Joong-Won Park

Twenty‐four‐week clevudine therapy showed potent and sustained antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post‐treatment follow‐up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24‐week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg‐positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Clevudine is highly efficacious in hepatitis B e antigen‐negative chronic hepatitis B with durable off‐therapy viral suppression

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (e‐CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were −4.25 and −0.48 log10 copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log10 reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well‐maintained during the post‐treatment follow‐up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. Conclusion: A 24‐week clevudine therapy was well‐tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e‐CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission. (HEPATOLOGY 2007.)

Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and progression of tumor, including hepatocellular carcinoma (HCC), and elevated VEGF levels in serum and tissues have been known to be related with poor prognosis in patients with HCC. However, the effect of such polymorphisms of the VEGF gene on HCC prognosis has not been elucidated. In the present study, we investigated the association between VEGF gene polymorphisms and HCC patient prognosis. The study involved 416 HCC patients treated at the National Cancer Center Korea from November 2000 to December 2005. The median patient age was 57 years, and 328 patients (78.8%) were men. A total of 19 polymorphisms were analyzed, and the hazard ratios (HRs) for genotypes and haplotypes were determined in terms of risk for overall survival using Cox proportional hazard regression analysis. Of the 19 alleles, 7 showed no heterozygous allele. PHASE analysis identified a total of 36 haplotypes. The −2578 to −1498 region of the VEGF gene showed a strong linkage disequilibrium (correlation coefficient, r2 = 0.91; Lewontins D′, D′ = 0.982). The adjusted HRs were 0.67 [95% confidence interval (CI), 0.46 to 0.99] for −634CC genotype carriers and 0.57 (95% CI, 0.36 to 0.92) for homozygous haplotype 1 (Ht1: CCGAGCCC at −2578/−1203/−1190/−1179/−1154/−634/−7/+936) carriers compared with noncarriers. Conclusion: These findings suggest that VEGF polymorphisms may be significant prognostic indicators for HCC patients. (HEPATOLOGY 2007.)

Cholestasis confers resistance to the rat liver mitochondrial permeability transition

BACKGROUND & AIMS Bile salts can cause hepatocyte death by inducing the mitochondrial permeability transition (MPT). However, the slow progression of human cholestatic liver diseases suggests that hepatocytes adapt to resist the MPT. Bcl-x, a protein, and increased mitochondrial cardiolipin, a membrane lipid, elevate the threshold for the MPT. Our aims were to determine if liver mitochondria become resistant to the MPT during cholestasis and, if so, if the resistance is mediated by Bcl-x and/or increased cardiolipin. METHODS Hepatocytes and liver mitochondria were obtained from bile duct-ligated (BDL) rats and sham-operated rats (control). RESULTS After addition of glycochenodeoxycholate (GCDC), the magnitude of the MPT was reduced in mitochondria from BDL rats vs. controls. Although Bcl-xL was not increased, mitochondrial cardiolipin content was significantly greater in BDL rats vs. controls. Cell viability was also increased in hepatocytes from BDL rats vs. controls after treatment with GCDC. Feeding BDL rats a fatty acid-deficient diet prevented the increase in mitochondrial cardiolipin content; mitochondria and hepatocytes from these rats were susceptible to the MPT and hepatocellular death by GCDC. CONCLUSIONS These data suggest that an increase in mitochondria cardiolipin content occurs during cholestasis as an adaptive phenomenon to resist cell death by the MPT.

Clinical trials of combined molecular targeted therapy and locoregional therapy in hepatocellular carcinoma: past, present, and future.

Background: Sorafenib, a multikinase inhibitor that targets angiogenesis in hepatocellular carcinoma (HCC), has become a standard treatment for advanced-stage HCC and has shown survival benefits in recent clinical trials. Transarterial chemoembolization (TACE) and sorafenib are currently standard treatments for intermediate and advanced-stage HCC, respectively. Combined locoregional therapy, including TACE and molecular targeted therapies such as sorafenib, is an issue under active investigation in an attempt to improve the outcomes of patients with unresectable HCC. Summary: Various clinical trials of these combined strategies have been conducted; however, the designs of these studies are diverse in terms of treatment modalities and schedules; comparisons with controls, baseline tumor stages, and hepatic functional reserves; and outcome measures. Key Messages: This article reviews heterogeneity in the design of recent clinical trials of combined locoregional and molecular targeted therapies and briefly addresses future study directions.

Learning curve for living‐donor liver transplantation in a fledgling cancer center

Hepatocellular carcinoma (HCC) has become one of the main indications for liver transplantation. To keep abreast of the times, a comprehensive cancer center may have to perform liver transplantation as a treatment option for HCC. We introduce a learning curve for living‐donor liver transplantation (LDLT) and present our initial experience in a new cancer center as an example to any center considering LDLT. A total of 51 consecutive adult right liver LDLTs performed from January 2005 to January 2008 were analyzed by comparing the first 17 transplants performed with the help of an outside experienced team (group 1) with the middle 17 (group 2) and the last 17 cases (group 3) performed in our center independently. There was no hospital mortality in donors and recipients. In a mean follow‐up of 34 months (range: 12–48 months), there was only one case of late mortality in donor and recipient, respectively. A total of four donors and 12 recipients underwent re‐operations. The warm ischemic time was significantly longer in group 2 than that in groups 1 and 3. Otherwise, there was no significant difference in the operative outcomes among the three groups. Thorough preparation and the assistance of an experienced liver transplantation team at the beginning can facilitate a more rapid learning curve and bring about a good outcome even in a small, newly established institution.

ROLE OF ADJUVANT CHEMORADIOTHERAPY FOR RESECTED EXTRAHEPATIC BILIARY TRACT CANCER

PURPOSE To evaluate the effect of adjuvant chemoradiotherapy (CRT) on locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) for patients with extrahepatic biliary tract cancer treated with curative resection. METHODS AND MATERIALS The study involved 168 patients with extrahepatic biliary tract cancer undergoing curative resection between August 2001 and April 2009. Of the 168 patients, 115 received adjuvant CRT (CRT group) and 53 did not (no-CRT group). Gender, age, tumor size, histologic differentiation, pre- and postoperative carbohydrate antigen 19-9 level, resection margin, vascular invasion, perineural invasion, T stage, N stage, overall stage, and the use of adjuvant CRT were analyzed to identify the prognostic factors associated with LRC, DFS, and OS. RESULTS For all patients, the 5-year LRC, DFS, and OS rate was 54.8%, 30.6%, and 33.9%, respectively. On univariate analysis, the 5-year LRC, DFS, and OS rates in the CRT group were significantly better than those in the no-CRT group (58.5% vs. 44.4%, p=.007; 32.1% vs. 26.1%, p=.041; 36.5% vs. 28.2%, p=.049, respectively). Multivariate analysis revealed that adjuvant CRT was a significant independent prognostic factor for LRC, DFS, and OS (p<.05). CONCLUSION Our results have suggested that adjuvant CRT helps achieve LRC and, consequently, improves DFS and OS in patients with extrahepatic biliary tract cancer.

Worse outcome of sorafenib therapy associated with ascites and Child-Pugh score in advanced hepatocellular carcinoma

The outcomes of sorafenib therapy in patients with advanced hepatocellular carcinoma (HCC) and impaired liver function remain unresolved. Although Child–Pugh (CP) classification is widely used for patient categorization, heterogeneity within a given CP class makes outcomes less predictable. The aim was to investigate the prognostic significance of CP score elements on the outcome of sorafenib in patients with advanced HCC and impaired liver function.

Severity and timing of progression predict refractoriness to transarterial chemoembolization in hepatocellular carcinoma

Background and Aim:  Patients with hepatocellular carcinoma (HCC) that is refractory to repeated transarterial chemoembolization (TACE) are considered for systemic therapy, but TACE refractoriness is not well defined. The aim of this study was to determine the characteristics of patients whose HCC is refractory to repetitive TACE.

Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial.

207Background: C, an inhibitor of MET, VEGFR, and AXL, has previously shown clinical activity in pts with advanced HCC. This phase 3 trial (NCT01908426) evaluated C vs P in previously treated pts with advanced HCC. Methods: In this double-blind, global, phase 3 trial, pts were randomized 2:1 to receive C (60 mg qd) or matched P stratified by disease etiology (HBV, HCV, other), geographic region (Asia, other), and presence of extrahepatic spread and/or macrovascular invasion (EHS/MVI). Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, ECOG PS ≤1, and must have received prior sorafenib. Pts received up to two lines of prior systemic therapy for HCC and must have progressed following at least one. The primary endpoint was overall survival (OS). Secondary endpoints were investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The study was designed to detect a hazard ratio (HR) for OS of 0.76 (90% power, 2-sided α = 0.05) at the final analysis wit...