Showing papers by "Kwang Hyub Han published in 2013"

Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90.

Abstract: Background/Purpose: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) have an extremely poor prognosis and relatively few trea

A nationwide seroepidemiology of hepatitis C virus infection in South Korea

Abstract: Background & Aims The aim of this study was to reveal nationwide seroprevalence of HCV infection in South Korea by a large-scale survey. Methods From January to December 2009, a total of 291 314 adults underwent health check-up in 29 centres nationwide. The data concerning anti-HCV antibody and biochemical tests were obtained from all participants. Among subjects with positive anti-HCV, such data as HCV RNA, genotypes and treatment detail were additionally analysed. Results Using an estimated 2009 population of Korea, the age, sex and area-adjusted anti-HCV positive rate was 0.78%. Anti-HCV prevalence in female patients (0.83%) was higher than that in male patients (0.75%). Gradual increase in anti-HCV positivity was observed, from 0.34% in those aged 20–29 years to 2.31% in those >70 years. The age- and sex-adjusted anti-HCV prevalence varied in different areas, being higher in Busan and Jeonnam (1.53–2.07%), mid-level in Seoul and surrounding districts (0.50–0.61%) and lower in Jeju (0.23%). The comparative analysis of laboratory variables between anti-HCV (+) and anti-HCV (−) group revealed significantly higher levels of alanine aminotransferase and lower levels of serum lipids in anti-HCV (+) group. Among 1 718 anti-HCV positive subjects, serum HCV RNA was measured only in 478 people, of whom 268 (56.1%) patients had detectable HCV RNA in serum. Among 50 patients for whom assessment of response to antiviral therapy was feasible, overall sustained virological response was achieved in 84% of patients. Conclusion The prevalence of HCV infection is low in South Korea. Studies to analyse risk factors are warranted to reduce HCV infection.

Consensus recommendations and review by an International Expert Panel on Interventions in Hepatocellular Carcinoma (EPOIHCC)

Abstract: Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate-stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non-response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long-term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens.

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia–Pacific region

Abstract: Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide. Although hepatitis B still remains the most common risk factor worldwide, chronic hepatitis C virus (HCV) infection is the driving force for the increased incidence of HCC especially in Western countries and Japan. In hepatitis B virus (HBV)-endemic areas, after successful vaccination programs against HBV, chronic HCV infection is now emerging as an important cause of chronic liver diseases. Unlike patients with chronic hepatitis B, those with chronic hepatitis C (CHC) develop HCC in the presence of established cirrhosis in most cases. However, a significant minority of CHC develops HCC in the absence of cirrhosis. Although HCV is a RNA virus with little potential for integrating its genetic material into host genome, various HCV proteins, including core, envelope, and nonstructural proteins, have oncogenic properties by inducing oxidative stress, disturbing cellular regulatory pathways associated with proliferation and apoptosis, and suppressing host immune responses. Overall, a combination of virus-specific, host genetic, environmental, and immune-related factors are likely to determine progression to HCC. Strategies aimed at eliminating the virus may provide opportunities for effective prevention of the development of HCC. Pegylated interferon plus ribavirin therapy appears to be effective at reducing the risk of HCC in patients who achieve sustained virologic responses. In summary, with the emerging importance of CHC, mechanisms of HCV-associated hepatocellular carcinogenesis should be clarified to provide insight into advanced therapeutic and preventive approaches, which eventually decrease the incidence and mortality of HCC.

Prognostic value of α-fetoprotein and des-γ-carboxy prothrombin responses in patients with hepatocellular carcinoma treated with transarterial chemoembolization.

Abstract: Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) have been used as diagnostic tools for hepatocellular carcinoma (HCC). However, prediction of outcome using AFP and DCP has not been elucidated. We investigated the clinical role of AFP and DCP as predictors of treatment outcome in patients with HCC undergoing trans-arterial chemoembolization (TACE). Between January 2003 and December 2005, we enrolled 115 treatment-naive patients who received TACE as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 50% from the baseline level 1 month after TACE. Patients with AFP 0.05). Multivariate analyses showed that gamma-glutamyltranspeptidase and baseline AFP were predictors of PFS (all P < 0.05) and that male gender, the presence of liver cirrhosis, baseline DCP, number of measurable tumors and AFP response were independent predictors of OS (all P < 0.05). AFP response and higher baseline DCP level are significant predictors of OS in treatment-naive patients with HCC receiving TACE who showed pretreatment elevation of both AFP and DCP.

Characterization of focal liver masses using acoustic radiation force impulse elastography

Abstract: CONCLUSION: ARFI elastography provides additional information for the differential diagnosis of liver masses. However, our results should be interpreted in clinical context, because considerable overlap in ARFI values existed among liver masses.

Prognostic value of α-fetoprotein and des-γ-carboxy prothrombin responses in patients with hepatocellular carcinoma treated with transarterial chemoembolization

Abstract: Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) have been used as diagnostic tools for hepatocellular carcinoma (HCC). However, prediction of outcome using AFP and DCP has not been elucidated. We investigated the clinical role of AFP and DCP as predictors of treatment outcome in patients with HCC undergoing trans-arterial chemoembolization (TACE). Between January 2003 and December 2005, we enrolled 115 treatment-naive patients who received TACE as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 50% from the baseline level 1 month after TACE. Patients with AFP 0.05). Multivariate analyses showed that gamma-glutamyltranspeptidase and baseline AFP were predictors of PFS (all P < 0.05) and that male gender, the presence of liver cirrhosis, baseline DCP, number of measurable tumors and AFP response were independent predictors of OS (all P < 0.05). AFP response and higher baseline DCP level are significant predictors of OS in treatment-naive patients with HCC receiving TACE who showed pretreatment elevation of both AFP and DCP.

Prognostic significance of the worst grade in hepatocellular carcinoma with heterogeneous histologic grades of differentiation

Abstract: Background and aim Although tumor differentiation is a known prognostic factor after the treatment of hepatocellular carcinoma (HCC), there have not been any studies on the prognostic significance of tumor differentiation in HCC with heterogeneous histologic grades. In this study, we attempted to ascertain whether the major or the worst grade in mixed histologic type HCC determines the prognosis after liver resection. Methods From January 1996 to March 2010, a total of 724 patients underwent curative resection of HCC at Yonsei University Health System, Korea. Of those, we excluded 99 patients who had total necrosis because of previous treatment. Among the remaining 625 patients, we compared the homogeneous moderately differentiated group (HG2, n = 241), mixed histologic grades with the worst component as poorly differentiated group (M2, n = 142), and homogeneous poorly differentiated group (HG3, n = 156). The clinicopathologic features, disease-free survival (DFS) and overall survival (OS) in each group were analyzed. Results The DFS and OS were significantly lower in M2 than in HG2 (P = 0.004 and 0.025, respectively) whereas those of M2 were not significantly different from HG3. There were no significant differences in the clinicopathologic features of each group except that microvascular invasion was more frequently observed in M2 than in HG2. On multivariate analysis, being in the worst histologic group (M2 and HG3) was an independent poor prognostic factor for DFS and OS (P = 0.028 and Conclusions In patients with advanced histologic grade, the worst histologic grade may determine the prognosis after curative resection of HCC.

Survival of hepatocellular carcinoma patients may be improved in surveillance interval not more than 6 months compared with more than 6 months: a 15-year prospective study.

Abstract: GOALS To compare hepatocellular carcinoma (HCC) stage, treatment modality, and survival between groups submitted to different surveillance interval. BACKGROUND It is not clear if surveillance interval affects patient survival with HCC. STUDY Clinical data from 10,307 patients at risk for HCC were prospectively collected from 1990 to 2005. The characteristics of cancer and 5-year survival in patients diagnosed as HCC during follow-up were compared between surveillance interval of 6 months (n=219; 3.0 ± 1.7 cm vs. n=181; 4.0 ± 2.6 cm, P 6 months even after considering lead time with assumed tumor doubling time of 60 days. The 5-year survival of HCC patients surveyed between 2000 and 2004 was significantly higher compared with those surveyed between 1990 and 1994 or between 1995 and 1999 (41% vs. 17% and 19%, respectively, P<0.0001). Using a Cox regression model, Child-Pugh class, Japanese tumor-node-metastasis stage, and α-fetoprotein levels were independently associated with patient survival. CONCLUSIONS Our data show that surveillance ≤ 6 months might be associated with early detection of HCC and improved survival in a hepatitis B endemic area.

Number of Target Lesions for EASL and Modified RECIST to Predict Survivals in Hepatocellular Carcinoma Treated with Chemoembolization

Abstract: Purposes: To date, most studies about the optimal number of target lesions for enhancement criteria for hepatocellular carcinoma (HCC) have focused on cross-sectional analyses of concordance. We investigated the optimal number of target lesions for European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines in predicting overall survival (OS). Experimental Design: We analyzed 254 consecutive treatment-naive patients with HCC having at least 2 measurable target lesions undergoing transarterial chemoembolization. Kappa values for intermethod agreement of treatment responses were calculated for comparisons between use of maximum of 1, 2, 3, 4, or 5 targets versus use of all target lesions. Prognostic values of radiologic assessments according to number of target lesions for predicting OS were expressed as C-index. Results: By EASL and mRECIST guidelines, κ values between responses assessing the longest 2, 3, 4, or 5 targets and assessing all targets were 0.924, 0.977, 1.000, or 1.000 and 0.907, 0.959, 1.000, or 1.000, respectively, whereas those between responses assessing only one target and assessing all target lesions were 0.723 and 0.666, respectively. C-index when measuring the longest 1, 2, 3, 4, 5, and all targets was similar, ranging from 0.739 to 0.749 for EASL criteria and from 0.750 to 0.759 for mRECIST. From Cox regression analyses, radiologic response from each calculation method showed independently significant effects on OS for both guidelines, regardless of number of target lesions. Conclusions: Prognostic values for predicting OS were similar regardless of number of target lesions. Assessing the 2 largest targets rather than only 1 index lesion could be recommended considering high concordances from cross-sectional analyses. Clin Cancer Res; 19(6); 1503–11. ©2012 AACR .

Transient elastography-based risk estimation of hepatitis B virus-related occurrence of hepatocellular carcinoma: development and validation of a predictive model.

Abstract: Background The purpose of this study was to develop and validate a novel transient elastography-based predictive model for occurrence of hepatocellular carcinoma (HCC).

Role of surgical resection for multiple hepatocellular carcinomas.

Abstract: AIM: To clarify the role of surgical resection for multiple hepatocellular carcinomas (HCCs) compared to transarterial chemoembolization (TACE) and liver transplantation (LT). METHODS: Among the HCC patients who were managed at Yonsei University Health System between January 2003 and December 2008, 160 patients who met the following criteria were retrospectively enrolled: (1) two or three radiologically diagnosed HCCs; (2) no radiologic vascular invasion; (3) Child-Pugh class A; (4) main tumor smaller than 5 cm in diameter; and (5) platelet count greater than 50 000/mm3. Long-term outcomes were compared among the following three treatment modalities: surgical resection or combined radiofrequency ablation (RFA) (n = 36), TACE (n = 107), and LT (n = 17). The survival curves were computed using the Kaplan-Meier method and compared with a log-rank test. To identify the patients who gained a survival benefit from surgical resection, we also investigated prognostic factors for survival following surgical resection. Multivariate analyses of the prognostic factors for survival were performed using the Cox proportional hazard model. RESULTS: The overall survival (OS) rate was significantly higher in the surgical resection group than in the TACE group (48.1% vs 28.9% at 5 years, P < 0.005). LT had the best OS rate, which was better than that of the surgical resection group, although the difference was not statistically significant (80.2% vs 48.1% at 5 years, P = 0.447). The disease-free survival rates were also significantly higher in the LT group than in the surgical resection group (88.2% vs 11.2% at 5 years, P < 0.001). Liver cirrhosis was the only significant prognostic factor for poor OS after surgical resection. Clinical liver cirrhosis rates were 55.6% (20/36) in the resection group and 93.5% (100/107) in the TACE group. There were 19 major and 17 minor resections. En bloc resection was performed in 23 patients, multi-site resection was performed in 5 patients, and combined resection with RFA was performed in 8 patients. In the TACE group, only 34 patients (31.8%) were recorded as having complete remission after primary TACE. Seventy-two patients (67.3%) were retreated with repeated TACE combined with other therapies. In patients who underwent surgical resection, the 16 patients who did not have cirrhosis had higher 5-year OS and disease-free survival rates than the 20 patients who had cirrhosis (80.8% vs 25.5% 5-year OS rate, P = 0.006; 22.2% vs 0% 5-year disease-free survival rate, P = 0.048). Surgical resection in the 20 patients who had cirrhosis did not provide any survival benefit when compared with TACE (25.5% vs 24.7% 5-year OS rate, P = 0.225). Twenty-nine of the 36 patients who underwent surgical resection experienced recurrence. Of the patients with cirrhosis, 80% (16/20) were within the Milan criteria at the time of recurrence after resection. CONCLUSION: Among patients with two or three HCCs, no radiologic vascular invasion, and tumor diameters ≤ 5 cm, surgical resection is recommended only in those without cirrhosis.

Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis

Abstract: Although sorafenib has been approved for treating advanced hepatocellular carcinoma (HCC), its high cost, frequent adverse events, and unsatisfactory efficacy remain unresolved. We evaluated the efficacy and safety of the combination treatment of localized concurrent chemoradiation therapy (CCRT) for locally advanced HCC with portal vein thrombosis (PVT) and transarterial chemoembolization (TACE) for intrahepatic metastasis. Between January 2006 and June 2011, 30 patients with HCC with portal vein invasion and intrahepatic metastasis were enrolled. After TACE for intrahepatic metastasis, localized CCRT (45 Gy over 5 weeks with conventional fractionation and hepatic artery infusional chemotherapy using 5-fluorouracil as a radiosensitizer, administered during the first and fifth weeks of radiotherapy) was used to treat main HCC with PVT. The modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate tumor response. The median age of the patients (26 men, 4 women) was 51 years. Objective response rates were 30.0 % (9/30) and 32.1 % (9/28) in the intention-to-treat and per protocol analyses, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.5 and 9.8 months, respectively. Baseline α-fetoprotein (AFP) correlated significantly with PFS (P = 0.008), whereas baseline AFP, completion of the protocol, and overall radiological response influenced OS significantly (all P < 0.05). All adverse events were predictable and manageable with conservative care. Combination treatment of localized CCRT and TACE was effective and tolerable in patients with locally advanced HCC with PVT and intrahepatic metastasis. This protocol may be an alternative option when sorafenib cannot be prescribed.

Association between IL28B Polymorphisms and Spontaneous Clearance of Hepatitis B Virus Infection

Abstract: Background/Aims Single-nucleotide polymorphisms (SNPs) near the interleukin 28B gene (IL28B; interferon [IFN]-λ-3) are associated with outcomes of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection treated with peginterferon (PEG-IFN) alpha-based antiviral therapy. In this study, we investigated the influence of IL28B polymorphisms on spontaneous clearance of HBV infection in a large Korean cohort.

Investigation of Oncogenic Cooperation in Simple Liver-Specific Transgenic Mouse Models Using Noninvasive In Vivo Imaging

Abstract: Liver cancer is a complex multistep process requiring genetic alterations in multiple proto-oncogenes and tumor suppressor genes. Although hundreds of genes are known to play roles in hepatocarcinogenesis, oncogenic collaboration among these genes is still largely unknown. Here, we report a simple methodology by which oncogenic cooperation between cancer-related genes can be efficiently investigated in the liver. We developed various non-germline transgenic mouse models using hydrodynamics-based transfection which express HrasG12V, SmoM2, and a short-hairpin RNA down-regulating p53 (shp53) individually or in combination in the liver. In this transgenic system, firefly luciferase was co-expressed with the oncogenes as a reporter, allowing tumor growth in the liver to be monitored over time without an invasive procedure. Very strong bioluminescence imaging (BLI) signals were observed at 4 weeks post-hydrodynamic injection (PHI) in mice co-expressing HrasG12V and shp53, while only background signals were detected in other double or single transgenic groups until 30 weeks PHI. Consistent with the BLI data, tumors were observed in the HrasG12V plus shp53 group at 4 weeks PHI, while other transgenic groups failed to exhibit a hyperplastic nodule at 30 weeks PHI. In the HrasG12V plus shp53 transgenic group, BLI signals were well-correlated with actual tumor growth in the liver, confirming the versatility of BLI-based monitoring of tumor growth in this organ. The methodology described here is expected to accelerate and facilitate in vivo studies of the hepatocarcinogenic potential of cancer-related genes by means of oncogenic cooperation.

Feasibility of sorafenib combined with local radiotherapy in advanced hepatocellular carcinoma.

Abstract: Purpose Sorafenib is an effective systemic agent for advanced hepatocellular carcinoma. To increase its efficacy, we evaluated the feasibility and benefit of sorafenib combined with radiotherapy.

Early on-treatment change in liver stiffness predicts development of liver-related events in chronic hepatitis B patients receiving antiviral therapy.

Abstract: Backgrounds/Aims Monitoring fibrosis is mandatory for detailed prognostification in patients with chronic liver disease. We developed optimized cut-offs for liver stiffness (LS) values, based on the histological subclassification of cirrhosis, and investigated whether early on-treatment changes in LS values can predict long-term prognosis in patients with hepatitis B virus (HBV)-related advanced liver fibrosis receiving antiviral therapy. Methods Between 2005 and 2008, 103 patients with F3 or F4 fibrosis on liver biopsy were enrolled prospectively. Cirrhosis was subclassified into three groups (F4A, F4B and F4C) according to Laennec system. The primary end-point was occurrence of liver-related event (LRE), including decompensation, hepatocellular carcinoma and liver-related death. Results Suggested LS cut-offs for predicting F4B-FC (vs. F3-F4A) and F4C (vs. F3-F4B) were 11.6 and 18.2 kPa respectively. As proportions of patients with LRE occurrence increased according to histological subclassifications stage F3-4A vs. F4B-4C (7.4% vs. 17.1%) and stage F3-4B vs. F4C (13.8% vs. 18.8%), they also increased according to LS cut-off value of 11.6 kPa (5.9% vs. 23.1%) and 18.2 kPa (9.8% vs. 33.3%) respectively (all P < 0.05). Similarly, according to stratified LS values (<11.6, 11.6–18.2 and ≥18.2 kPa), overall incidence of LREs and each constituent event increased significantly (all P < 0.05). In addition, the observed changes in LS values between baseline and 6 months of follow-up showed significant correlations with LRE development. Conclusions Stratified LS values based on Laennec system and dynamic changes in LS values on follow-up may be helpful in assessing risk of LREs in subjects with HBV-related advanced liver fibrosis receiving antiviral therapy.

Investigation of Oncogenic Cooperation in Simple Liver-Specific Transgenic Mouse Models Using Noninvasive In Vivo Imaging

Abstract: Liver cancer is a complex multistep process requiring genetic alterations in multiple proto-oncogenes and tumor suppressor genes. Although hundreds of genes are known to play roles in hepatocarcinogenesis, oncogenic collaboration among these genes is still largely unknown. Here, we report a simple methodology by which oncogenic cooperation between cancer-related genes can be efficiently investigated in the liver. We developed various non-germline transgenic mouse models using hydrodynamics-based transfection which express HrasG12V, SmoM2, and a short-hairpin RNA down-regulating p53 (shp53) individually or in combination in the liver. In this transgenic system, firefly luciferase was co-expressed with the oncogenes as a reporter, allowing tumor growth in the liver to be monitored over time without an invasive procedure. Very strong bioluminescence imaging (BLI) signals were observed at 4 weeks post-hydrodynamic injection (PHI) in mice co-expressing HrasG12V and shp53, while only background signals were detected in other double or single transgenic groups until 30 weeks PHI. Consistent with the BLI data, tumors were observed in the HrasG12V plus shp53 group at 4 weeks PHI, while other transgenic groups failed to exhibit a hyperplastic nodule at 30 weeks PHI. In the HrasG12V plus shp53 transgenic group, BLI signals were well-correlated with actual tumor growth in the liver, confirming the versatility of BLI-based monitoring of tumor growth in this organ. The methodology described here is expected to accelerate and facilitate in vivo studies of the hepatocarcinogenic potential of cancer-related genes by means of oncogenic cooperation.

Efficacy of sorafenib monotherapy versus sorafenib-based loco-regional treatments in advanced hepatocellular carcinoma.

Abstract: BACKGROUND Although sorafenib is accepted as the standard of care in advanced hepatocellular carcinoma (HCC), its therapeutic benefit is marginal. Here, we aimed to compare the efficacy and safety of sorafenib monotherapy (S-M) and sorafenib-based loco-regional treatments (S-LRTs) in advanced HCC. METHODS From 2007 to 2012, 290 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) with S-M (n = 226) or S-LRTs (n = 64) were reviewed retrospectively. Survival outcomes and treatment-related toxicities between two groups were analyzed. RESULTS Variables related to tumor burden and liver function were similar between the groups (all P > 0.05). Within the entire population, the S-LRTs group had both longer median overall survival (OS) (8.5 vs 5.5 months, P = 0.001) and progression-free survival (PFS) (5.3 vs 3.0 months, P = 0.002) than the S-M group. Furthermore, the S-LRTs group had longer Os than the S-M group in a subgroup with neither extrahepatic spread (EHS) nor regional nodal involvement (RNI) (18.0 vs 7.8 months, P = 0.019) and in a subgroup with EHS and/or RNI (8.3 vs 4.8 months, P = 0.028). In addition, the S-LRTs group had longer PFS than the S-M group in the subgroup with neither EHS nor RNI (9.6 vs 3.2 months, P = 0.027). TREATMENT Related toxicity was similar between two groups. CONCLUSION Combined use of sorafenib and LRTs may provide better treatment outcomes without significantly increasing treatment-related toxicities, even in patients with EHS and/or RNI. Therefore, addition of active LRTs might be considered, if feasible.

Clinical Application of Liver Stiffness Measurement Using Transient Elastography: A Surgical Perspective

Abstract: Liver biopsy (LB) remains the gold standard for assessing the severity of liver fibrosis; however, LB is often limited by its invasiveness, sampling error, and intra-/inter-observer variability in histological interpretation. Furthermore, repeated LB examinations within a short time interval are ineligible in real clinical practice. Thus, due to the pressing need for non-invasive surrogates, over the past decade, significant progress has been made in non-invasively assessing liver fibrosis. Of the methods now available, transient elastography (TE) appears to be an excellent tool for assessing liver fibrosis and also has some prognostic value in surgical settings. Recent studies have proposed the extended role of TE in the surgical field, based on the concept that TE values show significant correlations with portal hypertension and hepatocellular carcinoma development. TE appears promising in predicting postoperative short-term outcomes such as hepatic insufficiency or complications and long-term outcomes such as recurrence or liver-related death. Furthermore, TE may be useful in predicting the severity of liver fibrosis progression due to recurrence of hepatitis C virus infection or other underlying liver diseases after transplantation. TE cannot completely replace other tests accompanied with hepatic surgical treatments, including LB, endoscopic examination, hepatic venous pressure gradient evaluation, or the indocyanine green retention test. However, TE represents an important non-invasive tool that enables more efficient and tailored management strategies for patients who were treated with liver resection or transplantation. This review discusses extended TE applications in the surgical setting, such as hepatic resection or transplantation.

Abnormal Liver Stiffness Assessed Using Transient Elastography (Fibroscan®) in HIV-Infected Patients without HBV/HCV Coinfection Receiving Combined Antiretroviral Treatment

Abstract: Background and Aims Liver stiffness measurement (LSM) using transient elastography (Fibroscan®) can identify individuals with potential underlying liver disease. We evaluated the prevalence of abnormal LSM values as assessed using LSM and its predictors in HIV-infected asymptomatic patients receiving combined antiretroviral treatment (cART) without HBV/HCV coinfection. Methods We prospectively recruited 93 patients who had consistently been undergoing cART for more than 12 months at Severance Hospital in Seoul, Republic of Korea, from June to December 2010. LSM values >5.3 kPa were defined as abnormal. Results Thirty-nine (41.9%) had abnormal LSM values. On multivariate correlation analysis, the cumulative duration of boosted and unboosted protease inhibitors (PIs) were the independent factors which showed a negative and positive correlation to LSM values, respectively (β = –0.234, P = 0.023 and β = 0.430, P<0.001). In multivariate logistic regression analysis, the cumulative exposure duration of boosted-PIs and γ-glutamyltranspeptidase levels were selected as the independent predictors which showed a negative and positive correlation with abnormal LSM values, respectively (odds ratio [OR], 0.941; 95% confidence interval [CI], 0.889–0.997; P = 0.039 and OR, 1.032; 95% CI, 1.004–1.060; P = 0.023). Conclusion The high percentage of HIV-infected asymptomatic patients receiving cART without HBV/HCV coinfection had abnormal LSM values. The cumulative exposure duration of boosted-PIs and γ-GT level were independent predictors which showed a negative and positive correlation with abnormal LSM values, respectively.

Antibody-Secreting Cells with a Phenotype of Ki-67low, CD138high, CD31high, and CD38high Secrete Nonspecific IgM during Primary Hepatitis A Virus Infection

Abstract: Although studies investigating the nature of Ab-secreting cells (ASCs) during acute infection with influenza or dengue virus found that the ASC response was dominated by virus-specific IgG secretion, the Ag specificity and phenotype of ASCs during primary acute viral infection were not identified. To this end, we investigated the nature of ASCs in direct ex vivo assays from patients with acute hepatitis A caused by primary infection with hepatitis A virus (HAV). We found that the frequency of CD27(high)CD38(high) ASCs was markedly increased in the peripheral blood during the acute phase of HAV infection. Moreover, substantial numbers of ASCs were non-HAV-specific and dominantly secreted IgM. We detected HAV-specific ASCs by staining with fluorochrome-tagged HAV-VP1 protein. As compared with HAV-specific ASCs, non-HAV-specific ASCs were Ki-67(low)CD138(high)CD31(high)CD38(high), demonstrating that non-HAV-specific ASCs had a bone marrow plasma cell-like phenotype whereas HAV-specific ASCs had a phenotype typical of circulating plasmablasts. These data suggest that non-HAV-specific ASCs might be mobilized plasma cells from the bone marrow or the spleen, whereas HAV-specific ASCs were newly generated plasmablasts. In this study, we provide evidence that pre-existing plasma cells are released into the circulation and contribute to Ag-nonspecific secretion of IgM during primary HAV infection.

Early Predictor of Mortality due to Irreversible Posthepatectomy Liver Failure in Patients with Hepatocellular Carcinoma

Abstract: Background Although mortality after liver resection has declined, posthepatectomy liver failure (PHLF) remains a major cause of operative mortality. To date there is not consensus on a definition for PHLF. However, there have been many efforts to define PHLF causing operative mortality. In the present study we sought to identify early predictors of death from irreversible PHLF.

Normal enhanced liver fibrosis (ELF) values in apparently healthy subjects undergoing a health check‐up and in living liver donors in South Korea

Abstract: Background The enhanced liver fibrosis (ELF) value is a non-invasive serum marker used for assessing liver fibrosis in chronic liver disease. To use the ELF value for the purpose of screening the general population and selecting subpopulations at high risk, it is important to know the normal range of ELF values as a prerequisite. Aims We aimed to define the normal range of ELF values by recruiting apparently healthy subjects and investigating factors influencing ELF values in subjects with minimal fibrotic burden. Methods ELF values were determined in a cohort of healthy subjects who underwent a health check-up and in healthy living liver donors who were screened for transplantation. None of subjects suffered from chronic heart disease, diabetes mellitus, metabolic syndrome, hepatitis B, hepatitis C, or human immunodeficiency virus infection, systemic autoimmune disease or liver dysfunction. Results Among 183 subjects analyzed, the normal ELF 5th through 95th percentile range was 5.95–8.73. Body mass index (P = 0.014) and male gender (P = 0.015) showed significant positive correlations with ELF value, whereas age did not. In multivariate linear regression analysis, platelet count was identified as the only independent factor influencing the ELF value (β=−0.006, P = 0.016). When considering the difference in ELF values between genders, the normal range of men was defined to be 6.72–8.93, this was slightly higher than that of women, 5.69–8.67. Conclusions We identified the normal range of ELF values and found that it can be significantly influenced by platelet count even in the healthy population.

Antiviral efficacies of currently available rescue therapies for multidrug-resistant chronic hepatitis B

Abstract: Background/Aims: The incidence of multidrug-resistant (MDR) chronic hepatitis B (CHB) during sequential lamivudine (LAM) and adefovir dipivoxil (ADV) treatment is increasing. We investigated the antiviral efficacies of various rescue regimens in patients who failed sequential LAM-ADV treatment. Methods: Forty-eight patients (83.3% of whom were HBeAg-positive) who failed sequential LAM-ADV treatment were treated with one of the following regimens: entecavir (ETV) (1 mg) monotherapy (n=16), LAM+ADV combination therapy (n=20), or ETV (1 mg)+ADV combination therapy (n=12). All patients had confirmed genotypic resistance to both LAM and ADV and were evaluated every 12 weeks. Results: The baseline characteristics and treatment duration did not differ significantly among the study groups. During the treatment period (median duration: 100 weeks), the decline of serum HBV DNA from baseline tended to be greatest in the ETV+ADV group at all-time points (week 48: -2.55 log10 IU/mL, week 96: -4.27 log10 IU/mL), but the difference was not statistically significant. The ETV+ADV group also tended to have higher virologic response rates at 96 weeks compared to the ETV monotherapy or LAM+ADV groups (40.0% vs. 20.0% or 20.0%, P=0.656), and less virologic breakthrough was observed compared to the ETV monotherapy or LAM+ADV groups (8.3% vs. 37.5% or 30.0%; P=0.219), but again, the differences were not statistically significant. HBeAg loss occurred in one patient in the ETV+ADV group, in two in the ETV monotherapy group, and in none of the LAM+ADV group. The safety profiles were similar in each arm. Conclusions: There was a nonsignificant tendency toward better antiviral effi cacy with ETV+ADV combination therapy compared to LAM+ADV combination therapy and ETV monotherapy for MDR CHB in Korea, where tenofovir is not yet available. (Clin Mol Hepatol 2013;19:29-35)

Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats

Abstract: We sought to determine the hepatic fibrosis-reversal effects upon simultaneous administration of lithospermate B (LAB), an anti-oxidant, and nivocasan, a caspase inhibitor, to rats compared with each compound alone. Liver fibrosis was induced in Sprague–Dawley rats by thioacetamide (TAA). Rats were treated with TAA and then given LAB and (or) nivocasan. Fibrotic areas were evaluated quantitatively by computerized morphometry. Apoptosis was assessed using a TUNEL assay, and immunohistochemical staining for malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE) was performed to assess oxidative stress levels. Real-time quantitative PCR was used to quantify expression of fibrosis-related genes. The degree of hepatic fibrosis was significantly reduced in rats treated with LAB and nivocasan compared to either treatment alone (P < 0.001). Treatment with each compound significantly decreased expression of fibrosis-related genes, such as type I collagen α1 (col1α1), α-SMA and TGF-β1 (P < 0.05). Co-treatment with LAB and nivocasan further reduced col1α1 expression compared to treatment with either compound. A TUNEL assay revealed that hepatocyte apoptosis was significantly decreased in the group treated with nivocasan compared to other groups (P < 0.01). Immunohistochemistry showed a decrease in MDA and 4HNE, reflecting amelioration of oxidative stress, when LAB or LAB+nivocasan was administered compared to nivocasan alone (P < 0.01). Nivocasan was found to inhibit caspase-1, -3, -7, -9 and gliotoxin-induced death of rat-derived hepatic stellate cells was inhibited by nivocasan administration without overexpression of α-SMA. Conclusions: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.

Discordance between Liver Biopsy and FibroTest in Assessing Liver Fibrosis in Chronic Hepatitis B

Abstract: Background and Aims The FibroTest (FT) demonstrated excellent diagnostic performance in the prediction of liver fibrosis in patients with chronic hepatitis B (CHB). Here, we aimed to identify predictors of discordance between FT and liver biopsy (LB) in Asian patients with CHB.