Hitomi Sezaki

Toranomon Hospital, Edo, Tōkyō, Japan

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Publications (189)556.64 Total impact

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    ABSTRACT: The present study was designed to assess the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time in virological non-responders (patients with positive HCV-RNA during and at end of treatment). The study enrolled 136 patients infected with HCV genotype 1b who received 12-week simeprevir-PEG-IFN-ribavirin therapy, and data of 87 patients were available for analysis. Twelve patients (14%) were considered virological non-responders, including 9 (75%) who showed absolute no-response (HCV RNA: ≥3.0 log IU/ml at 12 weeks after start of therapy). Multivariate analysis of these patients identified lack of response to prior treatment, use of low ribavirin dose, and old age as independent and significant determinants of virological non-response. Using ultra-deep sequencing, de novo variants of D168 were detected in all of 9 absolute non-responders. The majority of these variants emerged within 5 weeks of triple therapy. In comparison, de novo variants of Q80 were detected in only 3 of 9 absolute non-responders and emerged at 6-12 weeks. Variants of Q80 detected at baseline increased during the course of treatment in 5 of 9 absolute non-responders, while no such increase was noted in variants of R155 and/or A156 detected at baseline during the 12-week course. De novo variants of R155 and/or A156 were not detected in this study. The results demonstrated the emergence of simeprevir-resistant variants during the early stage of triple therapy. J. Med. Virol. 87:609-618, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Medical Virology 04/2015; 87(4):609-18. DOI:10.1002/jmv.24113 · 2.22 Impact Factor
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    ABSTRACT: A randomized controlled trial was conducted to evaluate the efficacy of impedance control of a radiofrequency interstitial thermal ablation system (RITA) used to treat hepatocellular carcinoma (HCC). Fifteen patients with hypervascular HCCs <20 mm in diameter were randomly treated with radiofrequency ablation (RFA) using conventional temperature control (group A) or impedance control methods (group B). RITA needle electrodes were used in all cases. We compared ablation time, extent of lesion ablation, and energy use between the two groups. The median long and short diameters of the axial cross sections of radiofrequency-induced necrotic areas visualized by CT were 32 mm (range, 26-36) and 25 mm (20-31) in group A and 32 mm (28-40) and 31 mm (24-37) in group B, respectively. The short diameter of group B patients was significantly greater than that of group A patients (p = 0.029). The median ablation time was 18.8 min in group A and 13.4 min in group B, thus significantly shorter in group B (p = 0.001). The energy requirement did not differ significantly between the groups. Impedance control of the RITA system resulted in an increased size of the ablation zone and a decreased ablation time. © 2015 S. Karger AG, Basel.
    Oncology 03/2015; DOI:10.1159/000375166 · 2.61 Impact Factor
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    ABSTRACT: Currently, non-alcoholic steatohepatitis (NASH) can only be diagnosed histopathologically. Our objective was to establish a new scoring system for the fibrotic stage of NASH. We enrolled 139 patients with histologically proven NASH and divided them into two groups to construct (n = 90) and validate (n = 49) a fibrotic score for NASH (FSN). We used 17 variables and their natural logarithmic transformations in the multivariate analysis. To assess the accuracy of the FSN in determining NASH advanced fibrosis (stages 3-4), we compared various fibrotic scores for NASH. In the construct group, multivariate regression analysis ultimately obtained the following function: z = 1.022 × ln (type IV collagen 7S) (ng/mL) - 0.00680 × (platelet count) (×10(9)/L) + 1.925 × ln (AST) (IU/L) - 1.239 × ln (ALT) (IU/L) + 0.249. Median values of the FSN for stages 1, 2, 3 and 4 were 1.87, 2.14, 3.26 and 3.89, respectively. The multiple regression coefficient and coefficient of determination were 0.70 and 0.46, respectively. In the validation group, the median value was 2.00, 2.83, 3.08 and 4.37 in each stage. With regard to the utility of the FSN for predicting advanced fibrosis of NASH (stage ≥3), the area under the receiver operating characteristic curves (AUROC), 0.909 (95 % CI 0.847-0.970, p < 0.001), was higher than that for the other fibrotic scores (APRI, NAFLD fibrosis score, FIB-4 index, BARD score, NIKEI) in the construct group. This simple scoring system accurately predicts fibrotic stage and discriminates patients with advanced fibrosis of NASH.
    Hepatology International 01/2015; DOI:10.1007/s12072-014-9605-x · 2.47 Impact Factor
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    ABSTRACT: AimTolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites.Methods Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, 5) after adding tolvaptan (3.75-11.25 mg/day) to conventional diuretics. Body weights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 (28-56) days.ResultsIn the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P<0.004). The numbers of good responders (≧3 kg reduction in 4 days), responders (<3 kg weight reduction), and non-responders (no weight reduction) were 7/15 (46.7%), 6/15 (40.0%), and 2/15 (13.3%), respectively. The 2 non-responders had concomitant chylous pleural effusion or spontaneous bacterial peritonitis. All patients continued tolvaptan for two weeks or longer and 6 (40%, 3 good responders and 3 responders) were treated for a median of 42 days without additional interventions. During this intermediate-term administration of tolvaptan, the median weight reduction was statistically significant (65.4, 61.9 and 56.9 kg on days 0, 7 and 42, respectively; P<0.030) and there was no serum sodium imbalance or renal dysfunction; but 2 of these 6 developed hepatic coma.Conclusion Tolvaptan safely alleviated fluid retention caused by hepatic cirrhosis. Intermediate-term administration of tolvaptan apparently helped maintain weight reduction achieved during the introduction phase.
    Hepatology Research 11/2014; DOI:10.1111/hepr.12455 · 2.22 Impact Factor
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    ABSTRACT: Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 08/2014; 86(8). DOI:10.1002/jmv.23966 · 2.22 Impact Factor
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    ABSTRACT: Background/AimsGenome-wide association studies (GWAS) recently indicated that polymorphisms in the human leukocyte antigen (HLA)-DP genes were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV, but the effect of HLA-DP gene polymorphisms on the effect of antiviral therapy was unknown. We here investigated whether such polymorphisms were associated with decreases in HBsAg levels and seroclearance in patients who received long-term lamivudine (LAM) treatment.Methods Japanese patients (202) who were hepatitis B e antigen-positive at baseline, received LAM as first-line treatment, and consented to HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535) were categorized into 2 cohorts, viz., a cohort who achieved virological response without rescue therapy (cohort 1) and those who did so with rescue therapy (cohort 2).ResultsSerum HBsAg levels declined significantly between year 3 and 9 from baseline among cohort 1 patients possessing ≥ 2 A-alleles at rs3077 and rs9277535. The percentages of such patients in cohort 1 patients with decreases in HBsAg ≥ 0.5 log IU/mL were higher than those with <2 A-alleles (71.8% [28/39] vs. 38.9% [23/59]; P = 0.004). However, there was no significant difference in cumulative HBsAg seroclearance rates between patients with ≥ 2 and those with < 2 A-alleles in cohort 1. In cohort 2, HBsAg seroclearance rates were higher in patients with ≥ 2 A-alleles than in those with < 2 A-alleles (P = 0.003).Conclusion We found an association between HLA-DP polymorphisms and decreases in HBsAg levels and seroclearance among HBeAg-positive patients treated with LAM.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014; 35(4). DOI:10.1111/liv.12652 · 4.41 Impact Factor
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    ABSTRACT: Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients in the USA and Europe. No confirmed report of resistance selection during treatment with TDF in treatment-naïve and nucleoside/nucleotide analog-treated chronic hepatitis B patients has yet been reported. Here, we report for the first time a patient with chronic hepatitis B and cirrhosis who emerged with virologic breakthrough during combination therapy with TDF and entecavir (ETV), against ETV-resistant virus. A 51-year-old Japanese woman with hepatitis B e-antigen (HBeAg), whose genotype was C, received ETV monotherapy continuously followed by TDF and ETV combination therapy, because her HBV DNA levels had been >3.5 log copies/mL. At the start of combination therapy, amino acid substitutions of the reverse transcriptase (rt) gene, rtL180M, rtT184I/M, and rtM204V, were detected. After this, serum HBV DNA decreased to less than 2.1 log copies/mL and remained at this level until 31 months of combination therapy, when it again began to increase. Amino acid substitutions of rtL180M, rtS202G, and rtM204V emerged and were associated with an increase in serum HBV DNA at virologic breakthrough. Long-term therapy with TDF against the ETV-resistant virus has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out.
    Drug Design, Development and Therapy 06/2014; 8:869-73. DOI:10.2147/DDDT.S65349 · 3.03 Impact Factor
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    ABSTRACT: Background: The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. Patients and Methods: We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. Results: In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). Conclusion: Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis. © 2014 S. Karger AG, Basel.
    Oncology 06/2014; 86(5-6):295-302. DOI:10.1159/000357713 · 2.61 Impact Factor
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    ABSTRACT: Alfa-fetoprotein (AFP) is used as a marker of early hepatocarcinogenesis. However, the impact of hepatitis B virus surface antigen (HBsAg) on this relationship in patients with HBV infection is not clear. The present study evaluated the relation between HBsAg and AFP levels at the initial visit in 1,610 untreated HBV patients, free of hepatocellular carcinoma (HCC) or severe hepatitis. The cumulative rate of HCC was significantly lower in patients with a low AFP level (≤10 µg/L; below the upper limit of normal) than in those with a high AFP level (≥11 µg/L) at the initial visit. In patients with HBsAg levels more than 500 IU/ml, HBsAg levels correlated significantly and negatively with AFP levels, and significantly with platelet count. Multivariate analysis of data of patients with HBsAg more than 500 IU/ml identified HBsAg (<7,000 IU/ml), albumin (<3.9 g/dl), platelet count (<20.0 × 10(4) /mm(3) ), gamma-glutamyl transpeptidase (≥50 IU/L), aspartate aminotransferase (≥34 IU/L), HBeAg (positive), and HBV core-related antigen (≥3.0 log U/ml) as determinants of a high AFP. Especially, in patients with HBsAg more than 500 IU/ml and low transaminase levels (below the upper limit of normal), HBsAg was identified as significant determinant of a high AFP. On the other hand, in patients with HBsAg less than 500 IU/ml, multivariate analysis identified albumin, gamma-glutamyl transpeptidase, and HBV core-related antigen as determinants of a high AFP. The results indicated that HBsAg level seems to affect, at least in part, the AFP levels, and that it can be used as a surrogate marker of early hepatocarcinogenesis. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 01/2014; 86(1). DOI:10.1002/jmv.23790 · 2.22 Impact Factor
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    ABSTRACT: The aim of this retrospective cohort study was to assess the cumulative incidence and predictive factors for intracerebral hemorrhagic stroke after the termination of interferon (IFN) therapy in Japanese patients with hepatitis C virus (HCV). A total of 4,649 HCV-positive patients treated with IFN were enrolled. The primary goal is the first onset of intracerebral hemorrhagic stroke. The mean observation period was 8.0 years. Evaluation was performed using the Kaplan-Meier method and the Cox proportional hazard model. A P-value of less than 0.05 was considered statistically significant. A total of 28 developed intracerebral hemorrhagic stroke. The cumulative incidence of intracerebral hemorrhagic stroke was 0.3% at 5 years, 0.8% at 10 years, and 1.7% at 15 years. Intracerebral hemorrhagic stroke occurred when patients had age increments of 10 years (hazard ratio: 2.77; 95% confidence interval (CI) 1.48-5.18; P = 0.001), hypertension (hazard ratio: 2.30; 95% CI 1.09-4.83; P = 0.021), liver cirrhosis (hazard ratio: 4.50; 95% CI 2.07-9.78; P < 0.001), and HCV non-clearance (hazard ratio: 3.22; 95% CI 1.22-8.53; P = 0.018). On the intracerebral hemorrhagic stroke based on the difference of liver fibrosis and efficacy of IFN therapy, HCV clearance reduced to 24.3% (1/4.11) compared to HCV non-clearance in cirrhotic patients (P = 0.040). In conclusion, HCV clearance reduced the development of intracerebral hemorrhagic stroke. In particular, HCV clearance reduced intracerebral hemorrhagic stroke to about one-fourth in cirrhotic patients. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 01/2014; 86(1). DOI:10.1002/jmv.23777 · 2.22 Impact Factor
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    ABSTRACT: Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long-term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide-naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow-up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed-up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.
    Journal of Viral Hepatitis 12/2013; DOI:10.1111/jvh.12211 · 3.31 Impact Factor
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    ABSTRACT: The clinical usefulness of detecting telaprevir-resistant variants is unclear. 252 Japanese patients infected with hepatitis C virus (HCV) genotype 1b, received triple therapy of telaprevir/peginterferon (PEG-IFN)/ribavirin, and were evaluated telaprevir-resistant variants by direct sequencing at the baseline and at the re-elevation of viral load. Analysis of the entire group indicated that 76% achieved sustained virological response. Multivariate analysis identified PEG-IFN dose (<1.3 μg/kg), IL28B rs8099917 (genotype non TT), telaprevir-resistant variants of aa 54 at the baseline (Detection), response to prior treatment (Non response), and leukocyte count (<5,000/mm(3)) as significant pretreatment factors of detection of telaprevir-resistant variants at the re-elevation of viral load. Especially, in 63 patients who showed non response to prior treatment, a higher proportion of patients undetected telaprevir-resistant variants at the baseline (54%) achieved sustained virological response than that of patients detected telaprevir-resistant variants at the baseline (0%). Furthermore, 2 patients, who did not achieve sustained virological response by the first course of triple therapy with telaprevir, received the second course of the triple therapy with telaprevir. They achieved sustained virological response by the second course, despite the persistence of very high frequency variants (98.1% for V36C) or the past history of the emergence of variants (0.2% for R155Q, and 0.2% for A156T) by ultra-deep sequencing. In conclusion, this study indicated that telaprevir-resistant variants at the re-elevation of viral load could be predicted by the combination of host, viral, and treatment factors. Resistant variants at the baseline might partly affect treatment efficacy, especially non response to prior treatment.
    Journal of clinical microbiology 11/2013; 52(1). DOI:10.1128/JCM.02371-13 · 4.23 Impact Factor
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    ABSTRACT: To compare the early virological effectiveness, sustained virological response and safety of telaprevir 1500 mg/day with telaprevir 2250 mg/day, when combined in triple therapy with pegylated interferon and ribavirin in Japanese patients with high viral loads of genotype 1 hepatitis C virus. The telaprevir 2250 mg/day and 1500 mg/day groups each contained 60 patients matched by age, sex and history of previous interferon-based treatment. Serum levels of genotype 1 hepatitis C virus RNA, hemoglobin levels, drug adherence and drug discontinuation rates were monitored during and after triple therapy. Patients receiving telaprevir 1500 mg/day had significantly lower telaprevir adherence and lower initial ribavirin dose but similar or superior pegylated interferon and ribavirin adherence and a lower rate of telaprevir discontinuation than did those receiving telaprevir 2250 mg/day. The early virological responses and sustained virological response rates were similar in both groups. Hemoglobin levels decreased to a greater extent in patients treated with telaprevir 2250 mg/day. Compared to triple therapy including telaprevir 2250 mg/day, that including telaprevir at a reduced dose of 1500 mg/day was associated with lower rates of anemia and similar antiviral efficacy. Such a regimen may meaningfully improve sustained virological response rates, especially among female and elderly Japanese patients.
    Hepatology Research 11/2013; 44(10). DOI:10.1111/hepr.12268 · 2.22 Impact Factor
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    ABSTRACT: The prevalence of hepatitis C virus (HCV) infection in elderly patients has been increasing in Japan. However, there are no reports on the safety and efficacy of the triple therapy of telaprevir, peginterferon, and ribavirin for elderly patients with chronic HCV infection. This study evaluated the safety and efficacy of triple therapy [12 weeks of telaprevir 1,500 mg/day, reduction dose, and 24 weeks of peginterferon and ribavirin] in 18 elderly Japanese patients aged >65 years, with chronic infection with HCV genotype 1b. Four patients received triple therapy with telaprevir 2,250 mg/day and the other 14 patients received telaprevir 1,500 mg/day. Sustained virological response-12 (HCV RNA negativity at 12 weeks after completion of therapy) was 50% (9 of 18 patients); while 4 of 18 (22%) patients discontinued triple therapy due to adverse events (skin rashes, anemia, poor appetite). The dose of telaprevir did not affect HCV RNA clearance rates. Regardless of the dose, 50% of the treated patients achieved sustained virological response-12, evaluated by intention-to-treat analysis. Furthermore, the fall in hemoglobin and the rise in serum creatinine were significantly milder in the telaprevir 1,500 mg group than the telaprevir 2,250 mg/day group. Further analysis showed that 67% (6 of 9 elderly patients) with IL28B gene (rs8099917) genotype TT, treated with telaprevir 1,500 mg, achieved sustained virological response-12. These results suggest that 24-week triple therapy with telaprevir 1,500 mg seems safe and efficacious for elderly Japanese patients infected with HCV genotype 1b. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 10/2013; 85(10). DOI:10.1002/jmv.23673 · 2.22 Impact Factor
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    ABSTRACT: Treatment of hepatocellular carcinoma located on the liver surface is frequently difficult because direct puncture of the tumor must be avoided during needle insertion. The aim of this study was to investigate the utility of a no-touch pincer ablation procedure that uses a multipolar radiofrequency ablation (RFA) system for a tumor located on the liver surface. The experimental animals were 3 pigs, and RFA was performed with 2 internally cooled bipolar electrodes. Three ablative procedures were compared: linear insertion at regular 13-mm intervals (Pattern-1; virtual target tumor size, 10 mm), fan-shape insertion; maximum interval 20-mm (Pattern-2; virtual target tumor size, 15 mm), and 25-mm (Pattern-3; virtual target tumor size, 20 mm). All electrodes were inserted at a 30-mm depth. For Pattern-1 and Pattern-2, ablation was performed on three other parts of the liver, and for Pattern-3, ablation was performed on two other parts. For the median transverse and longitudinal diameter to the shaft, with the Pattern-1 procedure, the ablative areas were 32×30 mm, and with the Pattern-2 procedure, the ablative areas were 27×30 mm with carbonization of the liver surface. In contrast, with the Pattern-3 procedure, the ablative areas were 45×26 mm; however, the ablative margin did not reach the surface, and carbonization was not apparent. The no-touch pincer ablation procedure (with an electrode interval ≤20 mm) may be useful when performed with two internally cooled bipolar electrodes for small nodules that protrude from the liver surface.
    Hepatology Research 09/2013; 44(12). DOI:10.1111/hepr.12240 · 2.22 Impact Factor
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    ABSTRACT: The aim of this study was to determine the pharmacodynamics of cisplatin following three different treatment procedures for intrahepatic arterial infusion therapy for hepatocellular carcinoma (HCC). We divided 13 HCC patients into the following three groups: group A, lone injection of cisplatin (n=3); group B, combined injection of cisplatin and lipiodol, with embolization using small gelatin cubes (GCs) (n=5); and group C, injection of suspended lipiodol with cisplatin powder, with embolization using small GCs (n=5). In each group, the free cisplatin concentration in the hepatic vein was measured at 0, 5, 10, and 30 minutes. The mean free cisplatin concentrations were as follows. For group A, the mean was 48.58 µg/mL at 0 minute, 7.31 µg/mL at 5 minutes, 5.70 µg/mL at 10 minutes, and 7.15 µg/mL at 30 minutes. For the same time points, for group B, the concentrations were 8.66, 4.23, 3.22, and 1.65 µg/mL, respectively, and for group C, the concentrations were 4.81, 2.61, 2.52, and 1.75 µg/mL, respectively. The mean area under the curve (AUC)0-infinity for the free cisplatin concentration was 7.80 in group A, 2.48 in group B, and 2.27 in group C. The AUC0-infinity for the free cisplatin concentration gradually decreased, from group A to group C. These results indicate that the combination of lipiodol and small GCs may be useful for delaying cisplatin drainage from the liver.
    Gut and liver 09/2013; 7(5):576-84. DOI:10.5009/gnl.2013.7.5.576 · 1.49 Impact Factor
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    ABSTRACT: Few studies have investigated the emergence of multidrug resistance to adefovir dipivoxil (ADV) plus lamivudine (LAM) combination therapy for patients with LAM-refractory chronic hepatitis B (CHB). In this retrospective study, we investigated the long-term clinical course of these patients with or without multidrug resistance mutations. We analyzed 406 Japanese patients with LAM-refractory CHB treated with combination therapy with follow-up for a median of 5.4 (0.5-9.5) years. Multidrug resistance of hepatitis B virus (HBV) DNA was analyzed using direct sequencing or cloning methods at baseline and viral breakthrough or insufficient decline during combination therapy. Ratio of patients with undetectable serum HBV DNA levels (<2.6 log copies/mL) during combination therapy was 63, 72, 75, 79, 82, 80 and 85 % at years 1 through 7, respectively. Substitutions associated with multidrug resistance were identified in 11 patients (2.7 %) at baseline, and in 12 patients (3 %) during therapy. HBV DNA levels of patients with rtA181S mutation at baseline and emergence of rtA181T + rtN236T double mutation or a wide variety of mutations during combination therapy could not be suppressed. Moreover, using ultra-deep sequencing, rtA181T/V mutations were detected at baseline in 7 of 10 patients with emergent multidrug resistance during combination therapy, although 6 of these 7 patients had very low frequency (<1 %) variants. Long-term ADV plus LAM combination therapy is effective in LAM-refractory patients. However, HBV DNA levels of the patients with multidrug resistance at baseline or during combination therapy sometimes could not achieve complete suppression or were re-elevated after a decrease.
    Journal of Gastroenterology 08/2013; 49(6). DOI:10.1007/s00535-013-0864-4 · 4.02 Impact Factor
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    ABSTRACT: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce HCC development, but agent such as lamivudine (LAM) has a high rate of drug resistance. We compared the incidence of HCC in 472 entecavir (ETV)-treated patients and 1143 non-treated HBV patients (control group). Propensity score matching eliminated the baseline differences, resulting in a sample size of 316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV group. The cumulative HCC incidence rates at 5-year were 3.7% and 13.7% for the ETV, and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for a number of known HCC risk factors, showed that patients in the ETV group were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95% CI: 0.15 to 0.91; P = 0.030). Both cohorts were applied into 3 previously reported risk scales and risk scores were generated based on age, gender, cirrhosis status, levels of ALT, HBeAg, baseline HBV DNA, albumin, and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored higher on respective risk scales. In a group analysis, we compared treatment effect between nucleos(t)ide analogues (NAs) which included matched LAM-treated patients without rescue therapy (n = 182). We found HCC suppression effect greater in etv-treated (P < 0.001) than non-rescued LAM-treated (P = 0.019) cirrhotic patients when they were compared with the control group. Conclusion: Long-term entecavir treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk of HCC. (HEPATOLOGY 2012.).
    Hepatology 07/2013; 58(1). DOI:10.1002/hep.26180 · 11.19 Impact Factor
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    ABSTRACT: Background The definitive diagnosis of nonalcoholic steatohepatitis (NASH) is currently based on histopathological assessment. This study aimed to elucidate the utility of a novel noninvasive method, three-dimensional magnetic resonance imaging (3D-MRI), for diagnosing advanced fibrosis in patients with NASH, using histopathological diagnosis as the reference standard. Methods This retrospective study included 30 consecutive patients who had been diagnosed with NASH by histopathology and had undergone 3D-MRI before biopsy. 3D-MRI provided a three-dimensional reconstruction of the liver from contrast-enhanced hepatobiliary phase MR images. In the present study, histopathological advanced fibrosis was defined as stage 3 and 4 NASH. Advanced fibrosis, diagnosed by 3D-MRI, was considered to be diffuse irregularity of the entire surface of the liver. The diagnostic features of 3D-MRI and the noninvasive evaluation systems (APRI, FIB-4 index, and BARD score) for identifying advanced and nonadvanced fibrosis of NASH were determined and compared. Results Nine (30 %) of the 30 study patients were diagnosed histopathologically with advanced fibrosis, and 11 (37 %) of 30 patients were diagnosed with advanced fibrosis using 3D-MRI. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 3D-MRI for diagnosing advanced fibrosis were 100, 90, 82, and 100 %, respectively. The sensitivities of APRI, the FIB-4 index, and BARD score ranged from 78 to 89 %, the specificities from 71 to 90 %, the PPVs from 54 to 78 %, and the NPVs from 88 to 94 %. Conclusion Compared with the common noninvasive methods for diagnosing advanced fibrosis associated with NASH, 3D-MRI was more accurate.
    Hepatology International 07/2013; 7(3). DOI:10.1007/s12072-012-9419-7 · 2.47 Impact Factor
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    ABSTRACT: BACKGROUND: Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years. METHODS: Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10(3)/mm(3); HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan-Meier life table method. RESULTS: The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p < 0.001)], and HBeAg-negative status [RR 3.75 (p < 0.001)] significantly influenced HBsAg seroclearance. CONCLUSIONS: In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.
    Journal of Gastroenterology 06/2013; 49(3). DOI:10.1007/s00535-013-0821-2 · 4.02 Impact Factor