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Takayo Takemura,
Yuichi Yoshida,
Shinichi Kiso,
Takashi Kizu,
Kunimaro Furuta,
Hisao Ezaki,
Mina Hamano,
Mayumi Egawa,
Norihiro Chatani,
Yoshihiro Kamada, Yasuharu Imai,
Shigeki Higashiyama,
Ryo Iwamoto,
Eisuke Mekada,
Tetsuo Takehara
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ABSTRACT: Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis.
Biochemical and Biophysical Research Communications 06/2013; · 2.48 Impact Factor
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Tsugiko Oze,
Naoki Hiramatsu,
Takayuki Yakushijin,
Masanori Miyazaki,
Sadaharu Iio,
Masahide Oshita,
Hideki Hagiwara,
Eiji Mita,
Yoshiaki Inui,
Taizo Hijioka, [......],
Harumasa Yoshihara,
Atsuo Inoue, Yasuharu Imai,
Takuya Miyagi,
Yuichi Yoshida,
Tomohide Tatsumi,
Tatsuya Kanto,
Akinori Kasahara,
Norio Hayashi,
Tetsuo Takehara
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear. METHODS: Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis. RESULTS: The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log10 decrease, 13 % (7/56) with 1-2 log10 decrease, 51 % (44/87) with 2-3 log10 decrease, 64 % (56/87) with 3-4 log10 decrease, 88 % (72/82) with more than 4 log10 decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response. CONCLUSIONS: The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.
Journal of Gastroenterology 05/2013; · 4.16 Impact Factor
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ABSTRACT: Twelve hepatocellular nodules were characterized in the resected livers from 3 patients (2 men and a woman) with alcoholic cirrhosis. Imaging techniques suggested that the nodules were hypervascular and may be hepatocellular carcinoma. Five nodules (4-31mm in diameter) were serum amyloid A-positive hepatocellular neoplasm, which shares features with inflammatory hepatocellular adenoma. The remaining 7 nodules (5-8mm) were focal nodular hyperplasia-like nodules showing focal or no immunostaining for serum amyloid A. The serum amyloid A-positive hepatocellular neoplasms showed increased cellular density, inflammatory infiltrate, sinusoidal dilatation, and ductular reaction to various degrees. These histologic features tended to be less extensive in focal nodular hyperplasia-like nodules. Three of 4 serum amyloid A-positive hepatocellular neoplasms showed slight hypointensity in the hepatobiliary phase on the magnetic resonance (MR) imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) enhancement. In contrast, 3 focal nodular hyperplasia-like nodules showed iso-intensity in the hepatobiliary phase. This study further confirms characteristics of serum amyloid A-positive hepatocellular neoplasm arising in alcoholic cirrhosis that share features with inflammatory hepatocellular adenomas. Serum amyloid A-positive hepatocellular neoplasms sometimes co-exist with focal nodular hyperplasia-like nodules and may show different findings on Gd-EOB-enhanced MR imaging.
Histology and histopathology 05/2013; · 2.48 Impact Factor
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ABSTRACT: Purpose: To identify patient characteristics and magnetic resonance (MR) imaging findings associated with subsequent hypervascularization in hypovascular nodules that show hypointensity on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with chronic liver diseases. Materials and Methods: Institutional review board approval was obtained, and informed consent was waived. At multiple follow-up gadoxetic acid-enhanced MR imaging examinations of 68 patients, 160 hypovascular nodules were retrospectively reviewed. A Cox regression model for hypervascularization was developed to explore the association of baseline characteristics, including patient factors (Child-Pugh classification, etiology of liver disease, history of local therapy for hepatocellular carcinoma [HCC], and coexistence of hypervascular HCC) and MR imaging findings (fat content, signal intensity on T2-weighted images, and nodule size). In addition, the growth rate was calculated as the reciprocal of tumor volume doubling time to investigate its relationship with subsequent hypervascularization by using receiver operating characteristic and Kaplan-Meier analyses. Results: The prevalence of subsequent hypervascularization was 31% (50 of 160 nodules). Independent Cox multivariable predictors of increased risk of hypervascularization were hyperintensity on T2-weighted images (hazard ratio [HR] = 8.7; 95% confidence interval [CI]: 3.6, 20.8), previous local therapy for hypervascular HCC (HR = 5.0; 95% CI: 1.8, 13.6), Child-Pugh B cirrhosis (HR = 3.6; 95% CI: 1.4, 9.5) and coexistence of hypervascular HCC (HR = 2.0; 95% CI: 1.0, 3.8). The mean growth rate was significantly higher in nodules that showed subsequent hypervascularization than in those without hypervascularization. Kaplan-Meier analysis based on the receiver operating characteristic cutoff level (1.8 × 10(-3)/day [tumor volume doubling time, 542 days]) showed that nodules with a higher growth rate had a significantly higher incidence of hypervascularization (P = 5.2 × 10(-8), log-rank test). Conclusion: Hyperintensity on T2-weighted images is an independent and strong risk factor at baseline for subsequent hypervascularization in hypovascular nodules in patients with chronic liver disease. Tumor volume doubling time of less than 542 days was associated with a high rate of subsequent hypervascularization. © RSNA, 2013.
Radiology 02/2013; 266(2):480-90. · 5.73 Impact Factor
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ABSTRACT: Objectives: To investigate the usefulness of the ultrasonography (US) fusion imaging system for radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Methods: Since the US fusion imaging system became available in 2010, we have conducted RFA with this system in all cases. The characteristics of 75 patients with 120 HCCs and 89 patients with 123 HCCs who underwent RFA before the introduction of this system (period A) and after it (period B), respectively, were retrospectively compared. Results: Significant difference in the characteristics of the patients and HCCs between the two periods was found only in the proportion of HCCs with poor conspicuity on grayscale US treated with RFA (1.7%, 2/120 for period A vs. 15.4%, 19/123 for period B, p < 0.01). Among the 19 HCCs with poor conspicuity on grayscale US for period B, 5 and 9 HCCs were identified on grayscale US and contrast-enhanced US, respectively, by the use of the US fusion imaging system, whereas the 5 remaining undetectable HCCs were treated by using the system in conjunction with reference images displayed side-by-side with grayscale US. Conclusion: Since the introduction of the US fusion imaging system, it has become possible to perform RFA for HCCs with poor conspicuity on grayscale US.
Oncology 01/2013; 84 Suppl 1:44-50. · 2.27 Impact Factor
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Masatoshi Kudo,
Osamu Matsui,
Michiie Sakamoto,
Azusa Kitao,
Tonsok Kim,
Shun-Ichi Ariizumi,
Tomoaki Ichikawa,
Satoshi Kobayashi, Yasuharu Imai,
Namiki Izumi,
Yasunari Fujinaga,
Shigeki Arii
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ABSTRACT: We summarize here the consensus reached at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan held in Kanazawa on July 20th and 21st, 2012, on the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the management of hepatocellular carcinoma (HCC). Currently, dynamic CT is the first choice of imaging modality when HCC is suspected. EOB-MRI is useful for differentiation and definitive diagnosis of HCC when dynamic CT/MRI does not show conclusive findings for HCC. In addition, contrast- enhanced ultrasound with Sonazoid is useful for making a decision on whether or not to treat a hypovascular lesion <1 cm when the nodules are shown with low intensity in the hepatocyte phase of EOB-MRI. Furthermore, EOB-MRI should be performed in selected cases of HCC ultrahigh-risk groups every 3-4 months, or EOB-MRI should be performed at least once at the first visit in all HCC ultrahigh-risk groups.
Oncology 01/2013; 84 Suppl 1:21-7. · 2.27 Impact Factor
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Yuki Makino, Yasuharu Imai,
Takumi Igura,
Masatoshi Hori,
Kazuto Fukuda,
Yoshiyuki Sawai,
Sachiyo Kogita,
Hideko Ohama,
Yasushi Matsumoto,
Masanori Nakahara,
Shinichiro Zushi,
Masanori Kurokawa,
Keisuke Isotani,
Manabu Takamura,
Norihiko Fujita,
Takamichi Murakami
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ABSTRACT: AIM: To demonstrate the usefulness of the computed tomography (CT) fusion imaging for the evaluation of treatment effect of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Eighty-five patients with 94 HCC with complete ablation judged on conventional side-by-side interpretation of pre-RFA and post-RFA CT at the time of RFA were included in this retrospective study. CT data was retrospectively used to create fusion images of pre-RFA and post-RFA CT using automatic rigid registration and manual correction referring to intrahepatic structures and hepatic contours around a tumor. Clinical factors including a minimal ablative margin (MAM) measured on fusion images were examined to prove risk factors for local tumor progression (LTP). RESULTS: LTP was observed in 13 (13.8%) tumors with a median follow up of 21.0 months (range, 2-75). The mean MAM on the fusion image was 1.4 ± 3.1 mm and 23 tumors (24.5%) were judged to be protruding from the ablation zone. Multivariate analysis revealed that protruding from the ablation zone was the only significant factor for LTP (hazard ratio, 7.09; 95% confidential interval, 2.26-22.3; P < 0.001). CONCLUSION: Some HCC were assessed as incomplete ablation on the CT fusion images, although considered completely ablated on side-by-side images at the time of treatment, and incomplete ablation was revealed to be the only independent risk factor for LTP. The CT fusion imaging enables quantitative and accurate evaluation of treatment effect of RFA.
Hepatology Research 12/2012; · 2.20 Impact Factor
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Naoki Harada,
Naoki Hiramatsu,
Tsugiko Oze,
Ryoko Yamada,
Mika Kurokawa,
Masanori Miyazaki,
Takayuki Yakushijin,
Takuya Miyagi,
Tomohide Tatsumi,
Shinichi Kiso, [......],
Eiji Mita,
Hideki Hagiwara,
Yoshiaki Inui,
Kazuhiro Katayama,
Shinji Tamura,
Harumasa Yoshihara, Yasuharu Imai,
Atsuo Inoue,
Norio Hayashi,
Tetsuo Takehara
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ABSTRACT: BACKGROUND: This study was conducted to evaluate Japanese treatment guidelines for patients with chronic hepatitis C virus (HCV) infection and normal alanine aminotransferase (N-ALT) levels from the viewpoint of the incidence of hepatocellular carcinoma (HCC). METHODS: Four groups of patients with chronic HCV infection treated with pegylated interferon (Peg-IFN) plus ribavirin, and classified according to the N-ALT guidelines, were examined for HCC incidence: group A (n = 353), ALT ≤30 IU/L and platelet (PLT) ≥15 × 10(4)/mm(3); group B (n = 123), ALT ≤30 IU/L and PLT <15 × 10(4)/mm(3); group C (n = 233), 30 < ALT ≤ 40 IU/L and PLT ≥15 × 10(4)/mm(3); and group D (n = 100), 30 < ALT ≤ 40 IU/L and PLT <15 × 10(4)/mm(3). The mean observation period was 36.2 ± 16.5 months RESULTS: In groups A and C, the HCC incidence was low even in patients with non-response (NR) (cumulative rates at 3 years, 0.0 and 2.9 %, respectively). In groups B and D, 14.5 and 5.3 % of NR patients had developed HCC at 3 years, but none of the patients with sustained virologic response (SVR) or relapse had developed HCC. In group B, no patients with mild fibrosis developed HCC irrespective of the antiviral effect of the treatment. Among patients with PLT <15 × 10(4)/mm(3) (group B plus group D), the HCC incidence was significantly lower in patients with SVR and relapse than in NR patients (p < 0.001, p = 0.021, respectively). CONCLUSION: These results suggest that N-ALT patients with PLT <15 × 10(4)/mm(3) could be candidates for early antiviral therapy.
Journal of Gastroenterology 09/2012; · 4.16 Impact Factor
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Koyo Higashitani,
Tatsuya Kanto,
Shoko Kuroda,
Sachiyo Yoshio,
Tokuhiro Matsubara,
Naruyasu Kakita,
Tsugiko Oze,
Masanori Miyazaki,
Mitsuru Sakakibara,
Naoki Hiramatsu,
Eiji Mita, Yasuharu Imai,
Akinori Kasahara,
Alato Okuno,
Osamu Takikawa,
Norio Hayashi,
Tetsuo Takehara
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ABSTRACT: BACKGROUND: Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses. METHODS: This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers. RESULTS: The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor. CONCLUSIONS: Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.
Journal of Gastroenterology 09/2012; · 4.16 Impact Factor
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Mika Kurokawa,
Naoki Hiramatsu,
Tsugiko Oze,
Takayuki Yakushijin,
Masanori Miyazaki,
Atsushi Hosui,
Takuya Miyagi,
Yuichi Yoshida,
Hisashi Ishida,
Tomohide Tatsumi, [......],
Hideki Hagiwara,
Eiji Mita,
Toshifumi Ito,
Yoshiaki Inui,
Kazuhiro Katayama,
Harumasa Yoshihara, Yasuharu Imai,
Eijirou Hayashi,
Norio Hayashi,
Tetsuo Takehara
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ABSTRACT: Nucleotide analogues have recently been approved for the treatment of patients with hepatitis B virus (HBV) infection. However, it is still controversial whether the decrease of HBV-DNA amount induced by treatment with nucleotide analogues can reduce the risk of hepatocellular carcinoma (HCC) development in HBV patients.
A total of 293 HBV patients without HCC who were treated with lamivudine (LAM) were enrolled in a multicenter trial. The incidence of HCC was examined after the start of LAM therapy, and the risk factors for liver carcinogenesis were analyzed. The mean follow-up period was 67.6 ± 27.4 months.
On multivariate analysis for HCC development in all patients, age ≥50 years, platelet count <14.0 × 10(4)/mm(3), cirrhosis, and median HBV-DNA levels of ≥4.0 log copies/ml during LAM treatment were significant risk factors. The cumulative carcinogenesis rate at 5 years was 3% in patients with chronic hepatitis and 30% in those with cirrhosis. For the chronic hepatitis patients, the log-rank test showed the significant risk factors related to HCC development to be age ≥50 years, platelet count <14.0 × 10(4)/mm(3), and hepatitis B e antigen negativity, but median HBV-DNA levels of <4.0 log copies/ml (maintained viral response, MVR) did not significantly suppress the development of HCC. In cirrhosis patients, however, the attainment of MVR during LAM treatment was revealed to reduce the risk of HCC development.
These results suggest that the incidence of HCC in HBV patients with cirrhosis can be reduced in those with an MVR induced by consecutive LAM treatment.
Journal of Gastroenterology 01/2012; 47(5):577-85. · 4.16 Impact Factor
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Takahisa Kawaguchi,
Yoshio Sumida,
Atsushi Umemura,
Keitaro Matsuo,
Meiko Takahashi,
Toshinari Takamura,
Kohichiroh Yasui,
Toshiji Saibara,
Etsuko Hashimoto,
Miwa Kawanaka, [......],
Sumio Kawata, Yasuharu Imai,
Miki Kokubo,
Toshihide Shima,
Hyohun Park,
Hideo Tanaka,
Kazuo Tajima,
Ryo Yamada,
Fumihiko Matsuda,
Japan Study Group of Nonalcoholic Fatty Liver Disease
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10-30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle.
To identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4 × 10(-10) (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6 × 10(-6)) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory-Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8 × 10(-6), OR = 1.96, 95%CI: 1.47-2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7 × 10(-16), OR = 2.18, 95%CI: 1.81-2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6 × 10(-4)), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6 × 10(-4)).
With these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population.
PLoS ONE 01/2012; 7(6):e38322. · 4.09 Impact Factor
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ABSTRACT: A multimodality fusion imaging system has been introduced for the clinical practice of diagnosis and treatment of hepatocellular carcinoma (HCC), especially for loco-regional treatment. An ultrasonography (US) fusion imaging system can provide a side-by-side display of real-time US images and any cross-sectional images of multiplanar reconstruction of CT or MRI that synchronize real-time US. The US fusion imaging system enables us to perform radiofrequency ablation (RFA) for HCCs difficult to detect on conventional US safely. Besides, we can evaluate the treatment effects of RFA easily at the bedside by combining the contrast-enhanced US and the US fusion imaging system. Fusion images of pre- and post-RFA CT have been utilized for the assessment of the treatment effects of RFA. Although the treatment effects of RFA have been conventionally evaluated, comparing pre- and post-RFA CT side-by-side, the evaluation tends to be inaccurate. On CT fusion images, the tumor and the ablation zone are overlaid and we can grasp the positional relation easily, leading to quantitative and more accurate evaluation. The multimodality fusion imaging system has become quite an important tool for loco-regional treatment of HCC because of its usefulness for both the guidance during the RFA procedure and the evaluation of its treatment effects.
Digestive Diseases 01/2012; 30(6):580-7. · 2.37 Impact Factor
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Yuki Makino,
Takumi Igura, Yasuharu Imai,
Kazuto Fukuda,
Yoshiyuki Sawai,
Sachiyo Kogita,
Naoto Uenoyama,
Yoshinori Doi,
Shinichi Kiso,
Naoki Hiramatsu,
Shinji Tamura,
Norio Hayashi,
Tetsuo Takehara
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ABSTRACT: A 30-year-old man was admitted to Osaka University Hospital for the treatment of gastric varices and assessment of indication for liver transplant. When he was 6 years old, liver dysfunction was pointed out and diagnosed as chronic inactive hepatitis by liver biopsy. At 13 years of age, the second liver biopsy proved congenital hepatic fibrosis (CHF). The third liver biopsy was performed when he was 30 years old, and the progression of hepatic fibrosis was confirmed. Besides CHF, we recognized oligophrenia, cerebellar ataxia, hypoplasia of cerebellar vermis and coloboma, leading to the diagnosis of COACH syndrome. COACH syndrome is quite rare, and our case is especially valuable because he was diagnosed as an adult case and the progression of hepatic fibrosis could be followed through several liver biopsies. We should be aware of COACH syndrome in mind when we encounter CHF patients.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2012; 109(7):1223-9.
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Tsugiko Oze,
Naoki Hiramatsu,
Changho Song,
Takayuki Yakushijin,
Sadaharu Iio,
Yoshinobu Doi,
Masahide Oshita,
Hideki Hagiwara,
Eiji Mita,
Toshifumi Ito, [......],
Masanori Miyazaki,
Atsushi Hosui,
Takuya Miyagi,
Yuichi Yoshida,
Tomohide Tatsumi,
Shinichi Kiso,
Tatsuya Kanto,
Akinori Kasahara,
Norio Hayashi,
Tetsuo Takehara
[show abstract]
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ABSTRACT: The timing to the first undetectable hepatitis C virus (HCV) RNA level is strongly associated with sustained virologic response in pegylated interferon (Peg-IFN) plus ribavirin combination therapy for patients with chronic hepatitis C (CH-C) with genotype 1. This study was conducted to clarify the impact of drug exposure to Peg-IFN on the timing of HCV RNA negativity in Peg-IFN plus ribavirin combination therapy for CH-C patients with genotype 1.
A total of 1409 patients treated with Peg-IFN alfa-2b plus ribavirin were enrolled and classified into four categories according to the Peg-IFN dosage. Furthermore, 100 patients were extracted from each Peg-IFN dosage category to adjust for characteristic factors, using the propensity score method.
Peg-IFN exposure was dose-dependently associated with the timing of HCV RNA negativity (p ≤ 0.001). The HCV RNA negative rate at week 4 decreased from 12% with a Peg-IFN dose of >1.5 μg/kg/week to 1-3% with a dose of <1.5 μg/kg/week (p ≤ 0.001), and at week 12 the rate had decreased from 44% with a dose of ≥1.2 μg/kg/week to 18% with a dose of <1.2 μg/kg/week (p = 0.001). Treatment failure (patients without a 1-log decrease of HCV RNA at week 4 or a 2-log decrease of HCV RNA at week 12, or positive at week 24) was found in 54-66% of patients given <1.2 μg/kg/week (p ≤ 0.001), and these patients accounted for 64% of the non-responders.
The timing of HCV RNA negativity depends significantly on the Peg-IFN dose. Reducing the Peg-IFN dose can induce a later virologic response or non-response in HCV genotype 1 patients treated with Peg-IFN plus ribavirin.
Journal of Gastroenterology 11/2011; 47(3):334-42. · 4.16 Impact Factor
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Hiromitsu Onishi,
Tonsok Kim, Yasuharu Imai,
Masatoshi Hori,
Hiroaki Nagano,
Yasuhiro Nakaya,
Takahiro Tsuboyama,
Atsushi Nakamoto,
Mitsuaki Tatsumi,
Seishi Kumano,
Masahiro Okada,
Manabu Takamura,
Kenichi Wakasa,
Noriyuki Tomiyama,
Takamichi Murakami
[show abstract]
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ABSTRACT: To retrospectively compare the accuracy of detection of hypervascular hepatocellular carcinoma (HCC) by multiphasic multidetector CT and by gadoxetate disodium-enhanced MR imaging.
After ethical approval, we analysed a total of 73 hypervascular HCC lesions from 31 patients suspected of having HCC, who underwent both gadoxetate disodium-enhanced MR imaging and multiphasic multidetector CT. Five blinded observers independently reviewed CT images, as well as dynamic MR images alone and combined with hepatobiliary phase MR images. Diagnostic accuracy (Az values), sensitivities and positive predictive values were compared by using the Scheffe post hoc test.
The mean Az value for dynamic and hepatobiliary phase MR combined (0.81) or dynamic MR images alone (0.78) was significantly higher than that for CT images (0.67, P < 0.001, 0.005, respectively). The mean sensitivity of the combined MR images (0.67) was significantly higher than that of dynamic MR alone (0.52, P < 0.05) or CT images (0.44, P < 0.05). The mean positive predictive values were 0.96, 0.95 and 0.94, for CT, dynamic MR alone and combined MR images, respectively.
Compared with multiphasic multidetector CT, gadoxetate disodium-enhanced MR imaging combining dynamic and hepatobiliary phase images results in significantly improved sensitivity and diagnostic accuracy for detection of hypervascular HCC.
Gadoxetate disodium is a new liver-specific MR imaging contrast agent. Gadoxetate disodium-enhanced MRI helps the assessment of patients with liver disease. It showed high diagnostic accuracy for the detection of hepatocellular carcinoma.
European Radiology 11/2011; 22(4):845-54. · 3.22 Impact Factor
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Naoki Hiramatsu,
Yuko Inoue,
Tsugiko Oze,
Nao Kurashige,
Takayuki Yakushijin,
Kiyoshi Mochizuki,
Takuya Miyagi,
Tomohide Tatsumi,
Shinichi Kiso,
Tatsuya Kanto, [......],
Tetsuo Takehara,
Masahide Oshita,
Eiji Mita,
Hideki Hagiwara,
Yoshiaki Inui,
Kazuhiro Katayama,
Shinji Tamura,
Harumasa Yoshihara, Yasuharu Imai,
Norio Hayashi
[show abstract]
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ABSTRACT: The antiviral effect of pegylated interferon (Peg-IFN) plus ribavirin combination therapy in chronic hepatitis C (CHC) patients with normal alanine aminotransferase (ALT) levels (N-ALT) has been reported to be equivalent to that for patients with elevated ALT levels (E-ALT). However, the actual antiviral effect in N-ALT patients remains obscure because efficacy can be overestimated in patients with an advantageous background.
In this study, 386 patients were extracted, for a matched case-control study, from 1320 CHC patients treated with Peg-IFN alpha-2b plus ribavirin combination therapy; 193 N-ALT patients [116 with hepatitis C virus genotype 1 (HCV-1), 77 with HCV genotype 2 (HCV-2)] were matched with 193 E-ALT patients by a propensity score method using the variables of age, sex, IFN treatment history, body mass index, and platelet counts.
On multivariate analysis for sustained virological response (SVR) in N-ALT patients, younger age, low HCV RNA level at baseline, and HCV-2 were significant factors. The matched case-control study showed that the SVR rates of N-ALT patients were equivalent to those of E-ALT patients; at 49 and 40% in the HCV-1 group (P = 0.146), and 78 and 81% in the HCV-2 group (P = 0.691). However, in N-ALT patients with non-SVR, approximately 40% showed ALT elevation at 24 weeks post-treatment.
Our findings indicate that the antiviral effect of Peg-IFN plus ribavirin therapy in N-ALT patients is comparable to that for E-ALT patients irrespective of their advantageous background; however, the application of this therapy for N-ALT patients, especially for those with HCV-1, should be considered carefully.
Journal of Gastroenterology 08/2011; 46(11):1335-43. · 4.16 Impact Factor
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Nihon Naika Gakkai Zasshi 06/2011; 100(6):1657-9.
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Tsugiko Oze,
Naoki Hiramatsu,
Takayuki Yakushijin,
Kiyoshi Mochizuki,
Kazuho Imanaka,
Akira Yamada,
Masahide Oshita,
Akira Kaneko,
Hideki Hagiwara,
Eiji Mita, [......],
Atsushi Hosui,
Takuya Miyagi,
Yuichi Yoshida,
Hisashi Ishida,
Tomohide Tatsumi,
Shinichi Kiso,
Tatsuya Kanto,
Akinori Kasahara,
Tetsuo Takehara,
Norio Hayashi
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ABSTRACT: Which patients with hepatitis C virus (HCV) genotype 1 can benefit from extended treatment with pegylated interferon (Peg-IFN) plus ribavirin is unknown, although the overall sustained virologic response (SVR) rate has been shown to improve in patients with a late virologic response (LVR), defined as detectable serum HCV RNA at week 12 and undetectable at week 24.
Among 1163 chronic hepatitis C patients with genotype 1 treated with Peg-IFN plus ribavirin combination therapy, 213 patients with an LVR were examined in this study. In addition, we selected 81 patients of matched sex and age from each of the 48- and 72-week treatment groups, using the propensity score, to compare the efficacy of the two treatment durations.
With 72-week treatment, the timing of HCV RNA disappearance and the hemoglobin level at baseline showed a strong correlation with the SVR on multivariate analysis. Earlier HCV RNA disappearance was associated with a better SVR rate, regardless of the ribavirin dose (HCV RNA disappearance at week 16, 74%; at week 20, 52%; and at week 24, 31%, p = 0.01). The SVR rate with 72-week treatment was higher than that with 48-week treatment, irrespective of age, sex, or the platelet value, and, especially in aged patients (≥65 years old), the SVR rate increased markedly with 72-week treatment (48 weeks, 25% vs. 72 weeks, 56%; p < 0.05).
An earlier response predicts a higher SVR rate in patients with an LVR given 72-week treatment. Extended treatment with Peg-IFN plus ribavirin for patients with an LVR improved the treatment efficacy, even for aged patients.
Journal of Gastroenterology 05/2011; 46(7):944-52. · 4.16 Impact Factor
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Tsugiko Oze,
Naoki Hiramatsu,
Takayuki Yakushijin,
Kiyoshi Mochizuki,
Masahide Oshita,
Hideki Hagiwara,
Eiji Mita,
Toshifumi Ito,
Yoshiaki Inui,
Hiroyuki Fukui, [......],
Atsushi Hosui,
Takuya Miyagi,
Hisashi Ishida,
Yuichi Yoshida,
Tomohide Tatsumi,
Shinichi Kiso,
Tatsuya Kanto,
Akinori Kasahara,
Tetsuo Takehara,
Norio Hayashi
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ABSTRACT: It is still not known which patients with chronic hepatitis C who failed to respond to previous pegylated interferon (Peg-IFN) plus ribavirin therapy can benefit from re-treatment.
Seventy-four patients (HCV genotype 1, n = 56, genotype 2, n = 18) were re-treated with Peg-IFN plus ribavirin.
On re-treatment, the sustained virologic response (SVR) rate was 41% for genotype 1 and 56% for genotype 2. With genotype 1, the factors associated with an SVR were previous treatment response and the serum hepatitis C virus (HCV) RNA level at the start of re-treatment. Patients with a ≥ 2-log decrease in HCV RNA at week 12 (partial early virologic response, p-EVR) in previous treatment had significantly higher SVR rates than those without these decreases (p < 0.001); no patient without a p-EVR in the previous treatment attained an SVR with re-treatment (0/16). All patients with <5 log(10) IU/ml of HCV RNA at the start of re-treatment attained an SVR (6/6), while only 33% (15/45) of those patients with ≥ 5 log(10) IU/ml of HCV RNA attained an SVR (p < 0.01). Among the patients with relapse in the previous treatment, those who attained an SVR on re-treatment required a longer duration of re-treatment than the duration of the previous treatment (re-treatment, 63.8 ± 13.0 weeks vs. previous treatment, 53.9 ± 13.5 weeks, p = 0.01).
Re-treatment of genotype 1 patients should be limited to patients with a p-EVR in the previous treatment and a low HCV RNA level at the start of re-treatment. In re-treatment with Peg-IFN plus ribavirin, longer treatment duration can contribute to increasing the anti-viral effect.
Journal of Gastroenterology 05/2011; 46(8):1031-7. · 4.16 Impact Factor
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Takashi Katsube,
Masahiro Okada,
Seishi Kumano,
Izumi Imaoka,
Yuki Kagawa,
Masatoshi Hori,
Kazunari Ishii,
Noboru Tanigawa, Yasuharu Imai,
Masatoshi Kudo,
Takamichi Murakami
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ABSTRACT: To investigate the usefulness of T2* mapping of liver on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI for estimating liver function.
33 patients were classified into 3 groups as follows: normal liver function (NLF) (n = 7); mild liver damage (MLD) (n = 16) with Child-Pugh A; severe liver damage (SLD) (n = 10) with Child-Pugh B. T2*-weighted gradient-echo (T2*W-GRE) and T1-weighted gradient-echo (T1W-GRE) images were obtained before and after Gd-EOB-DTPA administration (3, 8, 13, and 18 min; 5, 10,15, and 20min; respectively). T2* mapping of liver was calculated from T2*W-GRE, then T2* values of liver and T2* reduction rates of T2* value between pre- and post-contrast enhancement were measured. The increase rates of liver-to-muscle signal intensity (LMS) ratio on T1W-GRE between pre- and post-contrast enhancement were calculated.
T2* values on pre- and post-contrast showed no significant differences among three groups. Significant differences in T2* reduction rates were found among groups, and those of LCB were lower than those of other groups (NLF:MLD:SLD, 3.8:6.0:0.6% at 3 min, 8.2:10.3:1.0% at 8 min, 10.7:11.5:1.2% at 13 min, and 16.1:13.2:3.5% at 18 min, respectively) (P<0.05). Significant differences in increase rates of LMS ratio on T1W-GRE were identified (NLF:MLD:SLD, 1.53:1.46:1.35 at 5 min, 1.68:1.64:1.37 at 10 min, 1.79:1.76:1.44 at 15 min, and 1.89:1.78:1.49 at 20 min, respectively).
T2* reduction rate and increase rate of LMS ratio on T1W-GRE may allow us estimation of liver function according to Child-Pugh score.
European journal of radiology 04/2011; 81(7):1460-4. · 2.65 Impact Factor
