Publications (280)1198.08 Total impact
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Article: Preliminary analysis of risk factors for late rectal toxicity after helical tomotherapy for prostate cancer.
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ABSTRACT: The purpose of this study is to examine risk factors for late rectal toxicity for localized prostate cancer patients treated with helical tomotherapy (HT). The patient cohort of this retrospective study was composed of 241 patients treated with HT and followed up regularly. Toxicity levels were scored according to the Radiation Therapy Oncology Group grading scale. The clinical and dosimetric potential factors increasing the risk of late rectal toxicity, such as age, diabetes, anticoagulants, prior abdominal surgery, prescribed dose, maximum dose of the rectum, and the percentage of the rectum covered by 70 Gy (V70), 60 Gy (V60), 40 Gy (V40) and 20 Gy (V20) were compared between ≤ Grade 1 and ≥ Grade 2 toxicity groups using the Student's t-test. Multivariable logistic regression analysis of the factors that appeared to be associated with the risk of late rectal toxicity (as determined by the Student's t-test) was performed. The median follow-up time was 35 months. Late Grade 2-3 rectal toxicity was observed in 18 patients (7.4%). Age, the maximum dose of the rectum, V70 and V60 of the ≥ Grade 2 toxicity group were significantly higher than in those of the ≤ Grade 1 toxicity group (P = 0.00093, 0.048, 0.0030 and 0.0021, respectively). No factor was significant in the multivariable analysis. The result of this study indicates that the risk of late rectal toxicity correlates with the rectal volume exposed to high doses of HT for localized prostate cancer. Further follow-up and data accumulation may establish dose-volume modeling to predict rectal complications after HT.Journal of Radiation Research 03/2013; · 1.68 Impact Factor -
Article: The combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice.
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ABSTRACT: α-Galactosylceramide (α-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using α-GalCer and anti-cancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of α-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of non-treated mice and of mice treated with 5-FU or α-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. α-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant up-regulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but α-GalCer did not. The cytolytic activity of α-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against non-treated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of α-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. The present study suggests a promising new chemo-immunotherapy against metastatic liver cancer. © 2013 Wiley Periodicals, Inc.International Journal of Cancer 02/2013; · 5.44 Impact Factor -
Article: A multicenter survey of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan.
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ABSTRACT: Aim: This study aimed to clarify the factors associated the efficacy of re-treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. Methods: One hundred and forty-three patients who had previously shown relapse (n = 79), non-response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re-treated with PEG IFN plus ribavirin. Results: Twenty-five patients with intolerance to previous treatment completed re-treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re-treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re-treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin-28B major genotype responded significantly better and earlier to re-treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Conclusion: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re-treatment for HCV genotype 1 patients. Re-treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re-treatment.Hepatology Research 01/2013; 43(1):35-43. · 2.20 Impact Factor -
Article: Novel image analysis method using ultrasound elastography for noninvasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.
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ABSTRACT: It has been established that the long-term infection of chronic hepatitis C leads to the increased risk of hepatic fibrosis and hepatocellular carcinoma. Currently, histological diagnosis by invasive and painful liver biopsy is the gold standard for evaluating the hepatic fibrosis stage. Because of a side effect or patient inability to cope with the pain, it is difficult to assess the fibrosis stage frequently using liver biopsy. Recently, instead of liver biopsy, many articles have been published showing the usefulness of ultrasound elastography to evaluate the stage of hepatic fibrosis. We also reported the usefulness of real-time tissue elastography (RTE) for liver fibrosis staging in 2007. However, in our previous report, fibrosis classification was performed manually and the number of patients involved was also small. In the current study, the fibrosis staging is performed automatically using software by characterizing the elastography images. We have also increased the number of patients from 64 to 310. Thus, the aim of this study is to increase objectivity by using a newly developed automatic analysis method. We obtain the Liver Fibrosis Index (LFI), which is calculated from image features of RTE images, using multiple regression analysis performed on clinical data of 310 cases as the training data set. The correlation coefficient obtained between the LFI and the stage of hepatic fibrosis was r = 0.68, and significant differences exist between all stages of fibrosis (p < 0.001). Our new method seems promising since it has the ability to diagnose fibrosis even in the presence of inflammation.Oncology 01/2013; 84 Suppl 1:3-12. · 2.27 Impact Factor -
Article: Human BDCA3(+) dendritic cells are a potent producer of IFN-λ in response to hepatitis C virus.
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ABSTRACT: The polymorphisms in IL-28B (IFN-λ3) gene are strongly associated with the efficacy of HCV clearance. Dendritic cells (DCs) sense HCV and produce IFNs, thereby playing some cooperative roles with HCV-infected hepatocytes in the induction of interferon-stimulated genes (ISGs). BDCA3(+) DCs are discovered as a producer of IFN-λ upon toll-like receptor3(TLR3) agonist. We thus aimed to clarify the roles of BDCA3(+) DCs inanti-HCV innate immunity.Seventy healthy subjects and 20 patients with liver tumors were enrolled. BDCA3(+) DCs, in comparison with plasmacytoid DCs and myeloid DCs, were stimulated with TLR agonists, cell-cultured HCV (HCVcc) or Huh7.5.1 cells transfected with HCV/JFH-1. BDCA3(+) DCs were treated with anti-CD81 antibody, inhibitors for endosome acidification, TRIF-specific inhibitor or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-λ1, IL-28A/IFN-λ2 and IL-28B were quantified by subtype-specific ELISA. The frequency of BDCA3(+) DCs in PBMC was extremely low but higher in the liver. BDCA3(+) DCs recovered from PBMC or the liver released large amounts of IFN-λs, when stimulated with HCVcc or HCV-transfected Huh7.5.1.BDCA3(+) DCs were able to induce ISGs in the co-existing JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3(+) DCs with anti-CD81 antibody, cloroquine or bafilomycinA1 reduced HCVcc-induced IL-28B release, whereas BDCA3(+) DCs comparably produced IL-28B upon replication-defective HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3(+) DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3(+) DCs in healthy subjects with IL-28B major (rs8099917, TT) released more IL-28B than those with IL-28B minor genotype (TG). Conclusion: Human BDCA3(+) DCs,having tendency of being accumulated in the liver, recognize HCV by a CD81-, endosome- and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-λ3,the ability of which is superior in subjects with IL-28B major genotype. (HEPATOLOGY 2012.).Hepatology 12/2012; · 11.66 Impact Factor -
Article: Fibrosis score consisting of four serum markers successfully predicts pathological fibrotic stages of chronic hepatitis B.
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ABSTRACT: AIM: In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis B, multivariate regression analysis was performed using multiple fibrosis markers. METHOD: A total of 227 patients from seven hepatology units and institutes were diagnosed by needle biopsy as having chronic liver disease caused by hepatitis B virus. Twenty-three variables and their natural logarithmic transformation were employed in the multivariate analysis. Multiple regression function was generated from data of 158 patients in one hospital, and validation was performed using the other data of 69 patients from six other hospitals. RESULTS: After stepwise variable selection, multivariate regression analysis finally obtained the following function: z = 1.40 × ln (type IV collagen 7S) (ng/mL) - 0.017 × (platelet count) (×1000(3) /mm(3) ) + 1.24 × ln (tissue inhibitor of matrix metalloproteinase-2) (ng/mL) + 1.19 × ln (α-2-macroglobulin) (mg/dL) - 9.15. Median values of fibrosis scores of F1 (n = 73), F2 (n = 42), F3 (n = 31) and F4 stages (n = 12) were calculated as 0.95, 2.07, 2.98 and 3.63, respectively. Multiple regression coefficient and coefficient of determination were 0.646 and 0.418, respectively. Validation with patient data from other institutions demonstrated good reproducibility of fibrosis score for hepatitis B (FSB), showing 1.33 in F1 (n = 27), 2.20 in F2 (n = 20), 3.11 in F3 (n = 20) and 5.30 in F4 (n = 2), respectively. CONCLUSION: A concise multiple regression function using four laboratory parameters successfully predicted pathological fibrosis stage of patients with hepatitis B virus infection.Hepatology Research 11/2012; · 2.20 Impact Factor -
Article: Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines.
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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 -
Article: Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection.
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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 -
Article: CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis.
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ABSTRACT: OBJECTIVE: MicroRNAs (miRNAs) act as tumour suppressor genes or oncogenes in the regulation of multiple carcinogenic processes. Aberrant miRNA expression is reported in Helicobacter pylori (H pylori)-related gastritis and gastric cancer. The cytotoxin-associated gene A (CagA) of H pylori has a pathophysiologically important role in gastric carcinogenesis. A study was undertaken to evaluate the effect of CagA on miRNA expression and its regulatory mechanism. METHODS: The effect of CagA on miRNA expression was assessed by comprehensive miRNA microarray. The mechanisms of the in vitro and in vivo effects of CagA on histone modification and DNA methylation and the involvement of CagA-dysregulated signal transduction on let-7, an important representative miRNA in gastric carcinogenesis, were investigated. RESULTS: In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation. CONCLUSIONS: H pylori CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation.Gut 08/2012; · 10.11 Impact Factor -
Article: Pitavastatin ameliorated the progression of steatohepatitis in ovariectomized mice fed a high fat and high cholesterol diet.
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ABSTRACT: AIM: Many studies indicate an accelerated progression of non-alcoholic steatohepatitis (NASH) in postmenopausal women. Very recently, we reported that estrogen deficiency enhanced the progression of steatohepatitis in mice fed a high fat and high cholesterol (HFHC) diet. Hypercholesterolemia is often observed in postmenopausal women, and recent studies indicate it to be an important risk factor for the progression of NASH. Statins can slow NASH progression in the estrogen-deficient state but the precise mechanisms of their effects are still unclear. METHODS: We investigated the effects of pitavastatin on steatohepatitis progression using ovariectomized (OVX) mice fed a HFHC diet or HFHC + pitava diet (containing 5 p.p.m. pitavastatin) for 6 weeks. RESULTS: Serum alanine aminotransferase and cholesterol levels significantly decreased in mice fed the HFHC + pitava diet compared with mice fed the HFHC diet. Real-time reverse transcription polymerase chain reaction representing hepatic inflammatory gene expressions significantly decreased in mice fed the HFHC + pitava diet compared with the HFHC-fed mice. Pitavastatin treatment also decreased both hepatic macrophage infiltration and hepatocyte chemokine (C-C motif) ligand 2 expression and improved the liver fibrosis condition when compared with the mice fed the HFHC diet. In addition, the enhanced spleen monocyte chemokine (C-C motif) receptor 2 expression in ovariectomized mice fed the HFHC diet was also decreased by pitavastatin administration. CONCLUSION: Our study demonstrated that the exacerbated steatohepatitis progression in OVX mice fed a HFHC diet could be attenuated by pitavastatin treatment at least through inhibition of hepatic macrophage infiltration. We concluded that statins should be useful for treating NASH in postmenopausal women.Hepatology Research 07/2012; · 2.20 Impact Factor -
Article: Interferon-α suppresses hepatitis B virus enhancer II activity via the protein kinase C pathway.
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ABSTRACT: HBV has two enhancer (En) regions each of which promotes its own transcription. En II regulates production of pregenomic RNA, a key product of HBV replication, more strongly than En I. Although IFN-α has been found to suppress En I activity, its effect on En II activity has not been examined. Here we used luciferase assay to demonstrate that IFN-α suppresses En II activity. Analysis with several deletion/mutation constructs identified two major segments, nt 1703-1727 and nt 1746-1770, within the En II sequence as being responsible for the suppressive effects of IFN-α. Pre-treatment with protein kinase C (PKC) inhibitors blocked this effect regardless of the expression levels of phospho-STAT1 and Mx upon IFN-α stimulation. These results indicate that IFN-α suppresses En II activity via the PKC pathway, which may be an alternative suppressive pathway for HBV replication. (136 words).Virology 07/2012; 432(2):452-9. · 3.35 Impact Factor -
Article: TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlated with angiogenesis.
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ABSTRACT: Angiogenesis is deemed to be a critical step in the development and progression of vascular-rich hepatocellular carcinoma (HCC). In this process, myeloid lineage cells, such as macrophages and monocytes, have been reported to act as vascular progenitor cells. TIE-2, a receptor of angiopoietins, conveys pro-angiogenic signals. We thus aimed to clarify the roles of TIE2-expressing monocytes (TEMs) in the clinical management of HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC and examined the frequency of TEMs, as defined as CD14(+) CD16(+) TIE2(+) cells, in the periphery and in the liver. The localization of TEMs in the liver was determined by immunofluorescence. Micro-vessel formation in the liver was quantified by counting CD34(+) cells. In HCC patients, the frequency of TEMs in the periphery was significantly higher than those in non-HCC groups, and also was higher in the liver than in the periphery. In patients who underwent local ablation or resection of HCC, the frequency of TEMs dynamically changed in parallel with the recurrence of HCC. Most TEMs were identified in the perivascular area of cancer tissues. A significant positive correlation was observed between micro-vessel density in HCC tissues and the peripheral or intra-tumor frequencies of TEMs, suggesting that TEMs are involved in angiogenesis in the liver. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 levels as a diagnostic for HCC. CONCLUSION: TEMs are increased in patients with HCC and change in parallel with the therapeutic response or recurrence. The frequency of TEMs can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver. (HEPATOLOGY 2012.).Hepatology 07/2012; · 11.66 Impact Factor -
Article: Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice.
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ABSTRACT: Aim: We previously demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is induced in response to several liver injuries. Because the HB-EGF knockout (KO) mice die in utero or immediately after birth due to cardiac defects, the loss of function study in vivo is limited. Here, we generated liver-specific HB-EGF conditional knockout mice using the interferon-inducible Mx-1 promoter driven cre recombinase transgene and investigated its role during acute liver injury. Methods: We induced acute liver injury by a single i.p. injection of carbon tetrachloride (CCl(4) ) in HB-EGF KO mice and wild-type mice and liver damage was assessed by biochemical and immunohistochemical analysis. We also used AML12 mouse hepatocyte cell lines to examine the molecular mechanism of HB-EGF-dependent anti-apoptosis and wound-healing process of the liver in vitro. Results: HB-EGF KO mice exhibited a significant increase of alanine aminotransferase level and also showed a significant increase in the number of apoptotic hepatocytes assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining at 24 h after CCl(4) injection. We also demonstrated that HB-EGF treatment inhibited tumor necrosis factor-α-induced apoptosis of AML12 mouse hepatocytes and promoted the wound-healing response of these cells. Conclusion: This study showed that HB-EGF plays a protective role during acute liver injury.Hepatology Research 07/2012; · 2.20 Impact Factor -
Article: Adiponectin negatively correlates with alcoholic and non-alcoholic liver dysfunction: Health check-up study of Japanese men.
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ABSTRACT: Aim: Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects. Methods: A total of 5588 Japanese male subjects who underwent a health check-up were classified into three groups according to alcohol consumption: non- or light drinkers (15 g/day ≥ ethanol); mild drinkers (15 g/day < ethanol ≤ 30 g/day); and moderate- or heavy drinkers (30 g/day < ethanol). Central obesity and insulin resistance were assessed by waist circumference (WC) and Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), respectively. Results: WC was significantly increased, while HOMA-IR was significantly decreased according to the extent of alcohol consumption. Serum alanine aminotransferase levels were significantly lower and serum APN levels were significantly higher in mild drinkers than in the other two groups. Multiple linear regression analysis showed that serum APN level served as the significant and independent determinant for liver dysfunction in the subjects with fatty liver, irrespective of alcohol consumption. However, WC became a non-significant determinant of liver dysfunction as alcohol consumption increased. Conclusion: Hypoadiponectinemia is a significant determinant for steatotic dysfunction for all levels of alcohol consumption, but central obesity was not a significant determinant for alcoholic fatty liver-induced liver dysfunction.Hepatology Research 07/2012; · 2.20 Impact Factor -
Article: Preliminary results of intensity-modulated radiation therapy with helical tomotherapy for prostate cancer.
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ABSTRACT: We present the preliminary results of intensity-modulated radiation therapy with helical tomotherapy (HT) for clinically localized prostate cancer. Regularly followed 241 consecutive patients, who were treated with HT between June 2006 and December 2010, were included in this retrospective study. Most patients received both relatively long-term neoadjuvant and adjuvant androgen deprivation therapy (ADT). Patients received 78 Gy in the intermediate high-risk group and 74 Gy in the low-risk group. Biochemical disease-free survival (bDFS) followed the Phoenix definition. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. The median follow-up time from the start date of HT was 35 months. The rates of acute Grade 2 gastro-intestinal (GI) and genitor-urinary (GU) toxicities were 11.2 and 24.5 %. No patients experienced acute Grade 3 or higher symptoms. The rates of late Grade 2 and 3 GI toxicities were 6.6 and 0.8 %, and those of late Grade 2 and 3 GU toxicities were 8.3 % and 1.2 %. No patients experienced late Grade 4 toxicity. The 3-year bDFS rates for low, intermediate, and high-risk group patients were 100, 100, and 95.8 %, respectively. We observed clinical relapse in two high-risk patients, resulting in a 3-year clinical DFS of 99.4 %. This preliminary report confirms the feasibility of HT in a large number of patients. We observed that HT is associated with low rates of acute and late toxicities, and HT in combination with relatively long-term ADT results in excellent short-term bDFS.Journal of Cancer Research and Clinical Oncology 07/2012; 138(11):1931-6. · 2.56 Impact Factor -
Article: Differential alteration of CD56bright and CD56dim natural killer cells in frequency, phenotype, and cytokine response in chronic hepatitis C virus infection
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ABSTRACT: BackgroundNatural killer (NK) cells play an important role in immune responses to virus infection. The cell population consists of CD56bright (bright-subset) and CD56dim (dim-subset) subsets that possess armed functions of cytokine production and cytolysis, respectively. How these subsets are involved in chronic hepatitis C virus infection (CHC) remains obscure. MethodsWe investigated the frequency, phenotype, and cytokine response of these subsets in blood from CHC patients and healthy subjects (HS). ResultsDim-subset, but not bright-subset, showed lower frequency in the patients than in HS. Bright-subset from the patients more frequently expressed the NKG2A/CD94 inhibitory receptor than that from HS, while both subsets from the patients expressed lower levels of the NKG2D activating receptor. Both subsets from the patients displayed a significantly higher level of the signal transducer and activator of transcription (STAT) 1, compared with the HS. Upon stimulation with interferon-α, bright-subset activated less STAT4, required for interferon-γ production, and dim-subset activated more STAT1, required for cytolysis, in the patients than in HS. ConclusionsThese results indicate alterations of NK cell subsets in frequency, phenotype, and cytokine response in CHC, which might be associated with the immune pathogenesis of CHC. KeywordsNK cells–CD56bright –CD56dim –HCV–Chronic hepatitisJournal of Gastroenterology 04/2012; 46(8):1020-1030. · 4.16 Impact Factor -
Article: Low incidence of benign lesions in resected suspicious renal masses greater than 2 cm: Single-center experience from Japan.
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ABSTRACT: To assess the incidence of benign renal lesions in our Japanese clinical experience with surgical resection. A total of 411 renal masses harvested by radical or partial nephrectomy between January 1991 and April 2011 at our institution were retrospectively assessed. The incidence of benign lesions in 1-cm increments in diameter was determined, and a logistic regression model was used to assess relationships between the incidence of benign lesions and other factors. Histological examination confirmed a total of 18 (4.4%) benign lesions. The incidence of benign lesions was 42.8% for nodules <1 cm and 10.0% for nodules 1 to <2 cm. In contrast, the incidence of benign lesions in each 1-cm increment between 2 and 6 cm was 4.1-4.9%. The incidence of benign lesions 2 to <4 cm was 4.8% and of benign nodules ≥6 cm was just 0-1.0%. The incidence of benign lesions ≥2 cm (3.5%) was significantly lower than that of masses <2 cm (16.2%; P < 0.001). Multivariate analysis showed that female gender (odds ratio 3.68) and smaller mass size (<2 cm; odds ratio 4.84) were significant predictors for benign lesions. The incidence of benign lesions among renal masses ≥2 cm in diameter was found to be much lower than previously reported. This should be taken into account when designing strategies for the management of suspicious small renal masses.International Journal of Urology 04/2012; 19(8):729-34. · 1.75 Impact Factor -
Article: Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.
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ABSTRACT: Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and vascular endothelial growth factor (VEGF) also contributes tumor growth. Recently, interferon (IFN) α has been reported to be effective for prevention of hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro, cobalt chloride-treated VEGF induction and hypoxia responsive element (HRE) promoter activity were inhibited by IFNs and this abrogation was cancelled by introduction of small interfering RNA for STAT1. Immunoprecipitation/chromatin immunoprecipitation analyses showed STAT1 bound to hypoxia-inducible factor (HIF)-1α and dissociated HIF-complex from HRE promoter lesion. In a xenograft model using Balb/c nude mice, tumor growth was suppressed by IFNα through inhibition of VEGF expression and it was oppositely enhanced when STAT1-deleted cells were injected. This augmentation was due to upregulation of VEGF and hyaluronan synthase 2. In human samples, 29 HCCs were resected, divided into two groups based on STAT1 activation in tumor and the clinical features were investigated. Patients with suppressed STAT1 activity had a shorter recurrence-free survival. Histological and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed portal vein microinvasion and increased VEGF levels in tumors from suppressed STAT1 group. These human samples also showed a reverse correlation between VEGF and STAT1-regulated genes expression. These results in vitro and in vivo suggested that IFNα are potential candidates for prevention of vessel invasion acting through inhibition of VEGF expression and need to be properly used when STAT1 expression is suppressed.International Journal of Cancer 04/2012; 131(12):2774-84. · 5.44 Impact Factor -
Article: The long-term results with delayed-combined androgen blockade therapy in local or locally advanced prostate cancer.
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ABSTRACT: To evaluate long-term clinical outcomes in cT1c-T3a prostate cancer patients following delayed-combined androgen blockade therapy. From January 2001 to December 2004, 92 cT1c-T3a prostate cancer cases were enrolled. Medical castration and anti-androgen treatment were used sequentially as delayed-combined androgen blockade therapy. Time to prostate-specific antigen biochemical failure was estimated, and risk factors for prostate-specific antigen biochemical failure were evaluated. The average patient age was 76.4 years (range, 59-91 years), the median observation period was 52.8 months (range, 26-106.6 months) and the median pre-treatment prostate-specific antigen level was 14 ng/ml (range, 3.68-492 ng/ml). The TNM classification distribution was as follows: T1c, n= 27; T2a, n = 39; T2b, n = 20; and T3a, n = 6. In the multivariate analysis, Gleason's score ≥8 (P < 0.05; hazard ratio, 3.02), prostate-specific antigen nadir >1.4 ng/ml (P = 0.001; hazard ratio, 8.76) and a half-life of the prostate-specific antigen level >1.2 months (P < 0.005; hazard ratio, 6.3) during the initial 6 months of luteinizing hormone-releasing hormone agonist monotherapy were significant independent risk factors for prostate-specific antigen biochemical failure with luteinizing hormone-releasing hormone agonist monotherapy. The high-risk group, which had at least one of these three risk factors, had a shorter time to prostate-specific antigen biochemical failure than the low-risk group, during luteinizing hormone-releasing hormone agonist monotherapy (P < 0.0001). For the total delayed-combined androgen blockade therapy observation period, the free-prostate-specific antigen biochemical failure rate was 88.3% at 5 years. Only a maintenance period following luteinizing hormone-releasing hormone agonist monotherapy (P < 0.005; hazard ratio, 16.8) was revealed to be a significant independent risk factor for prostate-specific antigen biochemical failure with total delayed-combined androgen blockade. The free-prostate-specific antigen biochemical failure rate of delayed-combined androgen blockade therapy in our study was as valuable as those in other androgen deprivation therapy of previous reports.Japanese Journal of Clinical Oncology 03/2012; 42(6):534-40. · 1.78 Impact Factor -
Article: Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma: A crucial role of CD25(-) FOXP3(-) T cells.
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ABSTRACT: Regulatory T cells (Tregs) play pivotal role in cancer-induced immunoediting. Increment of CD25(high+) FOXP3(+) natural Tregs has been reported in patients with hepatocellular carcinoma (HCC); however, the involvement of other type of Tregs remain elusive. We aimed to clarify whether FOXP3(-) Tregs are increased and functionally suppressive or not in patients with HCC. We enrolled 184 hepatitis C-infected patients with chronic liver diseases or HCC, 57 healthy subjects and 27 HCC patients with other etiology. Distinct Treg subsets were phenotypically identified by the expression of CD4, CD25, CD127 and forkhead/winged helix transcription factor (FOXP3). Their gene profiles, frequency and suppressor functions against T cell proliferation were compared among the subjects. To examine the molecules involving in Treg differentiation, we cultured naive CD4(+) T cells in the presence of HCC cells and dendritic cells. We determined two types of CD4(+) CD127(-) T cells with comparable regulatory ability; one is CD25(high+) cells expressing FOXP3 (CD25(high+) FOXP3(+) Tregs) and the other is CD25(-) cells without FOXP3(-) expression (CD25(-) FOXP3(-) cells). The peripheral or intrahepatic frequency of CD25(-) FOXP3(-) Tregs in HCC patients is higher than those in other groups, of which significance is more than CD25(high+) FOXP3(+) cells. Of importance, CD25(-) FOXP3(-) Tregs, but not CD25(high+) FOXP3(+) cells, dynamically change in patients accompanied by the ablation or the recurrence of HCC. CD25(-) FOXP3(-) T cells with CD127(-) IL-10(+) phenotype are inducible in vitro from naive CD4(+) T cells, in which programmed cell death 1 ligand 1, immunoglobulin-like transcript 4 and human leukocyte antigen G are involved.. In conclusion, CD25(-) FOXP3(-) Tregs with suppressive capacity are increased in patients with HCC, suggesting their distinct roles from CD25(+) FOXP3(+) Tregs.International Journal of Cancer 03/2012; 131(11):2573-83. · 5.44 Impact Factor
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Institutions
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1986–2013
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Osaka City University
- Department of Biochemistry
Ōsaka-shi, Osaka-fu, Japan
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2010–2012
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Kansai Rosai Hospital
Itami, Hyogo-ken, Japan -
Chiba University
- Department of Medicine and Clinical Oncology
Chiba-shi, Chiba-ken, Japan -
Nippon Telegraph and Telephone
Tokyo, Tokyo-to, Japan
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2003–2012
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Aichi Cancer Center
Ōsaka-shi, Osaka-fu, Japan
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1990–2012
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Osaka University
- • Gastroenterology and Hepatology
- • School of Medicine
- • Department of Molecular Therapeutics
- • Clinical Laboratory
- • Department of Integrated Medicine
- • Biochemistry
Ibaraki, Osaka-fu, Japan
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2011
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Toranomon Hospital
Tokyo, Tokyo-to, Japan
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2009
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Okayama University
- Department of Gastroenterology and Hepatology
Okayama-shi, Okayama-ken, Japan
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2008
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Memorial Hospital of Rhode Island
Pawtucket, RI, USA -
Social Insurance Chukyo Hospital
Nagoya-shi, Aichi-ken, Japan
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2004–2005
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Osaka National Hospital
Ōsaka-shi, Osaka-fu, Japan
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1996–2004
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Osaka Kosei Nenkin Hospital
Ōsaka-shi, Osaka-fu, Japan
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2002
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Kyoto University
- Department of Urology
Kyoto, Kyoto-fu, Japan
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1997
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Osaka Minami Medical Center
Ōsaka-shi, Osaka-fu, Japan
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