Showing papers by "Kwang Hyub Han published in 2016"

Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients

Abstract: Little is known about stopping rules of nucelos(t)ide analog (NA) treatment for chronic hepatitis B (CHB). A total of 113 consecutive patients with CHB (45 HBeAg-positive and 68 HBeAg-negative CHB patients), who met the cessation criteria of NA treatment as per the Asian-Pacific Association for the Study of the Liver (APASL) guideline, were enrolled in this prospective cohort study. The primary endpoint was to evaluate virological relapse (VR) rate within 1 year, which was defined as reappearance of hepatitis B virus (HBV)–DNA > 2000 IU/mL after cessation of NA treatment. In this cohort, entecavir was used in 81 (71.7 %) and lamivudine in 32 (28.3 %) patients. Within 1 year after NA treatment, VR occurred in 26 (57.8 %) HBeAg-positive patients and in 37 (54.4 %) HBeAg-negative patients. In univariate and subsequent multivariate analysis, age > 40 years [odds ratio (OR) 10.959; 95 % confidence interval (CI) 2.211–54.320; P = 0.003) and a pre-treatment HBV DNA level >2000,000 IU/mL (OR 9.285; 95 % CI 1.545–55.795; P = 0.036) were identified as independent risk factors for VR in HBeAg-positive patients, and age > 40 years (OR 6.690; 95 % CI 1.314–34.057; P = 0.022) and an end-of-treatment HBcrAg level >3.7 log IU/mL (OR 3.751; 95 % CI 1.187–11.856; P = 0.024) were identified in HBeAg-negative patients. During follow up, neither hepatic decompensation nor hepatocellular carcinoma (HCC) occurred, and HBV DNA suppression was achieved in all patients who received antiviral re-treatment. Our data suggested that the APASL stopping rule could be applied if a candidate was properly selected using individual risk factors. However, regular monitoring should be performed after cessation of NA treatment and long-term outcomes need to be evaluated further.

Combined use of AFP, PIVKA-II, and AFP-L3 as tumor markers enhances diagnostic accuracy for hepatocellular carcinoma in cirrhotic patients.

Abstract: Objective: As data on the effectiveness of tumor markers in detecting hepatocellular carcinoma (HCC) in cirrhotic patients are limited, we investigated the diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3). Material and methods: This retrospective study enrolled 361 cirrhotic patients with HCC, and 276 cirrhotic patients without HCC occurrence. Results: Most patients were men (n = 431, 67.7%); the median age was 57.0 years. The main etiology of chronic liver disease was chronic hepatitis B (n = 467, 73.3%). The sensitivity and specificity of combined three biomarkers was 87.0 and 60.1% in overall HCC, and 75.7 and 60.1% in early HCC, respectively (cutoff: 20 ng/mL for AFP, 40 mAU/mL for PIVKA-II, and 5% for AFP-L3). The area under the receiver operating characteristic curve (AUROC) for HCC diagnosis was 0.765 (95% confidence interval [CI], 0.728–0.801) for AFP; 0.823 (95%...

Discrimination of Nonalcoholic Steatohepatitis Using Transient Elastography in Patients with Nonalcoholic Fatty Liver Disease.

Abstract: Background/aims The accuracy of noninvasive markers to discriminate nonalcoholic steatohepatitis (NASH) is unsatisfactory We investigated whether transient elastography (TE) could discriminate patients with NASH from those with nonalcoholic fatty liver disease (NAFLD) Methods The patients suspected of NAFLD who underwent liver biopsy and concomitant TE were recruited from five tertiary centers between November 2011 and December 2013 Results The study population (n = 183) exhibited a mean age of 406 years and male predominance (n = 111, 607%) Of the study participants, 89 (486%) had non-NASH and 94 (514%) had NASH The controlled attenuation parameter (CAP) and liver stiffness (LS) were significantly correlated with the degrees of steatosis (r = 0656, P 250 dB/m; P = 0013, OR 3399, 95% CI 1295–8291 for LS>70 kPa; and P 60 IU/L], we developed a novel CLA model for discriminating patients with NASH The CLA model showed good discriminatory capability, with an area under the receiver operating characteristic curve (AUROC) of 0812 (95% CI 0724–0880) To assess discriminatory power, the AUROCs, as determined by the bootstrap method, remained largely unchanged between iterations, with an average value of 0833 (95% CI 0740–0893) Conclusion This novel TE-based CLA model showed acceptable accuracy in discriminating NASH from simple steatosis However, further studies are required for external validation

No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection

Abstract: Postmarketing cases of hepatitis B virus (HBV) reactivation during hepatitis C treatment have been reported. We analyzed serum samples from patients in a clinical trial of ledipasvir-sofosbuvir in Taiwan and Korea. Of the 173 patients enrolled, 103 (60%) had been previously infected with HBV. None showed evidence of HBV reactivation.

Addition of tumor multiplicity improves the prognostic performance of the hepatoma arterial-embolization prognostic score.

Abstract: Background & Aims The hepatoma arterial-embolization prognostic (HAP) score predicts survival outcome in patients with hepatocellular carcinoma (HCC) treated with trans-arterial chemoembolization (TACE). We validated the HAP score in Korean subjects with HCC and investigated whether its prognostic performance is improved with additional parameters. Methods A total of 280 patients with HCC treated with TACE between 2003 and 2009 were included. Validation and modification of HAP score were performed based on multivariate Cox regression models. Results The median age of the study population (211 men, 69 women) was 60 years. Viral etiology of HCC accounted for 80.4% (n = 181 for hepatitis B, 44 for hepatitis C). The median overall survival (OS) was 40.5 months. On multivariate analysis, together with the original components of the HAP score (serum albumin 0.9 mg/dl, alpha-foetoprotein >400 ng/ml, and tumor size >7 cm), tumor number ≥2 was selected as an independent unfavorable prognostic factor for OS (hazard ratio 2.3; P < 0.001). Accordingly, a modified HAP-II (mHAP-II) score was established by adding tumor number ≥2. Although both HAP and mHAP-II scores discriminated the four different risk groups (log-rank test, all P < 0.001), the mHAP-II score performed significantly better than the HAP score, as per the areas under receiver-operating curves predicting OS at 3 years (0.717 vs. 0.658) and 5 years (0.728 vs. 0.645), respectively (all P < 0.05). Conclusions Although the HAP score predicted OS for Korean subjects with HCC undergoing TACE, the addition of tumor number significantly improved the prognostic performance. The mHAP-II score can be used for accurate prognostication and selection of optimal candidates for TACE.

Risk prediction for patients with hepatocellular carcinoma undergoing chemoembolization: development of a prediction model

Abstract: Backgrounds & Aims We aimed to generate and validate a novel risk prediction model for patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Methods Patients receiving TACE as the first-line therapy between 2006 and 2009 were selected from the databases of two major tertiary hospitals in Korea. This study population was randomly assigned into training (n = 340) and validation (n = 145) sets. From a multivariate Cox-regression model for overall survival (OS), tumour Size, tumour Number, baseline Alpha-foetoprotein level, Child–Pugh class and Objective radiological Response after the first TACE session were selected and then scored to generate a 10-point risk prediction model (named as “SNACOR” model) in the training set. Thereafter, the prognostic performance was assessed in the validation set. Results In the training set, the time-dependent areas under receiver-operating characteristic curves (AUROCs) for OS at 1-, 3- and 6-years were 0.756, 0.754 and 0.742 respectively. According to the score of the SNACOR model, patients were stratified into three groups; low- (score 0–2), intermediate- (score 3–6) and high-risk group (score 7–10) respectively. The low-risk group had the longest median OS (49.8 months), followed by intermediate- (30.7 months) and high-risk group (12.4 months) (log-rank test, P < 0.001). Compared with the low-risk group, the intermediate-risk (hazard ratio [HR] 2.13, P < 0.001) and high-risk group (HR 6.17, P < 0.001) retained significant risks of death. Similar results were obtained in the validation set. Conclusion A simple-to-use SNACOR model for patients with HCC treated with TACE might be helpful in appropriate prognostification and guidance for decision of further treatment strategies.

Consensus for Radiotherapy in Hepatocellular Carcinoma from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials

Abstract: A consensus meeting to develop practice guidelines and to recommend future clinical trials for radiation therapy (RT), including external beam RT (EBRT), and selective internal RT (SIRT) in hepatocellular carcinoma (HCC) was held at the 5th annual meeting of the Asia-Pacific Primary Liver Cancer Expert consortium. Although there is no randomized phase III trial evidence, the efficacy and safety of RT in HCC has been shown by prospective and retrospective studies using modern RT techniques. Based on these results, the committee came to a consensus on the utility and efficacy of RT in the management of HCC according to each disease stage as follows: in early and intermediate stage HCC, if standard treatment is not compatible, RT, including EBRT and SIRT can be considered. In locally advanced stage HCC, combined EBRT with transarterial chemoembolization or hepatic arterial infusion chemotherapy, and SIRT can be considered. In terminal stage HCC, EBRT can be considered for palliation of symptoms and reduction of morbidity caused by the primary tumor or its metastases. Despite the currently reported benefits of RT in HCC, the committee agreed that there is a compelling need for large prospective studies, including randomized phase III trial evidence evaluating the role of RT. Specifically studies evaluating the efficacy and safety of sequential combination of EBRT and SIRT are strongly recommended.

Phase I dose-escalation study of helical intensity-modulated radiotherapy-based stereotactic body radiotherapy for hepatocellular carcinoma

Abstract: // Jun Won Kim 1 , Jinsil Seong 2 , Ik Jae Lee 1 , Joong Yeol Woo 2 , Kwang-Hyub Han 3 1 Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 2 Department of Radiation Oncology, Yonsei Cancer Hospital, Yonsei University College of Medicine, Seoul, Korea 3 Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Correspondence to: Jinsil Seong, email: jsseong@yuhsac Keywords: stereotactic body radiotherapy, hepatocellular carcinoma, dose escalation, intensity-modulated radiotherapy Received: March 20, 2016 Accepted: April 16, 2016 Published: May 18, 2016 ABSTRACT Background: Phase I trial was conducted to determine feasibility and toxicity of helical intensity-modulated radiotherapy (IMRT)-based stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) Results: Eighteen patients (22 lesions) were enrolled With no DLT at 52 Gy (13 Gy/fraction), protocol was amended for further escalation to 60 Gy (15 Gy/fraction) Radiologic complete response rate was 889% Two outfield intrahepatic, 2 distant, 4 concurrent local and outfield, and 1 concurrent local, outfield and distant failures (no local failure at dose levels 3–4) occurred The worst toxicity was grade 3 hematologic in five patients, with no gastrointestinal toxicity > grade 1 At median follow-up of 28 months for living patients, 2-year local control, progression-free (PFS), and overall survival rates were 713%, 494% and 693%, respectively Multi-segmental recurrences prior to SBRT was independent prognostic factor for PFS ( p = 0033) Materials and Methods: Eligible patients had Child-Pugh’s class A or B, unresectable HCC, ≤ 3 lesions, and cumulative tumor diameter ≤ 6 cm Starting at 36 Gy in four fractions, dose was escalated with 2 Gy/fraction per dose-level CTCAE v 30 ≥ grade 3 gastrointestinal toxicity and radiation induced liver disease defined dose-limiting toxicity (DLT) Conclusions: Helical IMRT-based SBRT was tolerable and showed encouraging results Confirmatory phase II trial is underway

Transarterial chemoembolization versus transarterial radioembolization in hepatocellular carcinoma: optimization of selecting treatment modality.

Abstract: Hepatocellular carcinoma (HCC) of intermediate stage consists of diverse tumor and patient factors in terms of tumor number, size and liver function resulting in various outcomes given by transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using radioactive isotope, β-ray emitting Yttrium-90 with a short half-life and penetration depth, is an emerging intra-arterial brachytherapy characterized by potent anti-cancer effect given by radiation but minimal embolic effect. Although there is lack of study directly comparing the efficacy and safety between TACE and TARE in patients with unresectable HCC, several retrospective or small-scaled studies suggest that overall efficacy indicated by overall survival and time to progression is similar between two modalities and TARE has a superiority in the safety including postembolization syndrome, hospitalization days and outpatient-based therapy. In advanced HCC with portal vein (PV) invasion, TACE is not consistently recommended due to risk of hepatic decompensation or failure after procedure. On the contrary, available data suggest that TARE might be a promising treatment option in HCC with PV thrombosis if patient's liver function is preserved and the level of PV invasion is less than main trunk. Ongoing trials comparing TARE and sorafenib in advanced HCC would elucidate the role of this locoregional therapy. The need of a multidisciplinary team, complex steps of procedure and high cost of TARE are the hurdles to widespread recommendation of this therapy in intermediate or advanced HCC. The optimization of selection between TACE and TARE might be dependent on availability, experience, tumor factors and patient factors.

Autoimmune liver diseases in the Asia-Pacific region: Proceedings of APASL symposium on AIH and PBC 2016

Abstract: During the 25th annual meeting of the Asia–Pacific Association for the Study of the Liver (APASL 2016) in Tokyo, we organized and moderated an inaugural satellite symposium on the autoimmune liver diseases, autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Following the keynote lecture by John M. Vierling (USA), speakers from the Asia–Pacific region provided an up-to-date perspective on the epidemiology, clinical practice and research in AIH and PBC in the Asia–Pacific region. Although epidemiology and clinical features of AIH seem to be similar in East Asia compared to those in western countries, the majority of patients with AIH are detected at an advanced stage and have higher mortality rates in South Asia, indicating an unmet need for earlier diagnosis and the initiation of appropriate immunosuppressive treatment. PBC is more commonly seen in Australia and East Asia. As of 2016, clinical practice guidelines (CPG) for PBC have been published in Japan and China. Ursodeoxycholic acid (UDCA) is recommended as a first-line therapy by both CPG. Nevertheless, one of the unmet therapeutic needs in PBC is the treatment of patients refractory to or intolerant of UDCA. It is of interest that the prevalence of chronic hepatitis B (CHB) in PBC patients was low in Taiwan and mainland China where the prevalence of CHB is very high. In this review, we overview this exciting and epoch-making symposium.

Living Donor Liver Transplantation for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis after Concurrent Chemoradiation Therapy

Abstract: Locally advanced hepatocellular carcinoma (HCC) with portal vein thrombosis carries a 1-year survival rate <10%. Localized concurrent chemoradiotherapy (CCRT), followed by hepatic arterial infusion chemotherapy (HAIC), was recently introduced in this setting. Here, we report our early experience with living donor liver transplantation (LDLT) in such patients after successful down-staging of HCC through CCRT and HAIC. Between December 2011 and September 2012, eight patients with locally advanced HCC at initial diagnosis were given CCRT, followed by HAIC, and underwent LDLT at the Severance Hospital, Seoul, Korea. CCRT [45 Gy over 5 weeks with 5-fluorouracil (5-FU) as HAIC] was followed by HAIC (5-FU/cisplatin combination every 4 weeks for 3-12 months), adjusted for tumor response. Down-staging succeeded in all eight patients, leaving no viable tumor thrombi in major vessels, although three patients first underwent hepatic resections. Due to deteriorating liver function, transplantation was the sole therapeutic option and offered a chance for cure. The 1-year disease-free survival rate was 87.5%. There were three instances of post-transplantation tumor recurrence during follow-up monitoring (median, 17 months; range, 10-22 months), but no deaths occurred. Median survival time from initial diagnosis was 33 months. Four postoperative complications recorded in three patients (anastomotic strictures: portal vein, 2; bile duct, 2) were resolved through radiologic interventions. Using an intensive tumor down-staging protocol of CCRT followed by HAIC, LDLT may be a therapeutic option for selected patients with locally advanced HCC and portal vein tumor thrombosis.

The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter

Abstract: PURPOSE The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ0.407) or fasting C-peptide (ρ0.402) were demonstrated. CONCLUSION Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.

Gamma-glutamyl transpeptidase-to-platelet ratio is an independent predictor of hepatitis B virus-related liver cancer.

Abstract: Background and Aim Gamma-glutamyl transpeptidase-to-platelet ratio (GPR) can evaluate the degree of liver fibrosis. We investigated whether GPR can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Methods We retrospectively evaluated 1109 CHB patients that were enrolled between 2006 and 2012, and all patients had available data for the assessment of GPR at enrollment. Three risk groups were defined according to tertile stratification: GPR 0.24, high-risk (n = 369 [33.2%]). The predictive accuracy of GPR, fibrosis-4 (FIB-4), and aspartate transaminase-to-platelet ratio index (APRI) in predicting HCC development was tested. Results The median age of the study population (746 men and 363 women) was 50 years. During the follow-up period (median, 32 months; interquartile range, 19–57 months), 69 (6.2%) patients developed HCC. Together with age, male gender, diabetes mellitus, antiviral therapy, serum albumin, and alpha-fetoprotein, the relative risk of HCC development significantly increased from low-risk to high-risk GPR groups (hazard ratio [HR], up to 29.5; adjusted HR, up to 10.6; all P < 0.05). In addition, FIB-4 was calculated to be a significantly high relative risk of HCC development (HR, up to 20.1; adjusted HR, up to 7.3; all P < 0.05), whereas APRI was not (P = 0.168). The cumulative incidence of HCC development was significantly different among three risk groups (P < 0.001, log-rank test). Conclusions This study suggests that GPR can be used as a noninvasive marker to assess the risk of HCC development in CHB patients.

Red cell volume distribution width-to-platelet ratio in assessment of liver fibrosis in patients with chronic hepatitis B

Abstract: Background & Aims Precise assessment of liver fibrosis is necessary in patients with chronic liver disease. We investigated the performance of red cell volume distribution width-to-platelet ratio for the assessment of liver fibrosis in patients with chronic hepatitis B. Methods A total of 482 consecutive patients with chronic hepatitis B who underwent liver biopsy between October 2005 and May 2014 were recruited. Liver stiffness was measured using transient elastography. FIB-4 score, red cell volume distribution width-to-platelet ratio and the aspartate aminotransferase-to-platelet ratio index were also assessed. Results A total of 271 (56.2%) patients were males. The median age was 44 years. F1, F2, F3 and F4 fibrosis stages were identified in 68 (14.1%), 137 (28.4%), 64 (13.3%) and 213 (44.2%) of the patients respectively. The mean red cell volume distribution width-to-platelet ratio increased with liver fibrosis severity: F1, 0.065; F2, 0.077; F3, 0.097 and F4, 0.121 (P < 0.01). The area under the receiver operating characteristic curve of the red cell volume distribution width-to-platelet ratio for predicting significant fibrosis (≥F2) was 0.747. This result was inferior to transient elastography (0.866, P = 0.004), but comparable to FIB-4 (0.782, P = 0.427) and aspartate aminotransferase-to-platelet ratio index (0.716, P = 0.507). The area under the receiver operating characteristic curve of red cell volume distribution width-to-platelet ratio for predicting cirrhosis (F4) was 0.811, which was inferior to liver stiffness (0.915, P < 0.001), but comparable to FIB-4 (0.804, P = 0.805) and superior to aspartate aminotransferase-to-platelet ratio index (0.680, P < 0.001). Conclusions The accuracy of red cell volume distribution width-to-platelet ratio was acceptable for the assessment of liver fibrosis in patients with chronic hepatitis B. When transient elastography is not available, red cell volume distribution width-to-platelet ratio assessment is a simple method that can be used to reduce the need for liver biopsy.

Predicting Liver-Related Events Using Transient Elastography in Chronic Hepatitis C Patients with Sustained Virological Response.

Abstract: Background/Aims: Few studies have investigated prognostic factors for the development of liver-related events (LREs) in patients with chronic hepatitis C (CHC) who achieve sustained virological response (SVR). Methods: We analyzed 190 patients with CHC who achieved SVR after treatment with pegylated interferon (peg-IFN) plus ribavirin. LREs were defined as any complications related to cirrhosis, hepatocellular carcinoma (HCC), or liver-related mortality. Results: The mean age was 54.1 years, and 84 of the patients (44.2%) were male. The mean liver stiffness (LS) value at SVR was 7.1±5.4 kPa. During the follow-up period (median, 43.0 months), LREs occurred in 10 patients (5.3%; HCC in eight patients, ascites in one patient, and liver-related mortality in one patient). By multivariate Cox regression analysis, age, α-fetoprotein level, and LS value were independent predictors for LRE development (all p<0.05). Patients with LS values ≥7.0 kPa had a greater risk (hazard ratio, 9.472; 95% confidence interval, 1.018 to 88.126; p=0.048) for LRE development compared to those with LS values <7.0 kPa. Conclusions: The LS value at SVR is useful for predicting LRE development in CHC patients who achieve SVR after treatment with peg-IFN plus ribavirin. Thus, LRE surveillance strategies might be optimized according to the LS values at SVR, even with complete viral eradication. (Gut Liver 2016;10:429- 436)

A phase 3b study of sofosbuvir plus ribavirin in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 2 hepatitis C virus

Abstract: In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon-alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon-free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38-46% in Korea. This single-arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12-week duration) in chronic genotype 2 HCV-infected treatment-naive and treatment-experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment-naive and 100% (24/24) of treatment-experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on-treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment-emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all-oral, interferon-free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.

Hepatitis C Virus and Antiviral Drug Resistance.

Abstract: Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens

Real-life experience of sorafenib treatment for hepatocellular carcinoma in Korea: From GIDEON data

Abstract: Purpose The purpose of this study is to report real life experiences of sorafenib therapy for hepatocellular carcinoma (HCC) in Korea, using a subset of data from GIDEON (Global Investigation of Therapeutic Decisions in HCC and of Its Treatment with Sorafenib; a large, prospective, observational study). Materials and methods Between January 2009 and April 2012, a total of 497 patients were enrolled from 11 sites in Korea. Of these, 482 patients were evaluable for safety analyses. Case report forms of paper or electronic version were used to record safety and efficacy data from all patients. Results More patients of Child-Pugh A received sorafenib for > 8 weeks than did patients of Child-Pugh B (55.5% vs. 34.3%). Child-Pugh score did not appear to influence the starting dose of sorafenib, and approximately 70% of patients both in Child-Pugh A and B groups received the recommended initial daily dose of 800 mg (69.0% and 69.5%, respectively). The median overall survival (OS) and time to progression (TTP) were 8.5 months and 2.5 months. In Child-Pugh A patients, the median OS and TTP were 10.2 months and 2.5 months. The most frequent treatment-emergent drug-related adverse event was hand-foot skin reaction (31.7%), followed by diarrhea (18.0%). The incidence of treatment-emergent adverse events was similar in both Child-Pugh A (85.4%) and Child-Pugh B (84.8%) patients. Conclusion Sorafenib was well tolerated by Korean HCC patients in clinical settings, and the safety profile did not appear to differ by Child-Pugh status. Survival benefit in Korean patients was in line with that of a previous pivotal phase III trial (SHARP).

Cryoablation of Hepatocellular Carcinoma with High-Risk for Percutaneous Ablation: Safety and Efficacy

Abstract: The aim of this study was to evaluate the safety and effectiveness of cryoablation in the treatment of subcapsular hepatocellular carcinoma (HCC) adjacent to various organs. Twenty-eight patients with subcapsular HCC were treated with cryoablation in our institution. The degree of peri-procedural pain was measured using the visual analog scale (VAS). Technical success, local tumor progression, and overall disease progression rates were calculated. Procedure-related complications were identified by reviewing electronic medical records. Biochemical data, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels before and after the procedure were collected. Subcapsular HCC tumors were located near the gallbladder, colon, stomach, kidney, diaphragm, or abdominal wall. The technical success rate of cryoablation was 96.4 % (27/28). Local recurrence- and progression-free survival rates were 96 and 84 % at 6 months, and 82 and 43 % at 1 year, respectively. All patients survived during the follow-up period. The VAS pain score ranged from 0 to 3 (mean, 1.57). A major complication occurred in one patient (3.6 %) and minor complications occurred at a rate of 17.9 %. Transient elevations of serum AST, ALT, and bilirubin levels were observed. Cryoablation is a safe and an effective procedure for the treatment of subcapsular HCC adjacent to various major organs.

Transgenic mouse models generated by hydrodynamic transfection for genetic studies of liver cancer and preclinical testing of anti‐cancer therapy

Abstract: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide; however, the genetic mechanisms underlying its pathogenesis are incompletely understood. Genetically engineered mouse (GEM) models of HCC have been developed to elucidate the role of individual cancer-related genes in hepatocarcinogenesis. However, the expensive and time-consuming processes related to generating a GEM model discourage the development of diverse genotype models. Recently, a simple and inexpensive liver-specific transgenic approach was developed, in which a hydrodynamics-based transfection (HT) method was coupled with the Sleeping Beauty transposase system. Various HT models in which different oncogenic pathways are activated and/or tumor-suppressing pathways inactivated have been developed in recent years. The applicability of HT models in liver cancer research is expected to broaden and ultimately elucidate the cooperation between oncogenic signaling pathways and aid in designing molecular therapy to target altered pathways.

Entecavir plus tenofovir combination therapy in patients with multidrug-resistant chronic hepatitis B: results of a multicentre, prospective study.

Abstract: Background & Aims Sequential therapy posed a high risk of emergence of multidrug resistance and presented a management issue in chronic hepatitis B (CHB) treatment. We evaluated the antiviral efficacy and safety of entecavir (ETV) plus tenofovir (TDF) combination therapy in multidrug-resistant (MDR) CHB patients. Methods In this prospective, multicentre study, MDR CHB patients, defined as measurable serum HBV DNA (≥60 IU/ml) while on any rescue treatment regimen for at least 24 weeks and the presence of documented prior genotypic resistance to both nucleoside analogue(s) and nucleotide analogue, were treated with ETV 1.0 mg and TDF 300 mg combination therapy for 48 weeks. Results A total of 64 eligible patients who had previously failed to a median three lines of antiviral therapy (range, 2–6) were included. At baseline, median age was 47.0 years, 89.1% were HBeAg(+), and median HBV DNA was 4.24 (range, 2.11–6.73) log10 IU/ml. By week 4, 12, 24 and 48, 15/64 (23.4%), 36/64 (56.3%), 43/64 (67.2%) and 55/64 (85.9%) patients achieved a HBV DNA <60 IU/ml respectively. The mean reduction of HBV DNA from baseline to 4 and 48 weeks was 1.23 log10 IU/ml and 2.38 log10 IU/ml respectively. Although five patients experienced virological breakthrough, all were transient and no resistant mutation to TDF or novel mutation was detected in any patients. Conclusions In difficult-to-treat MDR CHB patients with a high exposure to multiple antiviral drugs, ETV plus TDF combination therapy can provide a very high rate of viral suppression through 48 weeks of treatment.

A phase IIIb study of ledipasvir/sofosbuvir fixed-dose combination tablet in treatment-naïve and treatment-experienced Korean patients chronically infected with genotype 1 hepatitis C virus.

Abstract: The standard-of-care regimen for chronic hepatitis C virus (HCV) infection in Korea, pegylated-interferon-alpha plus ribavirin, is poorly tolerated. Ledipasvir/sofosbuvir is a two-drug, fixed-dose combination tablet approved in the USA, European Union, and Japan for chronic genotype 1 HCV infection. This single-arm, phase IIIb study (NCT02021656) investigated the efficacy and safety of ledipasvir/sofosbuvir fixed-dose combination tablet for 12 weeks in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 1 HCV with or without compensated cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 99 % (92/93), with rates of 100 % (46/46) and 98 % (46/47) in treatment-naive and treatment-experienced patients, respectively. There were no on-treatment failures. One patient relapsed after the end of treatment. The most common treatment-emergent adverse events were headache (8 %, 7/93) and fatigue (6 %, 6/93). There were no grade 3 or 4 adverse events, seven grade 3 laboratory abnormalities, and one premature discontinuation of study treatment (due to nonserious mouth ulceration). None of the three reported serious adverse events were related to treatment. These data suggest that 12 weeks of ledipasvir/sofosbuvir is effective and well tolerated in treatment-naive and treatment-experienced Korean patients with chronic genotype 1 HCV infection.

Factors Influencing the Diagnostic Accuracy of Acoustic Radiation Force Impulse Elastography in Patients with Chronic Hepatitis B

Abstract: Background/aims To determine factors predictive of discordance in staging liver fibrosis using liver biopsy (LB) and acoustic radiation force impulse (ARFI) elastography in patients with chronic hepatitis B (CHB). Methods Consecutive patients with CHB who underwent LB and ARFI elastography on the same day from November 2010 to March 2013 were prospectively recruited from three tertiary hospitals. Results We analyzed 105 patients (median age of 47 years). The F0-1, F2, F3, and F4 fibrosis stages were identified in 27 (25.7%), 27 (25.7%), 21 (20.0%), and 30 (28.6%) patients, respectively. The areas under the receiver operating characteristics curves for ARFI elastography in assessing ≥ F2, ≥ F3, and F4 was 0.814, 0.848, and 0.752, respectively. The discordance of at least one stage between LB and ARFI was observed in 68 patients (64.8%) and of at least two stages in 16 patients (15.2%). In a multivariate analysis, advanced fibrosis stage (F3-4) was the only factor that was negatively correlated with one-stage discordance (p=0.042). Moreover, advanced fibrosis stage was negatively (p=0.016) correlated and body mass index (BMI) was positively (p=0.006) correlated with two-stage discordance. Conclusions Advanced fibrosis stage (F3-4) was a predictor of nondiscordance between LB and ARFI elastography; BMI also influenced the accuracy of ARFI elastography.

Subclassification of Barcelona Clinic Liver Cancer B and C hepatocellular carcinoma: A cohort study of the multicenter registry database

Abstract: BACKGROUND AND AIM We aimed to subclassify hepatocellular carcinoma (HCC) using Barcelona Clinic Liver Cancer intermediate and advanced stages, which include a highly heterogeneous population. METHODS From two registries ("random" and "voluntary" cohorts in the Korean Liver Cancer Study Group), patients who were newly diagnosed as HCC with intermediate or advanced stage between 2003 and 2005 were considered eligible. Overall survival (OS) was analyzed using Kaplan-Meier method with comparison by log-rank test. RESULTS Patients with intermediate-stage HCC (n = 994) were subclassified according to tumor size and Child-Pugh class. Patients with tumor size < 5 cm (B1), those with tumor size ≥ 5 cm and Child-Pugh A (B2), and those with tumor size ≥ 5 cm and Child-Pugh B (B3) had median OS of 30.73, 20.60, and 9.23 months, respectively (P < 0.001 by log-rank test). Among patients with advanced stage HCC (n = 1746), patients were subclassified according to presence of significant portal vein invasion (sPVI; defined as portal vein invasion in lobar, main, or contralateral branch) and extrahepatic spread (EHS). Patients with neither sPVI nor EHS (C1), those with either sPVI or EHS (C2), and those with both sPVI and EHS (C3) had median OS of 8.43, 4.63, and 3.63 months, respectively (P < 0.001 by log-rank test). CONCLUSION Subclassification of Barcelona Clinic Liver Cancer intermediate and advanced stages might be useful for determining patient prognosis and guiding treatment strategies for HCC.