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ABSTRACT: Polymorphisms in the primary microRNA region may be associated with natural course of hepatitis B virus (HBV) infection. This study evaluated if the mircoRNA 219-1 (miR-219-1) polymorphism can influence the susceptibility towards persistence of HBV infection and the progression to hepatocellular carcinoma (HCC) in patients with chronic HBV infection. A total of 1,439 individuals having either past or present evidence of HBV infection were enrolled for the study. The subjects were divided into four groups; (1) spontaneous recovery (n = 404), (2) chronic HBV carrier (n = 313), (3) chronic HBV carrier with cirrhosis (n = 305), and (4) hepatocellular carcinoma (n = 417). Genotyping was performed at three polymorphic variants (rs421446, rs107822, and rs213210) in the pri-miRNA region of miR-219-1. The rs421446 T allele was found to be strongly associated with HBV clearance (OR = 0.73, P = 0.0005 in a codominant model and OR = 0.67, P = 0.0009 in a dominant model, OR = 0.69, P = 0.04 in a recessive model, respectively). The rs107822 G allele was also found to be associated with HBV clearance (OR = 0.79, P = 0.008 in a codominant model and OR = 0.72, P = 0.01 in a dominant model, respectively). In haplotype analysis, ht2 (T-G-T) and ht1 (C-A-C) were found to be in significant association with the clearance of HBV. However, no significant association was observed between miR-219-1 polymorphism and the risk of HCC occurrence. This result suggests that polymorphisms in the pri-miRNA region of miR-219-1 might be a genetic factor for HBV clearance after infection. J. Med. Virol. 85:808-814, 2013. © 2013 Wiley Periodicals, Inc.
Journal of Medical Virology 05/2013; 85(5):808-814. · 2.82 Impact Factor
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ABSTRACT: Purpose:To prospectively assess the safety and mid-term therapeutic effectiveness of monopolar radiofrequency (RF) ablation with a multiple-electrode switching system for treating small- and medium-sized (≤5 cm) hepatocellular carcinomas (HCCs).Materials and Methods:The institutional review board approved this prospective study, and all patients gave informed consent. From February 2009 to January 2010, 166 patients (110 men and 56 women; age range, 38-86 years; mean age, 62 years ± 10 [standard deviation]) with 166 HCCs less than or equal to 5 cm in diameter were treated with monopolar RF ablation with a multiple-electrode switching system. One of three experienced radiologists performed the RF ablation. Technique effectiveness, ablation volume and time, and major complications were evaluated by means of computed tomography (CT) immediately after RF ablation and at follow-up CT examinations at 1 month and then every 3 months after the procedure. The overall survival, disease-free survival, and local tumor progression-free survival rates were evaluated by using the Kaplan-Meier method.Results:The technique effectiveness rate determined 1 month after RF ablation was 99.4%. Mean ablation parameters were as follows: volume, 85 cm(3) ± 54; maximum diameter, 61 mm ± 13; and minimum diameter, 43 mm ± 11. The major complication rate was 4.8%. The 6-month and 1-, 2-, and 3-year local tumor progression rates were 2%, 6%, 10%, and 11%, respectively. The overall survival rates at 1, 2, and 3 years after RF ablation were 99%, 97%, and 96%, and corresponding local tumor progression-free survival rates were 94%, 90%, and 89%, respectively. The disease-free survival rates at 1, 2, and 3 years after RF ablation were 75%, 60%, and 54%, respectively.Conclusion:Monopolar RF ablation with a multiple-electrode switching system in small- and medium-sized HCCs was safe and efficient, and it provided successful local tumor control and high local tumor progression-free survival rates because an adequate ablation volume was obtained.© RSNA, 2013.
Radiology 03/2013; · 5.73 Impact Factor
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ABSTRACT: AIM: Side population (SP) cells are known to be enriched in stem/progenitor-like cells. Transforming growth factor (TGF)-β signaling is associated with extracellular matrix (ECM) production in hepatic stellate cells. We hypothesized that the SP fraction in LX2 cells is associated with ECM deposition, which is regulated through TGF-β signaling. METHODS: We investigated the relationship between SP cells and TGF-β signaling in the hepatic stellate cell line LX2. The effects of TGF-β and SB431542 on the SP fraction and expression of collagen type I and phospho-Smad2 was determined. RESULTS: We identified 0.8-3% SP cells in LX2 cells. The growth rate of sorted SP and non-SP cells was similar to that of the original LX2 population, but population of the G0/G1 phase was increased in SP cells. Treatment of LX2 cells with TGF-β decreased the SP fraction in a dose-dependent manner and increased the production of collagen type I. Treatment of LX2 cells with SB431542 blocked the effect of TGF-β on the SP fraction and the expression of collagen type I. We cultured LX2 cells on collagen-coated dishes to observe the effect of ECM deposition on the SP fraction. The growth rate and cell cycle distribution was similar to that observed on normal tissue culture dishes, but the SP fraction was decreased when LX2 cells were cultured on collagen-coated plates. CONCLUSION: These results show that LX2 cells contain an SP fraction and that TGF-β signaling is involved in the induction of ECM deposition as well as the number of SP cells.
Hepatology Research 03/2013; · 2.20 Impact Factor
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Nam-Joon Yi,
Kyung-Suk Suh,
Suk-Won Suh,
Ye Rim Chang,
Geun Hong,
Tae Yoo,
Hyeyoung Kim,
Min Su Park,
Young Rok Choi,
Kwang-Woong Lee,
Chul-Woo Jung,
Jeong Hoon Lee, Yoon Jun Kim,
Jung-Hwan Yoon,
Hyo-Suk Lee
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ABSTRACT: BACKGROUND: Using a right liver (RL) graft improves the outcomes in adult living donor liver transplantation (ALDLT). Here we report the recent excellent outcomes of 238 consecutive RL transplantations in ALDLT. METHODS: Between January 2005 and June 2009, 238 consecutive adult recipients underwent RL transplantation; The middle hepatic vein (MHV) was reconstructed using artificial vascular grafts in 209 cases. Among these study subjects, UNOS status 1 and 2A were 12 (5.0 %) and 20 (8.4 %) patients, and the mean medical MELD score, was 19.9. Hepatitis B virus was the most common original liver disease in 184 patients (77.3 %). Hepatocellular carcinoma was diagnosed in 133 patients (56.3 %), and 102 patients (76.1 %) met the radiologic Milan criteria. The mean graft-versus-recipient weight ratio was 1.14 %. The primary endpoint of this study was the patient and graft survival rate. The mean follow-up period was 32 (0-69) months. RESULTS: The most common major complication was biliary complication (n = 62; 26 %). The 1-, 2-, and 5-year patient survival rates were 96, 95, and 94 %, and the graft survival rates were 99, 99, and 98 %. There were 4 hospital deaths (1.6 %). Eighteen late mortalities were observed after recurrence of hepatocellular carcinoma (HCC, n = 17) and one case of lymphoma recurrence. One case of graft failure 33 months after ALDLT was attributed to cholestatic fibrosing hepatitis B saved by re-ALDLT. On multivariate analysis, no drainage of MHV branches and accompanying HCC beyond Milan criteria were the risk factors for poor patients' survival rate (p < 0.05). CONCLUSIONS: Further technical innovation would be required to overcome biliary complications. The technical innovation using right liver draining MHV branches improved both patient and graft survival outcomes of ALDLT. Despite these advances, selection criteria for HCC are still hurdles, even in RL transplantation.
World Journal of Surgery 03/2013; · 2.36 Impact Factor
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Nam-Joon Yi,
Jong Young Choi,
Kyung-Suk Suh,
Jai Young Cho,
Minjung Baik,
Geun Hong,
Kwang-Woong Lee,
Won Kim, Yoon Jun Kim,
Jung-Hwan Yoon,
Hyo-Suk Lee,
Dong Goo Kim
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ABSTRACT: BACKGROUND: Combination therapy of intravenous hepatitis B immunoglobulin (ivHBIG) and nucleos(t)ide (NA) analogues is the best post-liver transplantation (LT) prophylactic measure for hepatitis B virus (HBV). However, to reduce the long-term drawbacks of ivHBIG, we evaluated the efficacy of sequential entecavir (ETV) monotherapy. METHODS: Twenty-nine candidates with HBV-related liver disease were prospectively enrolled. The patients were selected if the patient was suitable for one of the following inclusion criteria: (1) NA-naïve patients except for ETV, and (2) negative HB e antigen (HBeAg) and undetectable HBV DNA at the time of LT. Post-LT HBV prophylaxis consisted of 1-year combination therapy with ETV (0.5 mg daily) plus ivHBIG per 5 weeks, followed by ETV monotherapy. The primary endpoint was the 2-year recurrence rate of HB. The median follow-up period was 31 months. RESULTS: At the time of transplantation, HBeAg was positive in 21 % and HBV DNA was detectable in 52 % of the study participants. No HBV recurrence was reported during the first year. During the second year, HBV recurrence was noted in one who suffered from HCC recurrence without viral mutation. Recurrence free survival rates were 96.6 and 96.4 % at 1- and 2-year post-transplant by intention-to-treat analysis. One patient died of fungal infection. CONCLUSION: Sequential ETV monotherapy after 1-year combination therapy might be safe in NA-naïve replicators as well as non-replicators.
Journal of Gastroenterology 03/2013; · 4.16 Impact Factor
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ABSTRACT: Purpose:To determine the relationship between hepatitis B virus (HBV) DNA level and the survival of patients with hepatocellular carcinoma treated by means of transarterial chemoembolization (TACE).Materials and Methods:This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. From January 2005 to March 2007, 183 patients with HBV-related hepatocellular carcinoma who underwent TACE but never received antiviral therapy were consecutively enrolled in our cohort. All patients were tested for pre-TACE serum level of HBV DNA, and overall survival was measured from date of enrollment until death from any cause. Radiologic progression was evaluated by using the modified response evaluation criteria in solid tumors by means of independent radiologic assessment.Results:The median overall survival was 19 months (95% confidence interval: 13.7, 24.3) and median time to progression was 4 months (95% confidence interval: 3.03, 4.97). Multivariate analysis revealed that a high pre-TACE serum level of HBV DNA (> 2000 IU/L) was an independent risk factor for reduced overall survival (P = .021; hazard ratio [HR], 1.725), high cancer progression-related mortality (P = .014; HR, 1.936), and hepatic failure-related mortality associated with cancer progression (P = .005, HR, 3.908). Pre-TACE level of HBV DNA did not significantly affect hepatic failure-related mortality that was not caused by cancer progression.Conclusion:A high pre-TACE serum level of HBV DNA was associated with poor overall survival and rapid progression of hepatocellular carcinoma after TACE, and the cause of mortality was not hepatitis exacerbation but cancer progression.© RSNA, 2013.
Radiology 02/2013; · 5.73 Impact Factor
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ABSTRACT: PURPOSE: To evaluate retrospectively the efficacy of transarterial chemoembolization in patients with hepatocellular carcinoma (HCC) with hepatic vein invasion by comparing the results of conventional transarterial chemoembolization and modified transarterial chemoembolization. MATERIALS AND METHODS: From January 2000 to December 2009, 107 patients with HCC and hepatic vein invasion and Child-Pugh class A were treated by transarterial chemoembolization. Modified transarterial chemoembolization (conventional transarterial chemoembolization followed by additional infusion of 50-100 mg of cisplatin) has been undertaken since 2005. Clinical and radiologic data were reviewed and analyzed retrospectively. The overall survival rates were obtained by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Conventional transarterial chemoembolization was performed in 60 patients, and modified transarterial chemoembolization was performed in 47 patients. No significant differences were observed in major complications between the groups. The median survival was longer in the modified group compared with the conventional group (9.7 mo, 95% confidence interval [CI], 4.3-15.1, vs 6.7 mo, 95% CI, 4.8-8.5; P = .047). By subgroup analysis, modified transarterial chemoembolization increased survival of patients with a diffuse tumor type (8.9 mo, 95% CI, 5.9-11.9, vs 3.8 mo, 95% CI, 2.5-5.0; P = .000) and patients without metastasis (20.9 mo, 95% CI, 12.2-29.5, vs 7.3 mo, 95% CI, 4.1-10.5; P = .005). Multivariate analysis identified three independent predictive factors for mortality: diffuse tumor type (P = .001), metastasis (P = .009), and modified transarterial chemoembolization protocol (P = .003). CONCLUSIONS: A survival benefit was suggested with transarterial chemoembolization with additional cisplatin infusion over conventional transarterial chemoembolization in patients with HCC invading the hepatic vein.
Journal of vascular and interventional radiology: JVIR 02/2013; 24(2):274-283. · 1.81 Impact Factor
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Ji Yeon Seo,
Won Kim,
Jee Hye Kwon,
Eun Hyo Jin,
Su Jong Yu,
Hwi Young Kim,
Yong Jin Jung,
Donghee Kim, Yoon Jun Kim,
Jung-Hwan Yoon,
Hyo-Suk Lee
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ABSTRACT: BACKGROUNDS & AIMS: Intrahepatic recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) occurs as a result of direct dissemination or de novo oncogenesis. Hepatocellular carcinogenesis is related to the progression of cirrhosis, and noninvasive fibrosis scoring systems reflect the severity of hepatic fibrosis. Hence, the aim of this study was to elucidate the correlation between noninvasive fibrosis indices and intrahepatic distant recurrence (IDR) of HCC after RFA. METHODS: Patients with hepatitis B virus (HBV)-related, solitary HCC undergoing RFA were prospectively enrolled. Noninvasive serum fibrosis indices were calculated at the time of RFA. IDR was defined as recurrent HCC beyond >2 cm from the ablation margin of RFA. Predictors of IDR and overall survival were analysed by a Cox regression model. RESULTS: Two hundred forty-six patients received RFA as initial treatment, and the median follow-up duration was 19.7 months (IQR, 11.9-29.8). Among these cases, 133 (45.9%) showed IDR after RFA. In multivariable analysis, serum alpha-fetoprotein (AFP) (HR, 1.000; 95% CI, 1.000-1.001; P = 0.001) and age-platelet index (API) (1.19; 1.01-1.39; P = 0.033) were independent predictors of IDR. In particular, patients with API ≤7 showed a significantly higher recurrence-free survival rate than patients with API >7 (P = 0.004). With regard to overall survival, male sex (4.69; 1.52-14.52; P = 0.007), serum bilirubin (2.78; 1.31-5.90; P = 0.008) and AFP (1.000; 1.000-1.001; P = 0.006) were significantly correlated with shortened survival. CONCLUSION: High levels of AFP and API predict IDR of HBV-related HCC after RFA. Therefore, noninvasive fibrosis indices could play an important role in predicting IDR of HCC following percutaneous ablation.
Liver international: official journal of the International Association for the Study of the Liver 01/2013; · 3.82 Impact Factor
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Dong Hyeon Lee,
Yuri Cho,
Ji Yeon Seo,
Jung Hee Kwon,
Eun Ju Cho,
Eun Sun Jang,
Min-Sun Kwak,
Jae Youn Cheong,
Sung Won Cho,
Jeong-Hoon Lee,
Su Jong Yu,
Jung-Hwan Yoon,
Hyo-Suk Lee,
Chung Yong Kim,
Hyoung Doo Shin, Yoon Jun Kim
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ABSTRACT: Background: Polymorphisms near the IL28B gene have been proposed to be strongly associated with treatment response and the rate of spontaneous clearance of hepatitis C virus infection, and treatment response of hepatitis B virus (HBV) infection. In this study, we aimed to determine whether these polymorphisms could affect natural courses of HBV infection. Methods: Genetic variations were identified through direct DNA sequencing using TaqMan assay in 1,439 patients with past or present HBV infection. Subjects included 404 spontaneously recovered patients, 313 chronic hepatitis B (CHB) patients, 305 liver cirrhosis (LC) patients and 417 hepatocellular carcinoma (HCC) patients. Three polymorphisms near the IL28B gene, rs8099917T>G, rs12979860C>T and rs12980275A>G, were identified. Associations between these polymorphisms and HBV clearance, hepatitis B e antigen (HBeAg) clearance as well as HCC occurrence among patients were analyzed using logistic regression analyses adjusted for age and gender. Results: There were no significant associations between these polymorphisms and the HBV clearance both in CHB and LC groups. Similarly, these polymorphisms showed no significant associations with HBeAg clearance and the occurrence of HCC either. Discussion: No significant association was identified between polymorphisms near the IL28B gene and the natural courses of chronic HBV infection, including the HBV clearance and HCC occurrence.
Intervirology 01/2013; · 2.34 Impact Factor
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ABSTRACT: PURPOSE: Transarterial chemoembolization (TACE) is highly effective and safe therapeutic modality for unresectable hepatocellular carcinoma (HCC). However, the role of TACE for infiltrative HCC has never been elucidated owing to the concern about hepatic failure and subsequent mortality after the procedure. In this study, we aimed to document whether patients with infiltrative HCC would benefit from TACE. METHODS: Child-Pugh class A/B patients who were newly diagnosed as infiltrative HCC and treated with curative-intent TACE were enrolled. All radiological images were reviewed by a radiologist with more than 20 years of experience in TACE. RESULTS: Among 1,184 patients newly diagnosed as HCC, 233 (19.7 %) had infiltrative-type tumors and 128 (54.9 %) underwent curative-intent TACE. Although the median overall survival was 5.4 months (IQR 3.1-13.9 months) and 16 (12.5 %) patients had experienced significant complications, 19 (15.9 %) patients survived more than 2 years after the first diagnosis. In multivariable analysis, age >60 years old (HR 0.54, 95 % CI 0.31-0.92), Child-Pugh class A (HR 0.48, 95 % CI 0.30-0.76), and a major PVT without parasitic supply (HR 0.66, 95 % CI 0.44-0.99) were independent favorable prognostic factors. Development of significant complication after TACE was a significant hazard factor of survival (HR 1.99, 95 % CI 1.09-3.62). CONCLUSIONS: In carefully selected patients with preserved hepatic function and good performance, TACE may achieve long-term survival of infiltrative HCC patients with major PVT without parasitic supply. However, the risk of morbidity and immediate mortality after TACE should be considered to select subjects for the procedure.
Journal of Cancer Research and Clinical Oncology 01/2013; · 2.56 Impact Factor
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ABSTRACT: Serum bilirubin exerts antioxidant and cytoprotective effects. In addition, elevated serum bilirubin levels are associated with a decreased risk of metabolic and cardiovascular diseases. However, few studies have evaluated whether serum bilirubin is associated with non-alcoholic fatty liver disease (NAFLD), which is closely associated with other metabolic diseases. The aim of this study was thus to elucidate the association between serum total bilirubin levels and NAFLD.
A cross-sectional study of 17,348 subjects undergoing a routine health check-up was conducted. Subjects positive for hepatitis B or hepatitis C virus, or with other hepatitis history were excluded. NAFLD was diagnosed on the basis of typical ultrasonographic findings and an alcohol consumption of less than 20 g/day.
The mean age of the subjects was 49 years and 9,076 (52.3%) were men. The prevalence of NAFLD decreased steadily as the serum bilirubin level increased in both men and women (P<0.001 for both). Multivariate regression analysis adjusted for other metabolic risk factors showed that serum bilirubin level was inversely associated with the prevalence of NAFLD [odds ratio (OR)=0.88, 95% confidence interval (CI)=0.80-0.97]. Furthermore, there was an inverse, dose-dependent association between NAFLD and serum total bilirubin levels (OR=0.83, 95% CI=0.75-0.93 in the third quartile; OR=0.80, 95% CI=0.71-0.90 in the fourth quartile vs. lowest quartile, P for trend <0.001).
Serum bilirubin levels were found to be inversely associated with the prevalence of NAFLD independent of known metabolic risk factors. Serum bilirubin might be a protective marker for NAFLD.
Clinical and molecular hepatology. 12/2012; 18(4):383-90.
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Yuri Cho,
Dong Hyeon Lee,
Kwang Hyun Chung,
Eunhyo Jin,
Jeong-Hoon Lee,
Eun Ju Cho,
Su Jong Yu,
Jin Wook Kim,
Sook Hyang Jeong,
Jung-Hwan Yoon,
Hyo-Suk Lee,
Chung Yong Kim, Yoon Jun Kim
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ABSTRACT: BACKGROUND: The efficacy of adefovir (ADV) plus entecavir (ETV) combination in patients with chronic hepatitis B (CHB) who developed multidrug refractoriness had not been fully evaluated. We aimed to evaluate the efficacy of ADV plus ETV as compared to that of lamivudine (LAM) plus ADV in the patients with antiviral refractoriness to sequential LAM monotherapy and then ADV monotherapy. METHODS: Twenty-seven patients were treated with a combination of ADV plus ETV and 63 patients were treated with a combination of LAM plus ADV. The virological and biochemical parameters were compared between the two groups, retrospectively. RESULTS: Treatment with a combination of ADV plus ETV produced significantly superior virological response than that of a combination of LAM plus ADV. At 12 months, the HBV DNA declined more in the ADV plus ETV group than in the LAM plus ADV (-4.52 ± 1.956 vs. -2.65 ± 1.723 log(10)IU/mL; p = 0.001). The rate of a complete response at 12 months was greater in the ADV plus ETV group than that in the LAM plus ADV group (63.16 vs. 14.81 %, p < 0.001). CONCLUSION: In the patients with CHB refractory to both LAM and ADV, the response to ADV plus ETV was significantly superior compared to that of the LAM plus ADV in suppressing HBV DNA. The result indicates that ADV plus ETV can be used as a bridging therapy in the patients with refractoriness to both LAM and ADV, especially in the areas where tenofovir is not yet available.
Digestive Diseases and Sciences 11/2012; · 2.12 Impact Factor
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ABSTRACT: Although lamivudine (LAM) prophylaxis is recommended for patients infected with hepatitis B virus (HBV) undergoing chemotherapy for malignant disease, HBV reactivation sometimes occurs during or after LAM administration. The aim of this study was to determine predictors of LAM prophylactic failure in patients with malignancies. Patients with malignancies were routinely screened for serum hepatitis B surface antigen (HBsAg) from June 2002 to August 2008. All consecutive, HBsAg-positive patients received LAM prophylaxis during and after completion of chemotherapy. We assessed risk factors for virologic breakthrough and withdrawal hepatitis. Death without HBV reactivation was regarded as a competing risk event, which was adjusted by Fine and Gray's model. A total of 110 patients were included in this study. They received LAM prophylaxis for a median of 9.2 months. Virologic breakthrough occurred in 15 patients at a median of 10.9 months from the initiation of LAM prophylaxis. Withdrawal hepatitis occurred in 15 patients at a median of 2.4 months after cessation of LAM prophylaxis. Multivariable analysis showed that high baseline HBV DNA titer (≥2,000 IU/ml) (hazard ratio [HR], 9.94; P = 0.0063) and the use of rituximab (HR, 3.19; P = 0.027) were significant predictors of virologic breakthrough and that high baseline HBV DNA titer (HR, 5.90; P = 0.007), liver cirrhosis (HR, 10.4; P = 0.002), and distant metastasis (HR, 5.14; P = 0.008) were independent risk factors for withdrawal hepatitis. Patients with high viremia, liver cirrhosis, rituximab treatment, and distant metastasis are at high risk of prophylactic failure and need antiviral agents with a greater barrier to resistance.
Antimicrobial Agents and Chemotherapy 08/2012; 56(11):5511-9. · 4.84 Impact Factor
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ABSTRACT: Thymosin α-1 plus interferon α-2a offers superior efficacy over interferon α-2a alone in patients with chronic hepatitis B. The aim was to compare the antiviral efficacy of thymosin α-1 plus peginterferon α-2a and peginterferon α-2a alone in HBeAg-positive chronic hepatitis B patients.
HBeAg-positive CHB patients were enrolled in this prospective, randomized, open-label study. Fifty-one patients were assigned to either combination (26 patients; 180 μg of peginterferon α-2a weekly for 48 weeks and 1.6 mg of thymosin α-1 twice a week for the first 12 weeks) or monotherapy (25 patients; 180 μg of peginterferon α-2a weekly for 48 weeks) groups.
The rates of the combined response, defined as HBeAg seroconversion, HBV DNA suppression, and normalization of serum ALT, were 4/26 (15.4%) and 3/25 (12.0%) for the combination group and the monotherapy group at the end of treatment (p = 0.725), and 6/26 (23.1%) and 5/25 (20.0%) at the end of follow-up (p = 0.789), respectively. Based on multiple logistic regression analysis, a >2 log₁₀ IU/mL reduction of HBV DNA at week 12 was identified as an independent predictor for combined response (OR, 9.72; 95% CI, 1.33-71.06; p = 0.025) at the end of follow-up. A lower pretreatment HBV DNA level (≤ 7 log(10) IU/mL) was another predictor for combined response (OR, 9.64; 95% CI, 1.23-75.32; p = 0.031). No significant differences in adverse events were observed.
The short-term addition of thymosin α-1 was not superior to peginterferon α-2a alone in HBeAg-positive CHB patients on the basis of antiviral efficacy.
Scandinavian journal of gastroenterology 06/2012; 8-9(47):1048-55. · 2.08 Impact Factor
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Naoki Oishi,
Mia R Kumar,
Stephanie Roessler,
Junfang Ji,
Marshonna Forgues,
Anuradha Budhu,
Xuelian Zhao,
Jesper B Andersen,
Qing-Hai Ye,
Hu-Liang Jia,
Lun-Xiu Qin,
Taro Yamashita,
Hyun Goo Woo, Yoon Jun Kim,
Shuichi Kaneko,
Zhao-You Tang,
Snorri S Thorgeirsson,
Xin Wei Wang
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ABSTRACT: Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. Conclusion: Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC. (HEPATOLOGY 2012).
Hepatology 06/2012; · 11.66 Impact Factor
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ABSTRACT: MicroRNAs have been recently identified as important regulators that influence human carcinogenesis, cancer progression, and the interaction between the host and virus. This study investigates an association between microRNAs (miR-101-1, miR-101-2, and miR-338) and the risk of liver diseases through clearance of hepatitis B virus infection, development of liver cirrhosis, and hepatocellular carcinoma occurrence.
Genetic variations were genotyped using the TaqMan assay in 1439 Korean hepatitis B virus patients. To investigate the relationship between four polymorphisms in three microRNAs and the disease phenotypes, differences in frequency distribution of variations were analysed using logistic and multiple regression analyses after adjusting for age and gender as covariates.
We find that the rs7536540 polymorphism in miR-101-1 is significantly associated with development of liver cirrhosis and hepatocellular carcinoma occurrence. In addition, rs12375841 and its unique haplotype (ht2) in miR-101-2 show significant association with clearance of hepatitis B virus infection.
To our knowledge, this is the first study to examine a relationship between the three microRNA genes and the risk of hepatitis B-related liver diseases. We expect that the findings in this study will be helpful to further genetic studies in the pathophysiology of hepatitis B virus-related liver diseases.
Digestive and Liver Disease 05/2012; 44(10):849-54. · 3.05 Impact Factor
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ABSTRACT: Human v-Fos Finuel-Biskis-Jinkins (FBJ) murine osteosarcoma viral oncogene homolog (FOS) is located in 14q24.3. The FOS protein is a constituent of the activating protein-1 (AP-1) and its increased expression
in the hepatocellular carcinoma (HCC) have been reported. In this study, the association of FOS polymorphisms with the HBV infection and HCC occurrence were evaluated in Korean patients. After re-sequencing in 24 unrelated
healthy individuals, two common single nucleotide polymorphisms (SNPs) in regulatory regions that were selected based on linkage
disequilibrium were genotyped in a total of 1,093 Korean subjects including 656 HBV chronic carriers, who were further stratified
into chronic hepatitis/liver cirrhosis (CH/LC, n = 339) and HCC (n = 317) groups, and 437 spontaneously recovered (SR) controls. Logistic regression and Cox relative hazard analysis showed
no significant association of regulatory polymorphisms and haplotypes in FOS with HBV clearance and HCC development (P > 0.05, respectively).
KeywordsHepatitis B virus–Hepatocellular carcinoma–
FOS
–Single nucleotide polymorphism
Genes & genomics 04/2012; 33(4):327-333. · 0.44 Impact Factor
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Jason Yongha Kim,
Jeong-Hyun Kim,
Tae Joon Park,
Jin Sol Lee,
Charisse Flerida Pasaje,
Joon Seol Bae,
Byung-Lae Park,
Hyun Sub Cheong,
Hyo-Suk Lee, Yoon Jun Kim,
Hyoung Doo Shin
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ABSTRACT: Development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The transferrin (TF) gene encodes a blood plasma protein that delivers iron ion in the body. The iron uptake level has been shown to be different
in HCC tumor regions, indicating a possible association between iron uptake level and HCC. To investigate whether genetic
polymorphisms of TF are related with HBV clearance and/or HCC occurrence, we sequenced genomes of 24 individuals and detected 37 variants. Subsequently,
eight single nucleotide polymorphisms (SNPs) in TF including 4 in the promoter region, 1 in 5′UTR and 3 in coding regions were selected and genotyped in 1,101 Korean subjects
including 428 spontaneously recovered (SR) patients as controls and 673 chronic carriers (CC) as cases. Results of logistic
analyses adjusted for age and gender, however, revealed no significant associations of polymorphisms and haplotypes in the
TF gene with HBV clearance and HCC occurrence (P > 0.05). Since age of HBV infection is a risk factor in progression to HCC, further Cox proportional regression analysis
for age of HCC as a relative hazard was performed; but no association between TF polymorphisms and onset age of HCC was found (P > 0.05). Although TF gene polymorphisms have been previously reported to be associated with various diseases, our findings indicate that genetic
variations of the TF gene do not influence HBV clearance and HCC occurrence in a Korean population.
KeywordsTransferrin–Single nucleotide polymorphism–Hepatitis B virus infection–Hepatocellular carcinoma
Genes & genomics 04/2012; 33(3):209-215. · 0.44 Impact Factor
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ABSTRACT: The aim of this study was to characterize the relationship between the broad spectrum of hypothyroidism and NAFLD.
A cross-sectional study with 4648 health check-up subjects (2324 cases with hypothyroidism vs. age- and sex-matched controls) was conducted. The subjects were categorized as having either subclinical [thyroid-stimulating hormone (TSH) ≥4.1 mIU/L and normal free thyroixine (T(4)) level (0.7-1.8 ng/dl)] or overt hypothyroidism [free T(4)<0.7 ng/dl]. NAFLD was diagnosed on the basis of typical ultrasonographic findings, and alcohol consumption of less than 20 g/day in the absence of other causes of liver disease.
The mean age of the subjects was 48.6±11.8 years and 62.4% were female. NAFLD was significantly associated with hypothyroidism (30.2% patients vs. 19.5% control, p<0.001). The prevalence of NAFLD and abnormal liver enzyme levels (ALT>33/25 IU/L) increased steadily with increasing grades of hypothyroidism (for NAFLD, subclinical: 29.9% and overt: 36.3%; for abnormal ALT, 20.1% and 25.9%, p<0.001, respectively). Multivariate regression analysis showed that NAFLD was statistically significantly associated with hypothyroidism (odds ratio (OR) 1.38, 95% confidence interval (CI), 1.17-1.62) and the grade of hypothyroidism in a dose-dependent manner (OR 1.36, 95% CI, 1.16-1.61 in subclinical hypothyroidism and OR 1.71, 95% CI, 1.10-2.66 in overt hypothyroidism).
Subclinical hypothyroidism, even in the range of upper normal TSH levels, was found to be related to NAFLD in a dose-dependent manner. Hypothyroidism is closely associated with NAFLD independently of known metabolic risk factors, confirming a relevant clinical relationship between these two diseases.
Journal of Hepatology 03/2012; 57(1):150-6. · 9.26 Impact Factor
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ABSTRACT: There is little clinical information on the management of hepatitis B virus (HBV) that is resistant to multiple drugs including entecavir (ETV). The present retrospective cohort study assessed the antiviral efficacy of ETV/adefovir dipivoxil (ADV) combination therapy for ETV-resistant HBV with prior lamivudine (LAM) resistance, and either with or without previous ADV resistance. The cumulative probability of achieving a virological response (undetectable serum HBV DNA) was compared by Kaplan-Meier analysis and the Breslow method. Seventeen patients with ETV-resistant HBV who were treated with ETV/ADV combination therapy for at least 6 months at a tertiary care center, were included; seven had dual resistance to ETV and LAM [ADV-r(-) group] and 10 had triple resistance to ETV, LAM, and ADV [ADV-r(+) group]. The median follow-up period was 9 months (range, 6-23). A virological response was noted in seven patients after a median of 3 months (range, 3-12) of treatment; five in the ADV-r(-) group and two in the ADV-r(+) group. The cumulative probability of a virological response was significantly higher in the ADV-r(-) group than in the ADV-r(+) group (6 months cumulative probability, 57.1% vs. 11.1%). In conclusion, ETV/ADV combination therapy led to virological responses in five of seven patients with resistance to ETV and LAM, but a significantly poorer response in patients with prior ADV resistance than in those without prior ADV resistance. Therefore, ETV/ADV combination therapy could be a useful therapeutic option for ETV- and LAM-resistant HBV without prior ADV resistance.
Journal of Medical Virology 03/2012; 84(3):424-30. · 2.82 Impact Factor
