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1.  MiRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity via directly targeting Dnmt1 expression 
Hepatology (Baltimore, Md.)  2013;57(1):162-170.
MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced NF-κB activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF-κB activity by preferentially regulating the function of the NF-κB-suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. Dnmt1 was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-κB activity. MiRNA-140-knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency-related pathogenesis.
These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis.
PMCID: PMC3521841  PMID: 22898998
microRNA; HCC; DDX20; ribonucleoprotein; methallothionein
2.  Utility of single and double balloon endoscopy in patients with difficult colonoscopy: A randomized controlled trial 
AIM: To compare the utility of single-balloon colonoscopy (SBC) or double-balloon colonoscopy (DBC) for difficult colonoscopies.
METHODS: Between August 2008 and June 2010, patients in whom total colonoscopy failed within 30 min of insertion were assigned randomly to undergo either SBC or DBC. No sedatives were used. After the endoscopy, all patients were asked to evaluate pain during the procedure on a 10-point analog scale (1 = no pain; 10 = worst imaginable pain) with a questionnaire. The study outcomes were the cecal intubation rate and time, endoscopic findings, complications, and pain score.
RESULTS: The SBC and DBC groups included 11 and 10 patients, respectively. All but one SBC patient achieved total colonoscopy successfully. The cecal intubation times were 18 min (range: 10-85 min) and 12.8 min (range: 9.5-42 min) in the SBC and DBC groups, respectively (P = 0.17). No difference was observed in the prevalence of colon polyps between the SBC and DBC groups (45% vs 30%, P = 0.66). SBC showed advanced colon cancer in the ascending colon, which was inaccessible using conventional colonoscopy. The respective pain scores were 5 (1-10) [median (range)] and 5 (1-6) in the SBC and DBC groups (P = 0.64). No complications were noted in any patient.
CONCLUSION: The utility of single- and double-balloon endoscopy for colonoscopy seems comparable in patients with incomplete colonoscopy using a conventional colonoscope.
PMCID: PMC3732845  PMID: 23922470
Difficult colonoscopy; Double-balloon endoscopy; Single-balloon endoscopy; Double-balloon colonoscopy; Single-balloon colonoscopy
3.  Frequency, Risk Factors and Survival Associated with an Intrasubsegmental Recurrence after Radiofrequency Ablation for Hepatocellular Carcinoma 
PLoS ONE  2013;8(4):e59040.
In the treatment of hepatocellular carcinoma (HCC), hepatic resection has the advantage over radiofrequency ablation (RFA) in terms of systematic removal of a hepatic segment.
We enrolled 303 consecutive patients of a single naïve HCC that had been treated by RFA at The University of Tokyo Hospital from 1999 to 2004. Recurrence was categorized as either intra- or extra-subsegmental as according to the Couinaud's segment of the original nodule. To assess the relationship between the subsegments of the original and recurrent nodules, we calculated the kappa coefficient. We assessed the risk factors for intra- and extra-subsegmental recurrence independently using univariate and multivariate Cox proportional hazard regression. We also assessed the impact of the mode of recurrence on the survival outcome.
During the follow-up period, 201 patients in our cohort showed tumor recurrence distributed in a total of 340 subsegments. Recurrence was categorized as exclusively intra-subsegmental, exclusively extra-subsegmental, and simultaneously intra- and extra-subsegmental in 40 (20%), 110 (55%), and 51 (25%) patients, respectively. The kappa coefficient was measured at 0.135 (95% CI, 0.079–0.190; P<0.001). Multivariate analysis revealed that of the tumor size, AFP value and platelet count were all risk factors for both intra- and extra-subsegmental recurrence. Of the patients in whom recurrent HCC was found to be exclusively intra-subsegmental, extra-subsegmental, and simultaneously intra- and extra-subsegmental, 37 (92.5%), 99 (90.8%) and 42 (82.3%), respectively, were treated using RFA. The survival outcomes after recurrence were similar between patients with an exclusively intra- or extra-subsegmental recurrence.
The effectiveness of systematic subsegmentectomy may be limited in the patients with both HCC and chronic liver disease who frequently undergo multi-focal tumor recurrence.
PMCID: PMC3625228  PMID: 23593129
4.  Hepatitis C Virus and Hepatocellular Carcinoma 
Biology  2013;2(1):304-316.
Hepatitis C virus (HCV), a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.
PMCID: PMC4009856  PMID: 24832662
androgen receptor; apoptosis; gender difference; hepatitis C virus; hepatocellular carcinoma; inflammation
5.  Improvement of prognosis for unresectable biliary tract cancer 
AIM: To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer.
METHODS: A total of 186 consecutive patients with unresectable biliary tract cancer, who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan, were retrospectively analyzed. These patients were divided into three groups based on the year beginning chemotherapy: Group A (2000-2003), Group B (2004-2006), and Group C (2007-2009). The data were fixed at the end of December 2011. Overall survival and time-to-progression were analyzed and compared chronologically.
RESULTS: No patient characteristics were significantly different among the three groups. The gallbladder was involved in about half of the patients in each group, and metastatic biliary tract cancer was present in three quarters of the enrollees. In Group A, 5-fluorouracil-based chemotherapies were primarily selected as first-line chemotherapy, and only 24% were treated with second-line chemotherapy. In Group B, gemcitabine or S-1 monotherapy was mainly introduced as first-line chemotherapy, and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy. In Group C, the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy, and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy. The median time-to-progressions were 4.4 mo, 3.5 mo and 5.9 mo in Groups A, B and C, respectively (4.4 mo vs 3.5 mo vs 5.9 mo, P < 0.01). The median overall survivals were 7.1, 7.3, and 11.7 mo in Groups A, B and C (7.1 mo vs 7.3 mo vs 11.7 mo, P = 0.03). Induction rates of all three drugs (gemcitabine, platinum analogs, and fluoropyrimidine) in Groups A, B and C were 4%, 2% and 27% (4% vs 2% vs 27%, P < 0.01).
CONCLUSION: The prognosis of unresectable biliary tract cancer has improved recently. Using three effective drugs (gemcitabine, platinum analogs, and fluoropyrimidine) may improve the prognosis of this cancer.
PMCID: PMC3542759  PMID: 23326165
Unresectable; Biliary tract cancer; Gemcitabine; Platinum analogs; Fluoropyrimidine
6.  Soluble MICA and a MICA Variation as Possible Prognostic Biomarkers for HBV-Induced Hepatocellular Carcinoma 
PLoS ONE  2012;7(9):e44743.
MHC class I polypeptide-related chain A (MICA) molecule is induced in response to viral infection and various types of stress. We recently reported that a single nucleotide polymorphism (SNP) rs2596542 located in the MICA promoter region was significantly associated with the risk for hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) and also with serum levels of soluble MICA (sMICA). In this study, we focused on the possible involvement of MICA in liver carcinogenesis related to hepatitis B virus (HBV) infection and examined correlation between the MICA polymorphism and the serum sMICA levels in HBV-induced HCC patients. The genetic association analysis revealed a nominal association with an SNP rs2596542; a G allele was considered to increase the risk of HBV-induced HCC (P = 0.029 with odds ratio of 1.19). We also found a significant elevation of sMICA in HBV-induced HCC cases. Moreover, a G allele of SNP rs2596542 was significantly associated with increased sMICA levels (P = 0.009). Interestingly, HCC patients with the high serum level of sMICA (>5 pg/ml) exhibited poorer prognosis than those with the low serum level of sMICA (≤5 pg/ml) (P = 0.008). Thus, our results highlight the importance of MICA genetic variations and the significance of sMICA as a predictive biomarker for HBV-induced HCC.
PMCID: PMC3443094  PMID: 23024757
7.  The Effectiveness of Liraglutide in Nonalcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus Compared to Sitagliptin and Pioglitazone 
The Scientific World Journal  2012;2012:496453.
Background. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. Aims. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. Methods. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. Results. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, P < 0.01). On the other hands, the body weight significantly increased in pioglitazone group and did not change in sitagliptin group. Multivariate regression analysis indicated that administration of liraglutide as an independent factor of body weight reduction for more than 5% (OR 9.04; 95% CI 1.12–73.1, P = 0.04). Conclusions. Administration of liraglutide improved T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight.
PMCID: PMC3425807  PMID: 22927782
8.  Assessment of disease progression in patients with transfusion-associated chronic hepatitis C using transient elastography 
AIM: To evaluate the relationship between liver stiffness and duration of infection in blood transfusion-associated hepatitis C virus (HCV) patients with or without hepatocellular carcinoma (HCC).
METHODS: Between December 2006 and June 2008, a total of 524 transfusion-associated HCV-RNA positive patients with or without HCC were enrolled. Liver stiffness was obtained noninvasively by using Fibroscan (Echosens, Paris, France). The date of blood transfusion was obtained by interview. Duration of infection was derived from the interval between the date of blood transfusion and the date of liver stiffness measurement (LSM). Patients were stratified into four groups based on the duration of infection (17-29 years; 30-39 years; 40-49 years; and 50-70 years). The difference in liver stiffness between patients with and without HCC was assessed in each group. Multiple linear regression analysis was used to determine the factors associated with liver stiffness.
RESULTS: A total of 524 patients underwent LSM. Eight patients were excluded because of unsuccessful measurements. Thus 516 patients were included in the current analysis (225 with HCC and 291 without). The patients were 244 men and 272 women, with a mean age of 67.8 ± 9.5 years. The median liver stiffness was 14.3 kPa (25.8 in HCC group and 7.6 in non-HCC group). The patients who developed HCC in short duration of infection were male dominant, having lower platelet count, with a history of heavier alcohol consumption, showing higher liver stiffness, and receiving blood transfusion at an old age. Liver stiffness was positively correlated with duration of infection in patients without HCC (r = 0.132, P = 0.024) but not in patients with HCC (r = -0.103, P = 0.123). Liver stiffness was significantly higher in patients with HCC than in those without in each duration group (P < 0.0001). The factors significantly associated with high liver stiffness in multiple regression were age at blood transfusion (P < 0.0001), duration of infection (P = 0.0015), and heavy alcohol consumption (P = 0.043)
CONCLUSION: Although liver stiffness gradually increases over time, HCC develops in patients with high stiffness value regardless of the duration of infection.
PMCID: PMC3319966  PMID: 22493553
Transfusion-associated hepatitis C; Transient elastography; Hepatocellular carcinoma; Liver stiffness; Ultrasonography; Liver fibrosis
9.  Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma 
The Journal of Clinical Investigation  2011;121(10):4106-4117.
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium–specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.
PMCID: PMC3195452  PMID: 21926469
10.  Receptor for Activated Protein Kinase C: Requirement for Efficient MicroRNA Function and Reduced Expression in Hepatocellular Carcinoma 
PLoS ONE  2011;6(9):e24359.
MicroRNAs (miRNAs) are important regulators of gene expression that control physiological and pathological processes. A global reduction in miRNA abundance and function is a general trait of human cancers, playing a causal role in the transformed phenotype. Here, we sought to newly identify genes involved in the regulation of miRNA function by performing a genetic screen using reporter constructs that measure miRNA function and retrovirus-based random gene disruption. Of the six genes identified, RACK1, which encodes “receptor for activated protein kinase C” (RACK1), was confirmed to be necessary for full miRNA function. RACK1 binds to KH-type splicing regulatory protein (KSRP), a member of the Dicer complex, and is required for the recruitment of mature miRNAs to the RNA-induced silencing complex (RISC). In addition, RACK1 expression was frequently found to be reduced in hepatocellular carcinoma. These findings suggest the involvement of RACK1 in miRNA function and indicate that reduced miRNA function, due to decreased expression of RACK1, may have pathologically relevant roles in liver cancers.
PMCID: PMC3174171  PMID: 21935400
11.  IkappaB kinase beta regulates gastric carcinogenesis via IL-1α expression 
Gastroenterology  2010;139(1):226-38.e6.
To explore the role of IKKβ in gastric carcinogenesis, we established a conditional gastric mucosal epithelium IKKβ knockout mouse (IkkβΔST) that did not differ phenotypically or histologically from control mice (IkkβF/F). Gastric cancer was induced using N-methyl-N-nitrosourea (MNU). After 8 months, the mean number (±SE) of tumors per body was significantly less in the IkkβΔST group (0.80 ± 0.23) than in the IkkβF/F group (2.21 ± 0.48), although the size of tumors did not differ between groups (2.75 ± 0.99 vs. 2.89 ± 1.12 mm, respectively). We investigated the levels of several inflammatory cytokines in the stomach after a single oral dose of MNU and found that IL-1α was significantly up-regulated in control mice compared to IkkβΔST mice, whereas the levels of IL-1β, IL-6, and TNF-α were unchanged. MNU significantly increased apoptotic cell death in control mice compared to IkkβΔST mice, and apoptosis was dependent on decreased IL-1α expression. IL-1α also induced the proliferation of gastric cancer cells. Fewer tumors were observed in IL-1 receptor knockout mice (Il-1r−/−; 1.17 ± 0.44) than in control mice (2.42 ± 0.52). These results suggest that IKKβ regulates gastric carcinogenesis via IL-1α expression, which is associated with anti-apoptotic signaling and cell proliferation.
PMCID: PMC3156098  PMID: 20347815
12.  Distinct effects of p38α deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease 
Gastroenterology  2010;138(4):1255-1265.e9.
Background & Aims
p38α is a mitogen-activated protein kinase that mediates inflammatory responses, but its role in inflammatory bowel disease (IBD) is unclear. The effects of p38α inhibitors have been inconsisten in animal models and clinical studies of IBD, possibly arising from the different functions of p38α in different tissues or cell types. We investigated the effects of p38α inhibition in myeloid vs. the colonic epithelium.
We studied mice with myeloid cell-specific and intestinal epithelial cell-specific disruption p38α (LtrLysCre-p38αΔ/Δ mice and VillinCre-p38αΔ/Δ mice), as well as p38β, γ, and δ knockout. Colitis was induced using Dextran Sodium Sulfate (DSS) or 2.4.6-trinitrobenzene sulfonic acid (TNBS).
Mice with myeloid cell-specific deletion of p38α had less inflammation and an improved disease condition, compared with wild-type mice, whereas mice with intestinal epithelial cell-specific deletion of p38α had increased progression of colitis that resulted from disrupted intestinal epithelial homeostasis. The distinct effects of p38α disruption in different tissue types might underlie the unsuccessful therapeutic application of p38 inhibitors to colitis. We found that a γ-secretase inhibitor, which functions opposite that of a p38 inhibitor in the regulation of intestinal epithelial homeostasis, can significantly improve the effects of a p38 inhibitor in reducing colitis.
p38α has distinct functions in mouse myeloid cells vs. colonic epithelium; these differences should be taken into consideration in defining the role of p38α in inflammation and developing p38 inhibitors as therapeutics.
PMCID: PMC2846963  PMID: 20080092
p38α; colitis; knockout mice
13.  Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers 
Gemcitabine chemotherapy has been the standard for advanced pancreatic cancer for more than a decade. New oral fluoropyrimidines such as S-1 and capecitabine are other key drugs. Gemcitabine plus erlotinib was the only combination therapy that significantly prolonged survival, although the effect was minimal. Little or no improvement in survival with recent molecular-targeted drugs might be attributed to the very high incidence of K-ras gene mutation in pancreatic cancer. Recently, the non-gemcitabine-based-regimen of FOLFIRINOX showed significantly greater overall survival compared with gemcitabine for the first time. For biliary tract cancer, gemcitabine plus cisplatin combination chemotherapy has been proved to significantly prolong survival and will become the standard therapy. Further improvement in survival is expected by the addition of cetuximab.
PMCID: PMC3100481  PMID: 21611090
Cisplatin; Epidermal growth factor receptor; Gemcitabine; K-ras; S-1
14.  Long‐term prognosis of autoimmune pancreatitis with and without corticosteroid treatment 
Gut  2007;56(12):1719-1724.
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis, and has a favourable response to corticosteroid treatment (CST). Little is known, however, about the long‐term outcome of AIP. This study aimed to document the prognosis without and with CST, and to examine the indication for CST.
Patients and methods
The prognosis and clinical features of 23 patients without CST and 19 patients treated with CST from onset were investigated. In addition, factors concerning the late occurrence of unfavourable events related to AIP were examined.
The patients without CST were 19 men and four women, with an average age of 66 years. After an average observation period of 25 months, 16 patients (70%) developed unfavourable events including obstructive jaundice as a result of distal bile duct stenosis in four, growing pseudocyst in one, sclerogenic changes of extrapancreatic bile duct in nine, hydronephrosis as a result of retroperitoneal fibrosis in one, and interstitial nephritis in one. Patients with obstructive jaundice at onset showed a higher cumulative event occurrence rate (p = 0.025). The patients treated with CST were 16 men and three women, with an average age of 64 years. After an average observation period of 23 months, six patients (32%) developed unfavourable events consisting of interstitial pneumonia in three, and a recurrence of obstructive jaundice in three. In multivariate analysis, CST (HR 0.33, 95% CI 0.12–0.89, p = 0.029) and obstructive jaundice at onset (HR 3.09, 95% CI 1.14–8.32, p = 0.026) were significant predictive factors for unfavourable events.
CST could reduce AIP‐related unfavourable events. The early introduction of CST is recommended especially for patients with obstructive jaundice.
PMCID: PMC2095691  PMID: 17525092
autoimmune pancreatitis; corticosteroid; prognosis; sclerosing cholangitis; obstructive jaundice
15.  A large‐scale, multicentre, double‐blind trial of ursodeoxycholic acid in patients with chronic hepatitis C 
Gut  2007;56(12):1747-1753.
Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH‐C) therapy; however, sustained virological response is achieved in only about half of the patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon non‐responders.
CH‐C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200) or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST) and gamma‐glutamyl transpeptidase (GGT) were assessed. This study is registered at, identifier NCT00200343.
ALT, AST and GGT decreased at week 4 and then remained constant during drug administration. The median changes (150, 600 and 900 mg/day, respectively) were: ALT, −15.3, −29.2 and −36.2%; AST, −13.6, −25.0 and −29.8%; GGT, −22.4, −41.0 and −50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/l. Serum HCV‐RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups.
A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH‐C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.
PMCID: PMC2095694  PMID: 17573387
17.  Usefulness of multi-detector helical CT with multiplanar reconstruction for depicting the duodenal varices with multiple collateral shunt vessels 
Hepatology International  2010;4(4):775-778.
Duodenal varices are a rare complication in patients with portal hypertension. Bleeding from duodenal varices often results in a severe prognosis. Diagnosis of the disease is usually based on findings obtained by endoscopy or angiography. However, it occasionally fails to detect the lesion and demonstrate its porto-systemic shunt vessels which are necessary information to decide an appropriate treatment. Recent advances in CT may make it possible for us to reveal duodenal varices with complicated porto-systemic shunt vessels. We report the case of a 58-year-old man with liver cirrhosis with repeated bleeding from duodenal varices. Esophagogastroduodenoscopy (EGD) revealed multinodular varices in the third portion of the duodenum. Then we conducted a capsule endoscopy (CE) and found fresh blood in the duodenum, suggesting duodenal variceal hemorrhage. Angiography depicted the varices with one afferent and two efferent vessels. Abdominal CT examination was conducted using a four-channel multi-detector row CT scanner. The multiplanar reconstructed images revealed not only the varices, but also three afferent and two efferent vessels. The patient was treated by surgical ligation and sclerotherapy, because of its complicated porto-systemic shunt and reserved liver function. No gastrointestinal bleeding has been seen after the surgery. Our case suggests the usefulness of multi-detector CT with multiplanar reconstruction (MPR) for the diagnosis and therapeutic decision of duodenal varices.
PMCID: PMC2994612  PMID: 21286350
Varices; Computed tomography; Duodenum; Surgical hemostasis
18.  Evaluation of long-term entecavir treatment in stable chronic hepatitis B patients switched from lamivudine therapy 
Hepatology International  2010;4(3):594-600.
Current Japanese guidelines recommend that patients should be switched from lamivudine to entecavir when they meet certain criteria. This analysis examines the efficacy and safety of long-term entecavir therapy in patients who were switched to entecavir after 24 weeks’ lamivudine therapy in Japanese studies ETV-047 and ETV-060.
The Phase II Japanese study ETV-047 assessed the efficacy of different entecavir doses when compared with lamivudine. A total of 33 Japanese patients who received lamivudine 100 mg daily in ETV-047 entered the open-label rollover study ETV-060 and subsequently received treatment with entecavir 0.5 mg daily. Hepatitis B virus (HBV) DNA suppression, alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroconversion, and resistance were evaluated among patients with available samples for up to 96 weeks. Safety was assessed throughout the treatment period.
After 96 weeks of entecavir therapy in ETV-060, 90% of patients achieved HBV DNA <400 copies/mL as compared to 21% of patients who completed 24 weeks of lamivudine therapy in ETV-047. Increasing proportions of patients achieved ALT normalization and HBeAg seroconversion following long-term entecavir treatment. No patients experienced virologic breakthrough, and substitutions associated with entecavir resistance were not observed in patients with detectable HBV DNA. Entecavir was well tolerated during long-term treatment.
Switching lamivudine-treated patients with chronic hepatitis B to entecavir results in increased virologic suppression with no evidence of resistance through 2 years of entecavir therapy. These findings support recommendations in the current Japanese treatment guidelines that stable lamivudine patients should be switched to entecavir.
PMCID: PMC2939999  PMID: 21063482
Japanese; Chronic hepatitis B; Entecavir; Lamivudine; Switch
19.  Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma 
Hepatology International  2010;4(2):439-474.
The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations.
The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements.
Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.
PMCID: PMC2900561  PMID: 20827404
Hepatocellular carcinoma; Consensus statements; Recommendations; Epidemiology; Diagnosis; Treatment algorithm
20.  Chronic hepatitis B: whom to treat and for how long? Propositions, challenges, and future directions 
Hepatology International  2010;4(1):386-395.
Recent guidelines of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver 2008 update of the “Asian-Pacific consensus statement on the management of chronic hepatitis B” offer comprehensive recommendations for the general management of chronic hepatitis B (CHB). These recommendations highlight preferred approaches to the prevention, diagnosis, and treatment of CHB. Nonetheless, the results of recent studies have led to an improved understanding of the disease and a belief that current recommendations on specific therapeutic considerations, including CHB treatment initiation and cessation criteria, particularly in patient populations with special circumstances, can be improved. Twelve experts from the Asia-Pacific region formed the Asia-Pacific Panel Recommendations for the Optimal Management of Chronic Hepatitis B (APPROACH) Working Group to review, challenge, and assess relevant new data and inform future updates of CHB treatment guidelines. The significance of and controversy about reported findings were discussed and debated in an expert meeting of the Working Group in Beijing, China, in November 2008. This review paper attempts to identify areas requiring improved CHB management and provide suggestions for future guideline updates, with special emphasis on treatment initiation and duration.
PMCID: PMC2836441  PMID: 20305758
Chronic hepatitis B (CHB); Hepatitis B virus (HBV); Nucleoside/nucleotide analog; Interferon alfa; HBV DNA; ALT
21.  Chronic hepatitis B: whom to treat and for how long? Propositions, challenges, and future directions 
Hepatology International  2010;4(1):386-395.
Recent guidelines of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver 2008 update of the “Asian-Pacific consensus statement on the management of chronic hepatitis B” offer comprehensive recommendations for the general management of chronic hepatitis B (CHB). These recommendations highlight preferred approaches to the prevention, diagnosis, and treatment of CHB. Nonetheless, the results of recent studies have led to an improved understanding of the disease and a belief that current recommendations on specific therapeutic considerations, including CHB treatment initiation and cessation criteria, particularly in patient populations with special circumstances, can be improved. Twelve experts from the Asia-Pacific region formed the Asia-Pacific Panel Recommendations for the Optimal Management of Chronic Hepatitis B (APPROACH) Working Group to review, challenge, and assess relevant new data and inform future updates of CHB treatment guidelines. The significance of and controversy about reported findings were discussed and debated in an expert meeting of the Working Group in Beijing, China, in November 2008. This review paper attempts to identify areas requiring improved CHB management and provide suggestions for future guideline updates, with special emphasis on treatment initiation and duration.
PMCID: PMC2836441  PMID: 20305758
Chronic hepatitis B (CHB); Hepatitis B virus (HBV); Nucleoside/nucleotide analog; Interferon alfa; HBV DNA; ALT
22.  Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B 
Hepatology International  2010;4(1):414-422.
Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudine-refractory Japanese patients treated with entecavir for 3 years.
Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples.
After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55% (36/65) of patients had hepatitis B virus (HBV) DNA of >400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of ≥1 × upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion. A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of >400 copies/mL, 84% (27/32) had ALT of ≥1 × ULN, and 15% (4/27) achieved HBe seroconversion. Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares.
Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.
PMCID: PMC2836436  PMID: 20305760
Japanese; Chronic hepatitis B; Entecavir; Lamivudine refractory; Lamivudine resistant
23.  Comparison of liver biopsy and transient elastography based on clinical relevance 
Liver stiffness measurement (LSM) by transient elastography has recently been validated for the evaluation of liver fibrosis in chronic liver diseases. The present study focused on cases in which liver biopsy and LSM were discordant.
Three hundred eighty-six patients with chronic hepatitis C who underwent a liver biopsy between December 2004 and April 2007 were studied. First, the optimal cut-off value of LSM was selected for the determination of cirrhosis based on the receiver operating characteristic curve. Then, the cases in which liver histology and evaluation by LSM were discordant were selected. Laboratory test results such as serum total bilirubin concentration, prothrombin activity, albumin concentration, platelet count and the aspartate aminotransferase to platelet ratio index, together with the presence of esophageal varices, were analyzed.
The optimal cut-off value was chosen to be 15.9 kPa for cirrhosis (fibrosis stage [F] 4) determination to maximize the sum of sensitivity (78.9%) and specificity (81.0%). There were 78 discordant cases: 51 patients showed an LSM of 15.9 kPa or higher and a fibrosis stage of F1 to F3 (high LSM group), and 27 patients had an LSM lower than 15.9 kPa and a fibrosis stage of F4 (low LSM group). Esophageal varices were seen in 11 patients in the high LSM group (n=51) and in no patients in the low LSM group (n=27) (P=0.0012). The aspartate aminotransferase to platelet ratio index was significantly higher in the high LSM group (1.49 versus 0.89, P=0.019). Other parameters did not differ significantly. However, platelet count, prothrombin activity and albumin concentration tended to be lower in the high LSM group.
Patients with a high LSM need proper attention for cirrhosis, even if liver biopsy does not reveal cirrhosis.
PMCID: PMC2661279  PMID: 18818788
Hepatitis C; Liver biopsy; Liver fibrosis
24.  Ultrasound surveillance for early detection of hepatocellular carcinoma among patients with chronic hepatitis C 
Hepatology International  2009;3(4):544-550.
Background and aims
Ultrasonography is the most frequently used modality in surveillance for HCC among patients with chronic hepatitis C. However, the optimal surveillance interval is still controversial and the usefulness of supplementary tumor marker determination has not been confirmed.
A total of 243 cases of naive HCC were detected among 1,431 patients with chronic hepatitis C under outpatient-based surveillance. The mode of HCC detection, including ultrasound surveillance interval, was retrospectively examined and the relation between the interval and detected tumor size was analyzed. Tumor volume doubling time was estimated from exponential increase in serum tumor marker levels when applicable.
HCC was first detected by ultrasonography in 221 patients. Ultrasound surveillance interval, ranging between 2 and 8 months, was not correlated with the size of tumor at detection. Patients with cirrhosis were likely to be surveyed at shorter intervals. The size of tumor exceeded 30 mm only in three (1.4%) cases. They were all positive for a biomarker and the estimated tumor doubling time was short. In 14 cases, HCC was first detected by CT indicated by abnormal rise in tumor marker levels despite negative ultrasound findings. In the remaining eight cases, ultrasonography had been replaced by CT as surveillance modality because of excessive obesity or coarseness of liver parenchyma.
Ultrasound surveillance at 6-month intervals was appropriate in general for the detection of HCC at a size smaller than 30 mm. However, in patient with established cirrhosis, more frequent screening would be needed to detect tumors of the same size.
PMCID: PMC2790585  PMID: 19669240
Hepatocellular carcinoma; Hepatitis C; Surveillance; Ultrasound; Tumor marker; Doubling time; Size of tumor; Surveillance interval
25.  Antiviral activity, dose–response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial 
Hepatology International  2009;3(3):445-452.
A randomized, double-blind, multicenter study (ETV-047) was conducted to evaluate the dose–response relationship of entecavir and compare its antiviral activity and safety with lamivudine in Japanese patients with chronic hepatitis B (CHB).
One hundred thirty-seven nucleoside-naive adult patients with CHB were randomized to once-daily oral doses of entecavir 0.01, 0.1, or 0.5 mg or lamivudine 100 mg for 24 weeks. The primary efficacy end point used to evaluate the dose–response relationship was mean change from baseline in serum hepatitis B virus (HBV) DNA level at week 22, as determined by polymerase chain reaction assay.
Entecavir demonstrated a clear dose–response relationship, with mean change from baseline in serum HBV DNA level of −3.11, −4.77, and −5.16 log10 copies/ml with entecavir 0.01, 0.1, and 0.5 mg, respectively. Entecavir 0.5 mg was superior to lamivudine 100 mg for the mean change in HBV DNA level (−5.16 vs. −4.29 log10 copies/ml; P = 0.007). The overall incidence of adverse events was comparable between treatment groups. Two patients discontinued treatment because of adverse events (one with liver cirrhosis [entecavir 0.5 mg] and one with grade 4 serum alanine aminotransferase (ALT) elevation, nausea, and malaise [lamivudine 100 mg]). Serum ALT flares were observed in four patients; flares were associated with 2 log10 reductions or more in HBV DNA level and resolved without dose interruption.
Entecavir 0.01–0.5 mg is well tolerated and produces a dose-dependent reduction in viral load in nucleoside-naive Japanese patients with CHB. Compared with lamivudine 100 mg, entecavir 0.1 mg demonstrated noninferiority and entecavir 0.5 mg was superior in this population.
PMCID: PMC2748381  PMID: 19669249
Chronic hepatitis B; Entecavir; Lamivudine; HBV DNA; ALT flare

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