; P = .004) were significantly associated with VRE bacteremia. One-year mortality was 31% (13/42) among recipients with enterococcal bacteremia, 5.0% (20/384) among nonbacteremic patients, and 11.1% (10/90) among patients with nonenterococcal bacteremia (P Conclusion In this study, enterococcal bacteremia showed high incidence in liver transplant recipients, especially with vancomycin resistance, occurred in early period after transplant, and was associated with increased mortality. High rates of resistance to vancomycin warrant further efforts to manage enterococcal infection in liver transplant recipients at our center.

Background/aim This study aimed to identify the survival benefit of intrahepatic tumour control by hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) or extrahepatic metastasis. Patients and methods Between 2010 and 2017, a total of 187 consecutive patients with advanced HCC were treated with HAIC. The survival outcomes and response rates to HAIC were analysed. Results The intrahepatic objective response (OR) rate of all enrolled patients was 18.7%. The survival outcome of patients with OR was significantly better from those without OR, irrespective of initial distant metastasis. Achievement of intrahepatic OR by HAIC and favourable liver function at the time of best response evaluation were two independent factors associated with better OS. Conclusion HAIC-induced intrahepatic tumour reduction significantly prolonged patient survival, irrespective of PVTT or initial distant metastasis.

Brain metastasis is a rare event in patients with hepatocellular carcinoma (HCC). This retrospective study aimed to identify the prognostic factors and determine the outcomes of patients with brain metastases from HCC. About 86 patients with brain metastases (0.6%) from HCC were identified from two institutions; of them, 32 underwent tumor-removing surgery or stereotactic radiosurgery (SRS) with or without adjuvant whole brain radiotherapy (WBRT) (group 1), 30 had WBRT alone (group 2), and 24 received conservative treatment (group 3). Estimates for overall survival (OS) after brain metastases were determined, and clinical prognostic factors were identified. The median OS after development of brain metastases was 50 days. About 75 (87.2%) patients had lung metastases at the time of brain metastasis diagnosis. Group 1 showed better OS, followed by group 2 and group 3, sequentially (p

Acute liver failure (ALF) caused by hepatitis A is a rare but fatal disease. Here, we developed a model to predict outcome in patients with ALF caused by hepatitis A. The derivation set consisted of 294 patients diagnosed with hepatitis A-related ALF (ALFA) from Korea, and a validation set of 56 patients from Japan, India, and United Kingdom. Using a multivariate proportional hazard model, a risk-prediction model (ALFA score) consisting of age, international normalized ratio, bilirubin, ammonia, creatinine, and hemoglobin levels acquired on the day of ALF diagnosis was developed. The ALFA score showed the highest discrimination in the prediction of liver transplant or death at 1 month (c-statistic, 0.87; 95% confidence interval [CI], 0.84-0.92) versus King's College criteria (KCC; c-statistic, 0.56; 95% CI, 0.53-0.59), U.S. Acute Liver Failure Study Group index specific for hepatitis A virus (HAV-ALFSG; c-statistic, 0.70; 95% CI, 0.65-0.76), the new ALFSG index (c-statistic, 0.79; 95% CI, 0.74-0.84), Model for End-Stage Liver Disease (MELD; c-statistic, 0.79; 95% CI, 0.74-0.84), and MELD including sodium (MELD-Na; c-statistic, 0.78; 95% CI, 0.73-0.84) in the derivation set (all P < 0.01). In the validation set, the performance of the ALFA score (c-statistic, 0.84; 95% CI, 0.74-0.94) was significantly better than that of KCC (c-statistic, 0.65; 95% CI, 0.52-0.79), MELD (c-statistic, 0.74; 95% CI, 0.61-0.87), and MELD-Na (c-statistic, 0.72; 95% CI, 0.58-0.85) (all P < 0.05), and better, but not statistically significant, than that of the HAV-ALFSG (c-statistic, 0.76; 95% CI, 0.61-0.90; P = 0.28) and new ALFSG indices (c-statistic, 0.79; 95% CI, 0.65-0.93; P = 0.41). The model was well-calibrated in both sets. Conclusion: Our disease-specific score provides refined prediction of outcome in patients with ALF caused by hepatitis A.

Background A real-life study is essential outside clinical trials. The aim is to evaluate the clinical outcomes of direct acting agents (DAA) for patients with chronic hepatitis C (CHC) in real practice. Methods We analyzed 590 consecutively enrolled patients with CHC-1b who received DAAs since 2015, when DAAs were introduced in Korea. The patients were checked for resistance-associated variants (RAV) against nonstructural protein 5A inhibitors and then daclatasvir/asunaprevir or sofosbuvir based regimens were chosen. Results The frequency of patients with cirrhosis and prior hepatocellular carcinoma (HCC) was 29.2% and 4.7%, respectively. For the RAV test, 10% were positive and in 3.6% the result was "indeterminate." Overall, 518 patients were treated with a 24-week regimen of daclatasvir/asunaprevir, 72 patients (RAV positive 75%) were treated with 12 weeks regimen of ledipasvir/sofosbuvir or daclatasvir/sofosbuvir. The SVR12 was 94.0% in the daclatasvir/asunaprevir, 98.2% in the ledipasvir/sofosbuvir, and 100% in the daclatasvir/sofosbuvir group. A total of 93.3% of SVR12 in the RAV-"indeterminate" patients was not difference 95.0% in the RAV-negative patients. Up to 1 year, de novo HCC occurrence and recurrence developed in 2.6% and 17.8%, respectively. HCC was more frequent in cirrhotic patients than in noncirrhotic patients (P = 0.000). α Fetoprotein (AFP) level at the end of treatment was a predicting factor for de novo HCC. Conclusions Optimizing the choice of DAAs according to RAV test resulted in high SVR among CHC-1b Korean patients. This real practice multicenter cohort study suggests the importance of AFP and HCC surveillance in cirrhotic patients even after successful HCV therapy.

To evaluate the efficacy and safety of 144-week tenofovir disoproxil fumarate (TDF) therapy in treatment-naive chronic hepatitis B (CHB) patients in Korean. In total, 579 treatment-naive CHB patients at 11 medical centers were enrolled retrospective and prospective from September 2015 to January 2016 by design (NCT02533544). We evaluated the complete virologic response (CVR) rate and the renal safety of TDF. The overall CVR rate was 69.4%, 87.0%, and 89.7% at weeks 48, 96, and 144, respectively. In the HBeAg-positive CHB patients, the CVR rate at weeks 48, 96, and 144 was 61.4%, 83.1%, and 89.6%, respectively. The rates of HBeAg loss and seroconversion at weeks 48, 96, and 144 were 16.6%, 23.5%, 34.1%, and 7.6%, 8.9%, 13.3%, respectively. In HBeAg-negative CHB patients, the CVR rate at weeks 48, 96, and 144 was 82.5%, 93.2%, and 90.0%, respectively. The rate of alanine aminotransferase normalization was 36.9%, 45.4%, and 46.8% at weeks 48, 96, and 144, respectively. Of the CHB patients, 0.9% showed an elevated creatinine (> 0.5 mg/dL from baseline). Age (≥ 60 years) was significantly associated with a decline in renal function at week 144 (P

After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance.A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell's C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation.Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis.The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients.After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients.

Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3’ end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.

Background and aim Serum Mac-2-binding protein glycosylation isomer (M2BPGi) has been studied as a marker for liver fibrosis or cirrhosis. This study explores the potential role of M2BPGi in predicting clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Methods A total of 226 HCC patients undergoing TACE were enrolled. Serum M2BPGi was measured at baseline. Receiver operating characteristic curve analysis was used to determine the cut-off value (= 2.82) of M2BPGi for prediction of patient outcomes. The prognostic performance of M2BPGi was compared with the hepatoma arterial embolization prognostic (HAP) score. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), radiologic response, and recurrence after complete response (CR). Results Median PFS was 14.5 months. Patients with low M2BPGi levels had significantly better OS and PFS than those with high M2BPGi levels. M2BPGi was an independent variable for PFS and OS. Patients were classified into three groups by combination of M2BPGi and the HAP score. The low-risk group had significantly better PFS and OS than the high-risk and intermediate-risk groups, whereas the differences between the high-risk and intermediate-risk groups were insignificant. The combination showed higher area under the receiver operating characteristic curve for 3-year PFS and OS than the HAP score alone. M2BPGi was a significant predictor of HCC recurrence after achieving CR. Conclusions Serum M2BPGi level is a useful prognostic indicator of PFS and OS in TACE-treated HCC patients, as well as recurrent cases, which cannot be predicted with the HAP score. The combination of M2BPGi and the HAP score enhances the detection of TACE-preferred patients.

The risk of reactivation of resolved hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-negative multiple myeloma patients after daratumumab has not been reported. Among 93 patients with daratumumab treatment, reactivation occurred in 6 patients (6.5%) with one hepatic failure. This is the first report demonstrating a considerable risk of reactivation of resolved HBV after daratumumab.

Although sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), the efficacy of sorafenib in patients with recurrent HCCs after liver transplantation (LT) has not been compared with that in patients without LT (non-LT).Between 2008 and 2019, a total of 832 consecutive HCC patients treated with sorafenib (790 in the non-LT group and 42 in the LT group) were enrolled. The primary outcome was overall survival (OS). Secondary outcomes were time-to-progression (TTP), objective response rate (ORR) and disease control rate (DCR). Treatment outcomes were assessed by multiple subgroup analyses and propensity-score matching (PSM).The median follow-up duration was 152.5 days. The LT group was younger and had smaller intrahepatic HCC than the non-LT group. The LT group showed significantly better OS (16.8 vs. 7.1 months, p 0.001), TTP, ORR and DCR than the non-LT group. The superior efficacy of sorafenib in the LT group was corroborated in multiple subgroup analyses stratified by metastasis, effective sorafenib maintenance dose, or Child-Turcotte-Pugh class A. LT was identified as an independent factor for favorable OS. Intrahepatic HCC was the strongest tumor-related factor for both OS and TTP and was significantly associated with tumor response and hepatic function. Finally, subanalyses including only patients with small intrahepatic HCC or PSM modeling showed no difference in sorafenib efficacy between the LT and the non-LT groups.Sorafenib provides better outcomes in the LT setting than the non-LT setting. This benefit may be associated with the smaller intrahepatic HCC coupled with preserved hepatic function in LT recipients.

We examined the effect of combination therapy with metformin and tacrolimus on immune parameters including T regulatory (Treg) and type 17 helper T (Th17) cells in vitro and in vivo in mice and in liver transplantation (LT) patients. T cell proliferation and subtypes after in vitro T cell activation or allogeneic stimulation were evaluated. RNA sequencing and microarray analysis were used to evaluate differences in gene expression. Metformin and tacrolimus were administered to mice with graft-versus-host disease (GVHD) and the effects in vivo were assessed. Five LT patients were treated with metformin and the changes in Treg and Th17 cells examined. Combination therapy decreased Type 1 helper T (Th1) and Th17 cells present after in vitro T cell activation, whereas genes associated with Treg were overexpressed. During in vitro allogeneic stimulation, combination therapy increased Treg cells and decreased T cell proliferation and pro-inflammatory markers. In mice with GVHD, combination treatment decreased the clinical and pathological severity of GVHD. In LT patients, addition of metformin increased the peripheral percentage of CD4+Treg and CD8+Treg cells and decreased CD4+Th17. Our study suggests that the addition of metformin to tacrolimus may improve immunological balance by increasing Treg cells and decreasing Th17 cells.

BackgroundNatural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.MethodsEpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.ResultsThe frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.ConclusionOur data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.

BACKGROUND & AIMS Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. METHODS A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post-treatment and defined as achieving both

Background/Aims There have been numerous efforts to reduce mother-to-child transmission (MTCT) of hepatitis B virus (HBV) with antiviral agents during pregnancy. However, there are limited data regarding the outcomes of pregnant women after delivery. This study was performed to evaluate the efficacy of antiviral agents in preventing MTCT of HBV and maternal long-term outcomes. Methods The HBV-infected pregnant women treated with antiviral agents to prevent MTCT were retrospectively reviewed. Forty-one pregnant women who received telbivudine or tenofovir during late pregnancy (28-34 week) were analyzed. Hepatitis B virus surface antibody (HBsAb) positivity was tested in 43 infants after 7 months of birth. Eleven mothers were followed >1 year after delivery. Results The mean HBV DNA titer before antiviral therapy was 8.67 (6.60–9.49) log copies/mL, and the median age at delivery was 32 years (range, 22–40). Eleven patients were treated with tenofovir and 30 with telbivudine. The median duration was 57 days (range, 23–100), and the median HBV DNA titer at birth was 5.06 log copies/mL (range, 2.06–6.50). Antiviral treatments were associated with significant HBV DNA reduction (P12 months, and an antiviral agent was administered. Conclusions Antiviral treatment during late pregnancy effectively reduced MTCT. Long-term follow-up should be required in such cases. In addition, given that maternal biochemical flare occurred in 18% of mothers, re-administration of antiviral agents might be required.

Background/Aims: Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy. Methods: A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-β and its downstream interferon-stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs. Results: The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-β. After DAA treatment, a significant decrease in the expression levels of IFN-β, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-β and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation. Conclusions: Pretreatment activation of IFN-β response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA-induced alleviation of extrahepatic manifestation of chronic HCV infection. (Clin Mol Hepatol 2018;24:302-310)

Background/Aims: Biliary complications are the most common donor complica tion following living donor liver transplantation (LDLT). The aim of this study is to investigate the long-term outcomes of biliary complications in right lobe adult-to-adult LDLT donors, and to evaluate the efficacy of endoscopic treatment of these donors. Methods: The medical charts of right lobe donors who developed biliary compli cations between June 2000 and January 2008 were retrospectively reviewed. Results: Of 337 right lobe donors, 49 developed biliary complications, including 36 diagnosed with biliary leakage and 13 with biliary stricture. Multivariate anal ysis showed that biliary leakage was associated with the number of right lobe bile duct orifices. Sixteen donors, five with leakage and 11 with strictures, underwent endoscopic retrograde cholangiography (ERC). ERC was clinically successful in treating eight of the 11 strictures, one by balloon dilatation and seven by endobi liary stenting. Of the remained three, two were treated by rescue percutaneous biliary drainage and one by conservative care. Of the five patients with leakage, four were successfully treated using endobiliary stents and one with conservative care. In overall, total 35 improved with conservative treatment. All inserted stents were successfully retrieved after a median 264 days (range, 142 to 502) and there were no recurrences of stricture or leakages during a median follow-up of 10.6 years (range, 8 to 15.2). Conclusions: All donors with biliary complications were successfully treated non-surgically, with most improving after endoscopic placement of endobiliary stents and none showing recurrence on long term follow-up.

Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76–1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41–0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73–83. ©2017 AACR.

Background The epidemiology of Adamantiades-Behcet's disease varies among ethnic populations worldwide. Trends in the incidence of Adamantiades-Behcet's disease have not been investigated based on the Korean National Health Insurance database. Objectives This study investigated the incidence and mortality of Adamantiades-Behcet's disease by age using nationwide population data in Korea. Methods A nationwide population-based cohort study was performed using the Korean National Health Insurance Claims Database from 2006 to 2015. The incidence of Adamantiades-Behcet's disease was calculated by age, sex, calendar year and habitat. And comorbid metabolic diseases were also analysed in patients with Adamantiades-Behcet's disease. Results The annual incidence of Adamantiades-Behcet's disease per 100 000 person-years was 3.976 (2.587 for males and 5.373 for females) from 2006 to 2015. The incidence of Adamantiades-Behcet's disease peaked among people in their 40s (6.561 per 100 000 person-years). Incidence was significantly higher in subjects with comorbid metabolic conditions, such as diabetes mellitus, hypertension and dyslipidemia. The mortality rate per 1000 person-years increased with age in patients with Adamantiades-Behcet's disease. Conclusions This study showed the incidence, prevalence and mortality of Adamantiades-Behcet's disease. Metabolic conditions increased the risk of Adamantiades-Behcet's disease among Koreans.

Background Ursodeoxycholic acid (UDCA) has been known that UDCA has prominent effects on liver, however, there is little known about its influence on autoimmune disease. Here, the benefit of UDCA on arthritis rheumatoid (RA) in vivo was tested. Methods RA mouse were induced using collagen II (CIA, collagen induced arthritis) where the disease severity or UDCA-related signaling pathway such as AMP-activated protein kinase (AMPK) or small heterodimer partner interacting leucine zipper protein (SMILE) was evaluated by westerblot and immunohistochemical staining. Gene expression was measured by realtime-polymerase chain reaction (PCR). Results The administration of UDCA effectively alleviated the arthritic score and incidence with decreased cartilage damage and lipid metabolic parameters. UDCA also suppressed the secretion of pro-inflammatory cytokines. It was confirmed that UDCA upregulated the expression of SMILE and transcriptional activity of PPARγ via controlling AMPK or p38 activity. Conclusions In the present study, the therapeutic effect of UDCA inducing SMILE through AMPK activation in rheumatoid arthritis mouse as well as other autoimmune disease was proposed.

Background The effect of prophylactic antiviral therapy (AVT) on survival of patients with hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine whether prophylactic AVT could improve long-term survival in patients undergoing transarterial chemotherapy (TAC). Methods Between 2002 and 2016, 2860 newly diagnosed HBV-related patients with HCC treated with TAC were screened to analyze 2 groups based on prophylactic use of antivirals. Treatment effects were analyzed using propensity score (PS) matching (1:1) separately for the entire cohort and each subgroup. The primary endpoint was overall survival. Results A total of 1547 patients met the inclusion criteria and 1084 were PS matched for the 2 groups. Median follow-up duration was 16.55 months. In the entire unmatched cohort, patients receiving prophylactic AVT survived significantly longer than those who did not. Among AVT-untreated patients, baseline high viremia and HBV reactivation during treatment were significantly associated with shorter survival. Regarding types of antivirals, survival was significantly longer for patients receiving high-potency antivirals than those receiving low-potency antivirals. Survival differed with antiviral response. In the PS-matched cohort, the prophylactic AVT group survived significantly longer than the nonprophylactic group, irrespective of viral status or tumor stage. Prophylactic AVT remained an independent factor for survival. The association of prophylactic AVT with decreased risk of mortality persisted in patient subgroups after adjusting for baseline risk factors. Sensitivity analyses also confirmed estimated treatment effects. Conclusions Prophylactic AVT is associated with significantly improved long-term survival among patients undergoing TAC. High-potency antivirals are indicated for this approach. Hepatitis B virus–associated morbidity is a well-known complication during transarterial chemotherapy (TAC). Our large-scale study demonstrated that prophylactic therapy with high-potency antivirals provides a significantly better survival in TAC-treated patients, irrespective of baseline viremia status or tumor stage.

Tumor-associated immune response plays a critical role in cancer pathogenesis. This study evaluated clinical implications of T cell cytokines and regulatory T cells (Tregs) in HCC patients treated with TACE. Whole blood was obtained for analysis of T cell cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-22, IFN-γ, and TNF-α) and Tregs from 142 HCC patients. Patients with CTP class A had a significantly lower proportion of detectable IL-4 or IL-6, but a higher proportion of detectable IL-22 than patients with CTP class B/C. IL-6 level was well correlated with tumor stage and undetectable IL-17A was associated with extrahepatic metastasis. The overall survival rate was significantly higher in patients who had undetectable IL-6 or detectable IL-22 than patients who did not. IL-6 among cytokines remained independently predictive factor for survival. Increased IFN-γ/IL-10 ratio and no increase in IL-6 level following TACE were associated with prolonged survival, and baseline Tregs could affect Th1/Th2 balance. T cell cytokines are associated with a variety of clinical aspects of HCC, and IL-6 is the most significant predictor of survival. A shift toward increased Th1 response and no increase in IL-6 level exert favorable immunologic effects on HCC prognosis.

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P &lt, 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.

Background/aims Hepatic damage during transarterial chemoembolization (TACE) is a critical complication in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Apart from its role in preventing HBV reactivation, there is some evidence for the benefits of preemptive antiviral therapy in TACE. This study evaluated the effect of preemptive antiviral therapy on acute hepatic deterioration following TACE. Methods This retrospective observational study included a prospectively collected cohort of 108 patients with HBV-related HCC who underwent TACE between January 2007 and January 2013. Acute hepatic deterioration following TACE was evaluated. Treatment-related hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, elevation of the bilirubin level, prolongation of prothrombin time, or elevation of the Child-Pugh score by ≥2 within 2 weeks following TACE. Univariate and multivariate analyses were conducted to identify factors influencing treatment-related decompensation. Preemptive antiviral therapy involves directing prophylaxis only toward high-risk chronic hepatitis B patients in an attempt to prevent the progression of liver disease. We regarded at least 6 months as a significant duration of preemptive antiviral treatment before diagnosis of HCC. Results Of the 108 patients, 30 (27.8%) patients received preemptive antiviral therapy. Treatment-related decompensation was observed in 25 (23.1%) patients during the follow-up period. Treatment-related decompensation following TACE was observed more frequently in the nonpreemptive group than in the preemptive group (29.5% vs. 6.7%, P=0.008). In the multivariate analysis, higher serum total bilirubin (Hazard ratio [HR] =3.425, P=0.013), hypoalbuminemia (HR=3.990, P=0.015), and absence of antiviral therapy (HR=7.597, P=0.006) were significantly associated with treatment-related hepatic decompensation. Conclusion Our findings suggest that preemptive antiviral therapy significantly reduces the risk of acute hepatic deterioration. Preventing hepatic deterioration during TACE by applying such a preemptive approach may facilitate the continuation of anticancer therapy and thus improve long-term outcomes.

Background and aims Entecavir (ETV) is a potent nucleoside analogue with high genetic barrier to resistance. In this study, real-life clinical experiences in the long-term use of ETV and the durability of its off-treatment effectiveness were analyzed. Materials and methods This study was based on a large real-life cohort of 2240 chronic hepatitis B patients treated with ETV between January 2006 and December 2012 using a centralized electronic data repository. Results Among 2240 patients, 804 patients were treatment naive and underwent ETV monotherapy. Their mean treatment duration was 712±493 days, with a cumulative proportion of patients achieving HBV DNA less than 300 copies/ml in 85.8, 95.7, and 97.6% at years 1, 2, and 3, respectively. Predictors for earlier virologic response were female sex, lower HBV DNA, higher alanine transaminase, lower platelet count, and HBeAg negativity at baseline. In patients who achieved virologic response and HBeAg loss, the cumulative relapse rate was 91.3% in 2 years after the cessation of treatment. During the treatment, 34 patients developed hepatocellular carcinoma, among whom 30 patients had cirrhosis before treatment initiation. ETV treatment showed efficient virologic response as the treatment duration was extended, but off-treatment efficacy was not durable, and the antiviral treatment showed some limitation in preventing hepatocellular carcinoma among liver cirrhosis patients, implying that treatment cessation should be taken into consideration more carefully. Conclusion This study from a real-life cohort may provide data on treating chronic hepatitis B patients more close to everyday clinical practice.

Cancer metastasis is strongly correlated with epithelial-mesenchymal transition (EMT), in which transforming growth factor-β (TGF-β) signaling plays a central role. CD44 has emerged as a cancer stem cell (CSC) marker that strongly induces EMT together with TGF-β1. This study aimed to investigate the link between high CD44 and TGF-β1 levels during EMT in HCC cell lines. FACS analysis showed high expression of CD44 in TGF-β1-positive SNU-368 cells and TGF-β1-negative SNU-354 cells. SNU-368 CD44(+) cells showed EMT through up-regulation of the AKT/GSK-3β/β-catenin pathway. By comparison, SNU-354 CD44(+) cells showed only increased N-cadherin expression, which was not accompanied by a decrease in E-cadherin expression, and also down-regulated the AKT/GSK-3β/β-catenin pathway. However, TGF-β1-stimulated SNU-354 cells (CD44/TGF-β1(+)) exhibited lower E-cadherin and higher N-cadherin expression with increased AKT/GSK-3β/β-catenin pathway activity. CD44/TGF-β1(+) SNU-354 cells also showed enhanced migration and formed larger spheres, while the TGF-β1-induced stem cell properties returned to their original state with the TGF-β1 inhibitor SB431542. SB431542-treated SNU-368 (CD44/TGF-β1(-)) cells also showed diminished N-cadherin and AKT/GSK-3β/β-catenin pathway activity and further decreased cell motility in a wound healing assay. However, CD44 knockdown in SNU-354 cells did not induce EMT even after treatment with TGF-β1. Finally, double inhibition of both CD44 and TGF-β1 further decreased migration and sphere formation more strongly than a single inhibition in SNU-368 cells. In conclusion, the current study demonstrated the synergistic interactions between CD44 and TGF-β1 in EMT induction and CSC properties through the AKT/GSK-3β/β-catenin pathway in HCC cells.

Hepatic osteodystrophy has been reported in patients with various chronic liver diseases, including liver cirrhosis. However, it has not been well investigated in patients with hepatitis B virus infection. The aim of this study was to investigate the association between hepatitis B surface antigen (HBsAg) seropositivity and bone mineral density (BMD) in a population representative of normal Koreans.Subjects with both HBsAg and BMD levels examined during the 2008-2010 Korea National Health and Nutrition Examination Surveys were included. HBsAg-seropositive (+) subjects were compared with those who were HBsAg-seronegative (-). BMD was measured at the lumbar spine and femur by dual-energy X-ray absorptiometry. Multivariable logistic regression was performed for BMD .In total, 11,306 participants were included in this study, among which 423 (3.7 %) were HBsAg(+): 153 premenopausal female (3.4 %), 83 postmenopausal female (3.5 %), and 187 male (4.2 %). Multivariable logistic regression analysis adjusted for age and body mass index showed that HBsAg(+) male had significantly lower BMD of the femoral neck than HBsAg(-) male (0.810 ± 0.009 vs. 0.827 ± 0.002 g/cm(2), p = 0.035). Further adjustment for waist circumference, smoking, drinking, exercise, income, occupation, and vitamin D levels showed that HBsAg(+) male had significantly lower BMD of the femur neck (0.810 ± 0.010 vs. 0.831 ± 0.002 g/cm(2), p = 0.032) and lumbar spine (0.953 ± 0.011 vs. 0.974 ± 0.003 g/cm(2), p = 0.049) than HBsAg(-) male.HBsAg seropositivity was significantly associated with lower BMD in male. Future long-term prospective studies investigating bone turnover markers and hormones are needed to better understand the pathophysiology and clinical significance of chronic hepatitis B virus-related hepatic osteodystrophy.

Background/Aims: We compared the recurrence of hepatocellular carcinoma (HCC) and the survival of patients who received radiofrequency ablation (RFA) after transarterial chemoembolization (TACE) with patients treated with TACE or RFA alone. Methods: This study included 201 patients with HCC, who were consecutively enrolled at Seoul St. Mary’s Hospital between December 2004 and February 2010. Inclusion criteria were a single HCC ≤ 5.0 cm or up to three HCCs ≤ 3.0 cm. We used a propensity score model to compare HCC patients (n = 87) who received RFA after TACE (TACE + RFA) with those who received TACE (n = 71) or RFA alone (n = 43). Results: The median follow-up period was 33.3 months (range, 6.8 to 80.9). The TACE + RFA group showed significantly lower local recurrence than the RFA or TACE groups (hazard ratio [HR], 0.309; 95% confidence interval [CI], 0.130 to 0.736; p = 0.008; and HR, 0.352; 95% CI, 0.158 to 0.787; p = 0.011, respectively). The overall survival was significantly better in the TACE + RFA group compared to the RFA group (HR, 0.422; 95% CI, 0.185 to 0.964; p = 0.041). However, the survival benefit was not different between the TACE + RFA and TACE groups (p = 0.124). Subgroup analysis showed that among patients with a tumor size < 3 cm, the TACE + RFA group had significantly better long-term survival than those in the TACE or RFA groups (p = 0.017, p = 0.004, respectively). Conclusions: TACE + RFA combination treatment showed favorable local recurrence and better overall survival rates in early-stage HCC patients. Patients with tumors < 3 cm are likely to benefit more from TACE + RFA combination treatment. Additional studies are needed for the selection of suitable HCC patients for TACE + RFA treatment.

BACKGROUND AND PURPOSE: Awareness of the potential for exposure to high doses of radiation from interventional radiologic procedures has increased. The purpose of this study was to evaluate image quality and dose reduction of low-dose cerebral angiography during diagnostic and therapeutic procedures for intracranial aneurysms. MATERIALS AND METHODS: A retrospective review of 1137 prospectively collected patients between January 2012 and June 2014 was performed. Beginning in April 2013, a dose-reduction strategy was implemented. Subjective image-quality assessment of 506 standard and 540 low-dose cerebral angiography images was performed by 2 neuroradiologists using a 5-point scale and was tested using noninferiority statistics. Radiation dose-area product and air kerma of 1046 diagnostic and 317 therapeutic procedures for intracranial aneurysms were analyzed and compared between groups before (group 1) and after (group 2) clinical implementation of a dose-reduction strategy. RESULTS: The image quality of the low-dose cerebral angiography was not inferior on the basis of results from the 2 readers. For diagnostic cerebral angiography, the mean dose-area product and air kerma were 140.8 Gy×cm(2) and 1.0 Gy, respectively, in group 1 and 82.0 Gy×cm(2) and 0.6 Gy in group 2 (P < .001, P < .001). For the neurointerventional procedure, the mean dose-area product and air kerma were 246.0 Gy×cm(2) and 3.7 Gy, respectively, in group 1 and 169.8 Gy×cm(2) and 3.3 Gy in group 2 (P < .001, P = .291). CONCLUSIONS: With low-dose cerebral angiography, image quality was maintained, and implementation of dose-reduction strategies reduced radiation doses in patients undergoing diagnostic and neurointerventional procedures for intracranial aneurysms.

Long-term results on hepatitis B virus (HBV) reactivation in patients with resolved infection during anti-cancer therapy are unknown. This study investigated long-term risk and therapeutic endpoints including hepatitis B surface antigen (HBsAg) seroclearance following antiviral therapy in patients developing reactivation of resolved HBV. The study included 528 consecutive HBsAg-negative/hepatitis B core antibody-positive patients who underwent rituximab treatment or hematopoietic stem cell transplantation (HSCT) between 2006 and 2016. Long-term outcomes of patients with reactivation after antiviral therapy were examined in comparison with 37 HBsAg-positive chronic carriers under the same medical settings. The 7-year cumulative rate of HBV reactivation was 10.8% and 57.9% in patients receiving rituximab treatment and HSCT, respectively. After antiviral initiation, patients with reactivation of resolved HBV showed significantly higher 1-year cumulative rates of hepatitis B e antigen seroconversion (69.2% vs. 22.6%, P = 0.008) and HBsAg seroclearance (61.8% vs. 3.3%, P

Recipients of liver transplantation (LT) require long-term immunosuppressive drug treatment, but lifelong immunosuppressive treatment has severe side effects. It is known that some LT recipients develop immune tolerance, and although the development of such operational tolerance should allow a decrease in the burden of immunosuppressive drug treatment, the factors that indicate operational tolerance are not clear. This study aimed to monitor immunological markers over time in LT recipients to identify those markers indicating the development of operational tolerance. We performed a prospective pilot study measuring immune markers, including the ratio of regulatory T (Treg) and T helper (Th) 17 cells in peripheral blood in the 14 most immunologically stable patients among 70 clinically stable LT recipients. The doses of immunosuppressive drugs given to these 14 LT recipients were tapered over time and they were monitored for immunological markers related to the development of immune tolerance. As the doses of immunosuppressive drugs were reduced, the Treg/Th17, Th1/Th17, and CD8/Th17 ratio in tolerant recipients was significantly increased compared with that of nontolerant recipients. These results suggest that monitoring of changes in the immune makers, including Treg/Th17 ratio during tapering of immunosuppression may allow prediction of the development of tolerance.

Cucurbitacin E (CuE) is a biochemical compound found in plants that are members of the family CuE has been studied for its roles in anti-inflammation and the inhibition of angiogenesis as well as for its properties as an antioxidant. CuE is a new agent that was identified as a selective inhibitor of the signal transducer and activator of transcription 3 (STAT3)-related pathway. STAT3, a pivotal transcription factor for Th17 differentiation, is critical for T cell alloactivation in acute graft-versus-host disease (aGvHD). We investigated whether CuE attenuates the development of aGvHD through the suppression of Th17 cells. The alloreactive proliferation of mouse and human T cells was reduced by CuE treatment. CuE also decreased pro-inflammatory cytokines, such as IL-17 and IFN-γ, in alloreactive T cells. STAT3-responsive and IL-17A-promoter activities were also suppressed by CuE treatment, confirming that activated STAT3 was decreased by CuE treatment. To construct an aGvHD-induced mouse line, splenocytes and bone marrow cells from C57BL/6 mice were transplanted into BALB/c mice with complete mis-matched major histocompatibility complex molecules. CuE was administered to aGvHD animals 3 days per week via intraperitoneal injection. CuE attenuated the severity of aGvHD disease-related scores compared to the vehicle group. CuE inhibited skin inflammation and fibrosis, as evidenced by the expression of α-Sma and Col-I in aGvHD mice compared to the vehicle group. Additionally, aGvHD mice treated with CuE showed improved histopathological features in the small and large intestines, whereas the vehicle group showed collapsed villi in the small intestine and cryptic structures in the large intestine. We also observed a marked reduction of pro-inflammatory cytokines in the intestinal tissue. Collectively, our data suggest that CuE could serve as a therapeutic agent for patients with aGvHD.

Epstein-Barr virus (EBV) causes various acute and chronic diseases. Chronic active EBV infection (CAEBV) is characterized by infectious mononucleosis-like symptoms that persist for more than 6 months with high viral loads in peripheral blood and/or an unusual pattern of anti-EBV antibodies. Severe CAEBV is associated with poor prognosis with severe symptoms, an extremely high EBV-related antibody titer, and hematologic complications that often include hemophagocytic lymphohistiocytosis. However, CAEBV which led to the development of aplastic anemia (AA) has not been reported yet. A 73-year-old woman was admitted to our hospital with intermittent fever, general weakness and elevated liver enzymes. In the serologic test, EBV-related antibody titer was elevated, and real-time quantitative-PCR in peripheral blood showed viral loads exceeding 104 copies/µg DNA. Liver biopsy showed characteristic histopathological changes of EBV hepatitis and in situ hybridization with EBV-encoded RNA-1 was positive for EBV. Pancytopenia was detected in peripheral blood, and the bone marrow aspiration biopsy showed hypocellularity with replacement by adipocytes. AA progressed and the patient was treated with prednisolone but deceased 8 months after the diagnosis due to multiple organ failure and opportunistic infection. Herein, we report a rare case of severe CAEBV in an adult patient accompanied by AA and persistent hepatitis. (Korean J Gastroenterol 2016;67:39-43)

Background: Evaluating a change in the screening rate for hepatocellular carcinoma (HCC) is critical for understanding screening implementation, and whether targeted population groups are receiving proper screening. This study examined recent nationwide changes in HCC screening use among hepatitis B virus (HBV)-infected populations after the introduction of the Korean National Cancer Screening Program and predictors of screening adherence. Methods: We analyzed 165 and 276 participants ≥40 years of age who were hepatitis B surface antigen-positive from 2001 (14,936 participants) to 2010-2011 (9159 participants) Korea National Health and Nutrition Examination Surveys, respectively. Demographic data, socioeconomic factors, and HCC screening use were collected by means of self-reported questionnaires. Results: The rate of HCC screening within the previous 2 years increased significantly from 17.5% in 2001 to 40.3% in 2010-2011 (P < 0.0001). The rate of HCC screening use increased from 2001 to 2010-2011 in all study populations. Subjects who had a higher income status and were aware of their infection were more likely to have undergone recent HCC screening. Conclusions: This study showed a substantial increase in HCC screening in high-risk HBV-infected subjects from 2001 to 2010-2011. However, the HCC screening participation rate remained suboptimal despite the introduction of the nationwide screening program. Efforts should be made to identify high-risk individuals and increase attendance at HCC screening events among high-risk groups.