Young Sok Lee

A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.

Reactivation of hepatitis B virus (HBV) during chemotherapy is well documented. However, there are limited data on this complication in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemotherapy. The aim of this study was to evaluate the efficacy of preemptive lamivudine therapy in reducing hepatitis due to HBV reactivation in patients with HCC undergoing transarterial chemo‐lipiodolization (TACL) and to seek predictors of this event. A total of 73 consecutive HCC patients undergoing TACL using epirubicin 50 mg/m2 and cisplatin 60 mg/m2 at monthly intervals were prospectively and randomly assigned to receive lamivudine 100 mg daily from the start of TACL (preemptive group) or not (control group). During the study, 11 (29.7%) of 37 patients in the control group and 1 (2.8%) of 36 patients in the preemptive group developed hepatitis due to HBV reactivation (P = .002). In addition, there were significantly more incidences of overall hepatitis (P = .021) and severe grade of hepatitis (P = .035) in the control group. With multivariate Cox regression model, a baseline HBV DNA level of more than 104 copies/mL was the only independent predictor of hepatitis due to HBV reactivation during chemo‐lipiodolization (P = .046). In conclusion, preemptive lamivudine therapy demonstrated excellent efficacy in reducing hepatitis due to HBV reactivation and hepatic morbidity during TACL. Preemptive therapy should be considered in HCC patients with an HBV DNA level of more than 104 copies/mL. Further studies are needed to confirm the value of this approach in patients with low‐level viremia. (HEPATOLOGY 2006;43:233–240.)

Long-term outcome of high-intensity focused ultrasound in advanced pancreatic cancer.

Objectives: The aim of this study was to evaluate safety and efficacy of high-intensity focused ultrasound (HIFU) for advanced pancreatic cancer (PC). Methods: Patients with PC TNM stage III or IV were included. Magnetic resonance imaging was performed 2 weeks before and after the HIFU. The ablating tumor volume was calculated by ratio of the nonperfused necrotic area of the planned area on contrast-enhanced T1-weighted image on post-HIFU magnetic resonance imaging. The ablation results were stratified into 4 ranges: 100% to 90% unenhanced area of targeting area, 90% to 50%, within 50%, and no change. Results: High-intensity focused ultrasound treatment was performed without severe adverse event in 46 patients, 49 times (male-female = 25:21; mean age, 60.7 ± 10.0; TNM stage 3-stage 4 = 18:28). Average size of the PC lesion was 4.2 ± 1.4 cm (1.6-9.3 cm). After HIFU treatment, ablating tumor volume was as follows: 90% to 100% in 38 lesions, 90% to 50% in 8, and within 50% in 3. Overall median survival (S1) from initial PC diagnosis was 12.4 months. Overall survival (S2) rates at 6, 12, and 18 months from HIFU were 52.2%, 30.4%, and 21.79%, respectively, with a median survival of 7.0 months Conclusions: High-intensity focused ultrasound is safe and effective, which induced excellent local tumor control in most patients with advanced PC.

Long-Term Results of Lamivudine Monotherapy in Korean Patients with HBeAg-Positive Chronic Hepatitis B: Response and Relapse Rates, and Factors Related to Durability of HBeAg Seroconversion

Objective: The aim of this study was to evaluate retrospectively the long-term effects of lamivudine in 461 Korean patients with chronic hepatitis B who were treated for more than 12 months. Methods: The annual rates of virological response and breakthrough were examined and the predictive factors for post-treatment relapse in 114 patients who achieved hepatitis B e antigen (HBeAg) loss or seroconversion after lamivudine therapy were also analyzed. Results: During follow-up, the rates of HBeAg seroconversion after 1, 2, 3, 4 and 5 years of treatment were 22.9, 33.2, 47.6, 54.2 and 58.8%, respectively, while those for virological breakthrough at 1, 2, 3 and 4 years were 8.2, 41.7, 55.7 and 64.8%, respectively. Ninety-five patients (20.6%) had HBeAg seroconversion and 19 (4.1%) showed HBeAg loss alone with disappearance of hepatitis B virus DNA in serum. Seroconversion was higher with prolonged treatment in patients who had elevated serum alanine aminotransferase. The cumulative relapse rates in the seroconversion group were 52.0 and 55.7% 1 and 2 years after treatment, respectively. Age and the duration of additional treatment were significant predictive factors for post-treatment relapse. Patients aged ≤40 who had additional treatment for >12 months after seroconversion had the lowest relapse rate (p < 0.001). Conclusions: These results suggest that additional treatment for over 12 months after HBeAg seroconversion in younger patients may produce a better long-term outcome.

E‐cadherin antagonizes transforming growth factor β1 gene induction in hepatic stellate cells by inhibiting RhoA–dependent Smad3 phosphorylation

Cadherins mediate cell‐cell adhesion and catenin (ctn)‐related signaling pathways. Liver fibrosis is accompanied by the loss of E‐cadherin (ECAD), which promotes the process of epithelial‐mesenchymal transition. Currently, no information is available about the inhibitory role of ECAD in hepatic stellate cell activation. Because of ECADs potential for inhibiting the induction of transforming growth factor β1 (TGFβ1), we investigated whether ECAD overexpression prevents TGFβ1 gene induction; we also examined what the molecular basis could be. Forced expression of ECAD decreased α‐smooth muscle actin and vimentin levels and caused decreases in the constitutive and inducible expression of the TGFβ1 gene and its downstream genes. ECAD overexpression decreased Smad3 phosphorylation, weakly decreased Smad2 phosphorylation, and thus inhibited Smad reporter activity induced by either treatment with TGFβ1 or Smad3 overexpression. Overexpression of a dominant negative mutant of ras homolog gene family A (RhoA) diminished the ability of TGFβ1 to elicit its own gene induction. Consistently, transfection with a constitutively active mutant of RhoA reversed the inhibition of TGFβ1‐inducible or Smad3‐inducible reporter activity by ECAD. Studies using the mutant constructs of ECAD revealed that the p120‐ctn binding domain of ECAD was responsible for TGFβ1 repression. Consistently, ECAD was capable of binding p120‐ctn, which recruited RhoA; this prevented TGFβ1 from increasing RhoA‐mediated Smad3 phosphorylation. In the liver samples of patients with mild or severe fibrosis, ECAD expression reciprocally correlated with the severity of fibrosis. Conclusion: Our results demonstrate that ECAD inhibits Smad3/2 phosphorylation by recruiting RhoA to p120‐ctn at the p120‐ctn binding domain, whereas the loss of ECAD due to cadherin switching promotes the up‐regulation of TGFβ1 and its target genes, and facilitates liver fibrosis. (HEPATOLOGY 2010.)

A nationwide seroprevalence of total antibody to hepatitis A virus from 2005 to 2009: age and area-adjusted prevalence rates

Background/Aims Recent outbreak of hepatitis A in Korea is clearly related to the epidemiological shift of hepatitis A virus (HAV). However, nationwide seroprevalence data have been limited. This study estimated the nationwide, age- and area-adjusted anti-HAV prevalence from 2005 to 2009. Methods Retrospective analysis of the results of total anti-HAV test in 25,140 cases which were requested by 1,699 medical institutions throughout the nation to Seoul Clinical Laboratory from Jan. 1 2005 to Dec. 31 2009 was performed. The estimated seroprevalence was adjusted by area and age of the standard population based on the 2005 Census data from Korea National Statistical Office. Results The area-adjusted anti-HAV prevalence in the children younger than 10 years were 33.4% in 2005 and 69.9% in 2009. The most susceptible age groups to HAV infection during the last 5 years were teenagers and the young adults in their age of twenties. The area-adjusted seroprevalence in 2009 were 11.9% in the age group of 20-29 years, 23.4% in the age group of 10-19 years, 48.4% in the age group of 30-39 years. The population in 40-49 years showed geographically different seroprevalence with the lowest rate in Seoul (80%). Conclusions The most susceptible age group to HAV infection is 10-29 years, while the young children less than 10 years showed about 70% seropositivity. The changing seroepidemiology should be monitored continuously for the proper vaccination and patient care.

Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease.

Background/Aims The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH. Methods One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8±13.5 years, mean±SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea. Results According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis ≥2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH. Conclusions Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.

Early Viral Kinetics of Telbivudine and Entecavir: Results of a 12-Week Randomized Exploratory Study with Patients with HBeAg-Positive Chronic Hepatitis B

ABSTRACT We characterized the early viral kinetic profiles of telbivudine and entecavir and the effects of these potent nucleoside analogs on hepatitis B virus (HBV) DNA and alanine aminotransferase levels in adults with hepatitis B e antigen-positive compensated chronic hepatitis B. Forty-four patients were enrolled in this open-label, parallel-group, multicenter study and randomized to receive telbivudine or entecavir for 12 weeks. Reductions in hepatitis B virus DNA and alanine aminotransferase levels from baseline to weeks 2, 4, 8, and 12 were assessed. Viral kinetic parameters, including viral clearance per day, loss of infected cells per day, and efficiency of inhibition of viral production, were estimated by using a biphasic mathematical model. Statistical analyses were limited to descriptive analyses. The 2 treatment groups achieved similar reductions in HBV DNA and alanine aminotransferase levels. Mean reductions in levels of hepatitis B virus DNA at week 12 were 6.6 ± 1.6 and 6.5 ± 1.5 log10 copies/ml for the telbivudine- and entecavir-treated patients, respectively. There were no significant differences between groups in values for mean viral clearance per day, mean loss of infected cells per day, or efficiency of blocking viral production. The safety profiles for both medications were favorable. During the first 12 weeks of treatment, telbivudine and entecavir demonstrated similar antiviral potencies, resulting in a rapid and profound suppression of serum hepatitis B virus DNA and reduction of alanine aminotransferase levels. No differences in the effects of these 2 agents on early viral kinetics were observed. Both medications were well tolerated.

Outcome after discontinuing antiviral agents during pregnancy in women infected with hepatitis B virus

BACKGROUND Women who are taking antiviral agents and become pregnant have several options that include, continuing therapy, ceasing drugs, or switching to safer drugs. However, there are limited data on the outcome in pregnant women after withdrawal of antiviral agents. OBJECTIVES We aimed to investigate the outcome of stopping antiviral agents in pregnant women with chronic hepatitis B virus (HBV) infection. STUDY DESIGN In this single-center, retrospective cohort study, 12 pregnant patients who had received antiviral therapy for HBV and cease drugs after awareness of pregnancy between 2003 and 2010 were enrolled. We retrospectively studied virologic and biochemical flares during pregnancy and postpartum period. RESULTS Median age at pregnancy was 30.5 (range, 24-35) years, median duration of antiviral drug before pregnancy was 15.3 (range, 3.0-131.3) months, and median HBV DNA at withdrawal of therapy was 4.8 (range, 1.7-8.0) log(10) copies/mL. Eight out of twelve patients (66.7%) had a viral rebound after stopping antiviral drugs during pregnancy. Severe hepatitis flares, defined as a 5-fold increase in serum alanine aminotransferase (ALT), were observed in six patients (50%) during pregnancy. However, all of these patients spontaneously recovered without an event of hepatic decompensation. High pretreatment ALT was associated with severe hepatitis flares after cessation of therapy during pregnancy. Five patients with at least 1-year treatment before pregnancy maintained low hepatitis activity after delivery. CONCLUSIONS Pregnant women with high pretreatment ALT or those treated less than 1 year before pregnancy have high risk of severe hepatitis flares after cessation of antiviral agents.

A pilot study of autologous CD34-depleted bone marrow mononuclear cell transplantation via the hepatic artery in five patients with liver failure

BACKGROUND AIMS Many rodent experiments and human studies on stem cell therapy have shown promising therapeutic approaches to liver diseases. We investigated the clinical outcomes of five patients with liver failure of various causes who received autologous CD34-depleted bone marrow-derived mononuclear cell (BM-MNC) transplantation, including mesenchymal stromal cells, through the hepatic artery. METHODS CD34-depleted BM-MNCs were obtained from five patients waiting for liver transplantation by bone marrow aspiration and using the CliniMACS CD34 Reagent System (Miltenyi Biotech, Bergisch Gladbach, Germany), and autologous hepatic artery infusion was performed. The causes of hepatic decompensation were hepatitis B virus (HBV), hepatitis C virus (HCV), propylthiouracil-induced toxic hepatitis and Wilson disease. RESULTS Serum albumin levels improved 1 week after transplantation from 2.8 g/dL, 2.4 g/dL, 2.7 g/dL and 1.9 g/dL to 3.3 g/dL, 3.1 g/dL, 2.8 g/dL and 2.6 g/dL. Transient liver elastography data showed some change from 65 kPa, 33 kPa, 34.8 kPa and undetectable to 46.4 kPa, 19.8 kPa, 29.1 kPa and 67.8 kPa at 4 weeks after transplantation in a patient with Wilson disease, a patient with HCV, and two patients with HBV. Ascites decreased in two patients. One of the patients with HBV underwent liver transplantation 4 months after the infusion, and the hepatic progenitor markers (cytokeratin [CD]-7, CD-8, CD-9, CD-18, CD-19, c-Kit and epithelial cell adhesion molecule [EpCAM]) were highly expressed in the explanted liver. CONCLUSIONS Serum albumin levels, liver stiffness, liver volume, subjective healthiness and quality of life improved in the study patients. Although these findings were observed in a small population, the results may suggest a promising future for autologous CD34-depleted BM-MNC transplantation as a bridge to liver transplantation in patients with liver failure.

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial

Objectives  Oltipraz, a cancer chemopreventive agent, has an anticirrhotic effect in animals. A phase II trial was designed to investigate the preliminary efficacy of oltipraz therapy in liver fibrosis or cirrhosis.