Advance

IDA Hiroshi

    Department of Medicine　Lecturer in Medical School
Last Updated :2024/04/23

Researcher Information

Degree

  • Medical degree（1996/03 Kyoto University）

URL

J-Global ID

Research Interests

  • B型肝炎   C型肝炎   肝細胞癌   膵液   胆汁   膵液・胆汁   DNAメチル化   RUNX3   

Research Areas

  • Life sciences / Gastroenterology

Academic & Professional Experience

  • 2009 - 2010  Kyoto University医学(系)研究科(研究院)助教

Published Papers

  • Tomoko Aoki; Masatoshi Kudo; Kazuomi Ueshima; Masahiro Morita; Hirokazu Chishina; Masahiro Takita; Satoru Hagiwara; Hiroshi Ida; Yasunori Minami; Masakatsu Tsurusaki; Naoshi Nishida
    Liver cancer 13 (1) 56 - 69 2024/02 
    INTRODUCTION: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. METHODS: This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4. RESULTS: The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group. CONCLUSION: The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.
  • 萩原 智; 上嶋 一臣; 西田 直生志; 依田 広; 三長 孝輔; 南 康範; 田北 雅弘; 青木 智子; 盛田 真弘; 千品 寛和; 松原 卓哉; 大丸 直哉; 稲村 昇; 工藤 正俊
    肝臓 (一社)日本肝臓学会 64 (11) 567 - 574 0451-4203 2023/11 
    症例は30代男性.幼少期に完全大血管転位III型に対してFontan手術が施行され,近医に定期的に通院していた.20XX年7月腹部USで多発肝腫瘤を指摘され当院紹介受診となった.造影CTにて最大13cmの多発肝細胞癌と判明した(BCLC stage B).画像上は門脈圧亢進所見や明らかな肝形態異常を認めなかったが,肝生検でCongestive Hepatic Fibrosis Score 3であり,実際には線維化の進展を認めていた.肝内多発のため外科手術やRFAの適応外であった.また最大径の腫瘍は肝外に突出しており,腹腔内破裂の危険性もあることから,まずTACEを施行した.再発に応じて各種抗癌剤治療を行い,生存中である.画像上は肝線維化を示唆する所見はなかったが,Fontan術後の特殊な循環動態では,肝線維化が進展している可能性があり,本症例を通して肝癌サーベイランスの重要性を再考する.(著者抄録)
  • Naoshi Nishida; Tomoko Aoki; Masahiro Morita; Hirokazu Chishina; Masahiro Takita; Hiroshi Ida; Satoru Hagiwara; Yasunori Minami; Kazuomi Ueshima; Masatoshi Kudo
    Cancers 15 (8) 2023/04 
    Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a "non-inflamed" tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (p = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the "inflamed" group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (p = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the "non-inflamed" tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA.
  • Masahiro Morita; Naoshi Nishida; Tomoko Aoki; Hirokazu Chishina; Masahiro Takita; Hiroshi Ida; Satoru Hagiwara; Yasunori Minami; Kazuomi Ueshima; Masatoshi Kudo
    Cancers 15 (8) 2023/04 
    Recently, the therapeutic combination of atezolizumab and bevacizumab was widely used to treat advanced hepatocellular carcinoma (HCC). According to recent clinical trials, immune checkpoint inhibitors (ICIs) and molecular target agents are expected to be key therapeutic strategies in the future. Nonetheless, the mechanisms underlying molecular immune responses and immune evasion remain unclear. The tumor immune microenvironment plays a vital role in HCC progression. The infiltration of CD8-positive cells into tumors and the expression of immune checkpoint molecules are key factors in this immune microenvironment. Specifically, Wnt/β catenin pathway activation causes "immune exclusion", associated with poor infiltration of CD8-positive cells. Some clinical studies suggested an association between ICI resistance and β-catenin activation in HCC. Additionally, several subclassifications of the tumor immune microenvironment were proposed. The HCC immune microenvironment can be broadly divided into inflamed class and non-inflamed class, with several subclasses. β-catenin mutations are important factors in immune subclasses; this may be useful when considering therapeutic strategies as β-catenin activation may serve as a biomarker for ICI. Various types of β-catenin modulators were developed. Several kinases may also be involved in the β-catenin pathway. Therefore, combinations of β-catenin modulators, kinase inhibitors, and ICIs may exert synergistic effects.
  • B型慢性肝炎患者に対するTAFの効果および安全性の検討
    萩原 智; 盛田 真弘; 千品 寛和; 青木 智子; 田北 雅弘; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 64 (Suppl.1) A425 - A425 0451-4203 2023/04
  • 高アンモニア血症に対するレボカルニチン自体の効果について
    萩原 智; 盛田 真弘; 千品 寛和; 青木 智子; 田北 雅弘; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 64 (Suppl.1) A432 - A432 0451-4203 2023/04
  • 切除不能HCCに対するABC conversion療法と造影超音波によるclinical CRの補助診断
    青木 智子; 南 康範; 依田 広; 千品 寛和; 田北 雅弘; 萩原 智; 上嶋 一臣; 鶴崎 正勝; 西田 直生志; 工藤 正俊
    超音波医学 (公社)日本超音波医学会 50 (Suppl.) S598 - S598 1346-1176 2023/04
  • Masatoshi Kudo; Tomoko Aoki; Kazuomi Ueshima; Kaoru Tsuchiya; Masahiro Morita; Hirokazu Chishina; Masahiro Takita; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Naoshi Nishida; Chikara Ogawa; Tetsu Tomonari; Noriaki Nakamura; Hidekatsu Kuroda; Atsushi Takebe; Yoshifumi Takeyama; Masaaki Hidaka; Susumu Eguchi; Stephen L. Chan; Masayuki Kurosaki; Namiki Izumi
    LIVER CANCER KARGER 2235-1795 2023/02 
    Introduction: Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or super selective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria.Methods: This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, super selective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone.Results: Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and three patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status.Discussion/Conclusion: The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread.
  • Satoru Hagiwara; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Chishina; Yoriaki Komeda; Akihiro Yoshida; Ah-Mee Park; Masako Sato; Akira Kawada; Hajime Nakano; Hiroshi Nakagawa; Masatoshi Kudo
    Scientific Reports Springer Science and Business Media LLC 12 (1) 2022/12 
    Abstract Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.
  • Yasunori Minami; Tomoko Aoki; Hirokazu Chishina; Masahiro Takita; Satoru Hagiwara; Hiroshi Ida; Kazuomi Ueshima; Naoshi Nishida; Masatoshi Kudo
    Cancers 14 (19) 2022/10 
    BACKGROUND: The treatment of the hepatitis C virus (HCV) has reduced the risk of hepatocellular carcinoma (HCC)-related mortality. Many patients with advanced HCC have achieved longer survival through systemic chemotherapy. However, survivors of HCC may develop liver cancer during and after treatment. Therefore, the present study investigated prognostic factors for survival in patients with HCV-related HCC in the new era of molecular targeted therapy. METHODS: A total of 359 patients with HCV-related HCC treated with first-line chemotherapy were reviewed. A Cox proportional hazards model and Kaplan-Meier curve were used to identify prognostic factors associated with survival outcomes. RESULTS: The median follow-up duration was 16.0 months (range, 1.0-115.7) and the median duration of first-line systemic therapy was 3.73 months (range, 0.7-86.9). The achievement of a sustained virological response (SVR) (p  <  0.001), albumin-bilirubin (ALBI) grade II/III (p  <  0.001), Barcelona Clinic Liver Cancer (BCLC) stage C (p  =  0.005), extrahepatic spread (p < 0.001), baseline AFP (alpha-fetoprotein) level ≥ 90 (p = 0.038), baseline DCP (des-γ-carboxy prothrombin) level ≥ 500 (p < 0.001), and a fibrosis-4 (FIB-4) index ≥ 4 (p  =  0.003) were identified as prognostic factors for overall survival. CONCLUSIONS: The achievement of SVR was most strongly associated with overall survival. Other factors, such as the BCLC stage, extrahepatic spread, baseline tumor marker (AFP/DCP) levels, ALBI grade, and FIB-4 index need to be considered in the management of patients with HCV-related HCC.
  • Satoru Hagiwara; Takeshi Yoshida; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Cishina; Yoriaki Komeda; Akihiro Yoshida; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo
    Hepatology research : the official journal of the Japan Society of Hepatology 52 (10) 888 - 892 2022/07 
    AIM: We report a rare case of immune-related cholangitis in which the natural course could be demonstrated. CASE PRESENTATION: Eight courses of pembrolizumab maintenance therapy were given as first-line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune-related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. CONCLUSION: No previous case reports have described the changes and progression in bile duct images in immune-related adverse events. Therefore, this case is noteworthy for considering the progression of immune-related cholangitis.
  • Satoru Hagiwara; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Cishina; Yoriaki Komeda; Akihiro Yoshida; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo
    Hepatology Research Wiley 1386-6346 2022/05
  • 上・下腸間膜動静脈奇形に伴う門脈圧亢進からの難治性腹水及び循環血液量低下に伴う血圧低下に対し血管内治療(IVR)にて改善しえた1例
    上原 広樹; 田北 雅弘; 杉森 啓伸; 岡井 夏輝; 野村 健司; 盛田 真弘; 千品 寛和; 青木 智子; 萩原 智; 依田 広; 南 康範; 上嶋 一臣; 西田 直生志; 工藤 正俊
    日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 116回 88 - 88 2022/02
  • Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo; Kosuke Minaga; Yoriaki Komeda; Ken Kamata; Masatomo Kimura; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuomi Ueshima; Yasunori Minami; Tomoko Aoki; Masahiro Takita; Masahiro Morita; Hirokazu Cishina; Hiroshi Ida; Ah-Mee Park; Naoshi Nishida
    Scientific Reports Springer Science and Business Media LLC 11 (1) 2021/12 
    AbstractImmune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
  • Satoru Hagiwara; Naoshi Nishida; Kazuomi Ueshima; Yasunori Minami; Yoriaki Komeda; Tomoko Aoki; Masahiro Takita; Masahiro Morita; Hirokazu Chishina; Akihiro Yoshida; Hiroshi Ida; Masatoshi Kudo
    Cells MDPI AG 10 (11) 3257 - 3257 2021/11 
    The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group (n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group (n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced.
  • Tomoko Aoki; Naoshi Nishida; Kazuomi Ueshima; Masahiro Morita; Hirokazu Chishina; Masahiro Takita; Satoru Hagiwara; Hiroshi Ida; Yasunori Minami; Akira Yamada; Keitaro Sofue; Masakatsu Tsurusaki; Masatoshi Kudo
    Liver cancer 10 (6) 615 - 628 2021/11 
    INTRODUCTION: Immune checkpoint inhibitors (ICIs) are promising agents for the treatment of hepatocellular carcinoma (HCC). However, the establishment of noninvasive measure that could predict the response to ICIs is challenging. This study aimed to evaluate tumor responses to ICIs using the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), which was shown to reflect Wnt/β-catenin activating mutation. METHODS: A total of 68 intrahepatic HCC nodules from 18 patients with unresectable HCC and Child-Pugh class A liver function who received anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy were enrolled in this study. All patients had viable intrahepatic lesions evaluable using the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI within the 6 months prior to the treatment. The relative enhancement ratio was calculated, and the time to nodular progression (TTnP) defined as 20% or more increase in each nodule was compared between higher or hypo-enhancement HCC nodules. Then, the progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) were compared between patients with and without HCC nodules with higher enhancement on hepatobiliary phase images. RESULTS: The median PFS was 2.7 (95% confidence interval [CI]: 1.4-4.0) months in patients with HCC nodules with higher enhancement (n = 8) and 5.8 (95% CI: 0.0-18.9) months in patients with hypointense HCC nodules (n = 10) (p = 0.007). The median TTnP of HCC nodules with higher enhancement (n = 23) was 1.97 (95% CI: 1.86-2.07) months and that of hypointense HCC nodules (n = 45) was not reached (p = 0.003). The ORR was 12.5% (1/8) versus 30.0% (3/10); the disease control rate was 37.5% (3/8) versus 70.0% (7/10), respectively, in patients with or without higher enhancement intrahepatic HCC nodules. CONCLUSION: The TTnP on HCC nodules with higher enhancement and the median PFS in patients who carried higher enhancement intrahepatic HCC nodules were significantly shorter than those in hypointense HCC nodules with anti-PD-1/PD-L1 monotherapy. The intensity of the nodule on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 monotherapy in patients with HCC.
  • Segmental arterial mediolysis(SAM)に伴う肝動脈瘤破裂に対して肝動脈塞栓術を施行した1例
    加藤 弘樹; 千品 寛和; 瀬海 郁衣; 盛田 真弘; 青木 智子; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 62 (Suppl.3) A824 - A824 0451-4203 2021/11
  • Yasunori Minami; Masahiro Morita; Hirokazu Chishina; Tomoko Aoki; Masahiro Takita; Satoru Hagiwara; Hiroshi Ida; Kazuomi Ueshima; Naoshi Nishida; Masatoshi Kudo
    Ultrasound in medicine & biology 47 (10) 2930 - 2935 2021/10 
    Developments in image fusion technology made it possible to visualize the ablative margin on ultrasound (US). The purpose of the present study was to assess the ablative area of radiofrequency ablation for hepatocellular carcinoma and compare it with the ablative hyperechoic zone with a non-enhanced area on contrast-enhanced US/contrast-enhanced computed tomography (CEUS/CECT) in the same cross-section. This retrospective study included 25 patients with 27 hepatocellular carcinomas. The long and short dimensions of the ablative hyperechoic zone were measured using B-mode US, and those of the non-enhanced area were assessed with CEUS/CECT on the same cross-section measured with B-mode US, using image fusion techniques. The technical effectiveness of ablation with an adequate ablative margin in a single session was determined in all patients. The long and short dimensions of the ablative hyperechoic zone ranged between 15.0 and 40.7 mm (mean: 27.3 ± 6.9 mm) and between 14.0 and 33.0 mm (mean: 23.3 ± 5.8 mm), respectively. R values for the long and short dimensions were 0.99 and 0.98, respectively, between B-mode US and CEUS, and 0.96 and 0.92, respectively, between B-mode US and CECT. The ablative hyperechoic zone may be regarded as a necrotic lesion after radiofrequency ablation.
  • Gd-EOB-DTPA-enhanced MRI肝細胞相で高信号の肝細胞癌は、PD-1/PD-L1療法への一次耐性を反映し予後不良である
    青木 智子; 上嶋 一臣; 盛田 真弘; 千品 寛和; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 鶴崎 正勝; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 62 (Suppl.2) A552 - A552 0451-4203 2021/09
  • Masahiro Morita; Naoshi Nishida; Kazuko Sakai; Tomoko Aoki; Hirokazu Chishina; Masahiro Takita; Hiroshi Ida; Satoru Hagiwara; Yasunori Minami; Kazuomi Ueshima; Kazuto Nishio; Yukari Kobayashi; Kazuhiro Kakimi; Masatoshi Kudo
    Liver Cancer 10 (4) 380 - 393 2235-1795 2021/07 
    Introduction: Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. Methods: Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. Results: Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein < 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8+ cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8+ tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (p < 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γresponse, inhibitory molecules, and regulatory T cells. Discussion/Conclusion: The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8+ TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI.
  • 進行肝癌に対する免疫チェックポイント阻害薬後レンバチニブ療法の画像評価
    青木 智子; 依田 広; 盛田 真弘; 南 知宏; 田北 雅弘; 萩原 智; 南 康範; 上嶋 一臣; 西田 直生志; 工藤 正俊
    超音波医学 (公社)日本超音波医学会 47 (Suppl.) S167 - S167 1346-1176 2020/11
  • 鑑別診断において造影超音波が有用であった多血性の肝内胆管癌の1例
    盛田 真弘; 南 康範; 青木 智子; 田北 雅弘; 萩原 智; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    超音波医学 (公社)日本超音波医学会 47 (Suppl.) S275 - S275 1346-1176 2020/11
  • 進歩する化学療法時代に注意すべき肝細胞癌の遠隔転移
    吉田 早希; 青木 智子; 上嶋 一臣; 盛田 真弘; 千品 寛和; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 鶴崎 正勝; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 61 (Suppl.3) A924 - A924 0451-4203 2020/11
  • 難治性腹水に対するデンバーシャント術の試み
    家村 郁衣; 青木 智子; 上嶋 一臣; 盛田 真弘; 千品 寛和; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 鶴崎 正勝; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 61 (Suppl.3) A946 - A946 0451-4203 2020/11
  • Tomoko Aoki; Masatoshi Kudo; Kazuomi Ueshima; Masahiro Morita; Hirokazu Chishina; Masahiro Takita; Satoru Hagiwara; Hiroshi Ida; Yasunori Minami; Masakatsu Tsurusaki; Naoshi Nishida
    Cancers 12 (10) 2020/10 
    Although programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD-1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4-8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5-100.0) mg and 12 (IQR, 64.4-100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3-11.8) and the median overall survival was 15.8 months (95% CI: 8.5-23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.
  • 鑑別診断に造影超音波が有用であった多血性の肝内胆管癌の1例
    吉田 早希; 南 康範; 盛田 真弘; 青木 智子; 田北 雅弘; 萩原 智; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 113回 103 - 103 2020/10
  • 全身化学療法により生存利益を得られる切除不能C型肝細胞癌の特徴
    青木 智子; 上嶋 一臣; 盛田 真弘; 千品 寛和; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 西田 直生志; 鶴崎 正勝; 工藤 正俊
    肝臓 (一社)日本肝臓学会 61 (Suppl.2) A647 - A647 0451-4203 2020/09
  • 切除不能肝細胞癌に対する免疫チェックポイント阻害薬不応後のレンバチニブ二次療法
    青木 智子; 上嶋 一臣; 盛田 真弘; 千品 寛和; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 西田 直生志; 鶴崎 正勝; 工藤 正俊
    肝臓 (一社)日本肝臓学会 61 (Suppl.2) A654 - A654 0451-4203 2020/09
  • 大塚 康生; 青木 智子; 南 知宏; 田北 雅弘; 萩原 智; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A291 - A291 0446-6586 2020/07
  • B型慢性肝炎患者(CH-B)に対する,ETVとTAFの前向き比較観察研究
    萩原 智; 盛田 真弘; 青木 智子; 田北 雅弘; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 61 (Suppl.1) A423 - A423 0451-4203 2020/04
  • B型慢性肝炎患者(CH-B)に対する,ETVとTAFの前向き比較観察研究
    萩原 智; 盛田 真弘; 青木 智子; 田北 雅弘; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 61 (Suppl.1) A423 - A423 0451-4203 2020/04 [Refereed]
  • Association between Genetic and Immunological Background of Hepatocellular Carcinoma and Expression of Programmed Cell Death-1
    Naoshi Nishida; Kazuko Sakai; Masahiro Morita; Tomoko Aoki; Masahiro Takita; Satoru Hagiwara; Yoriaki Komeda; Mamoru Takenaka; Yasunori Minami; Hiroshi Ida; Kazuomi Ueshima; Kazuto Nishio; Masatoshi Kudo
    Liver Cancer 2020 [Refereed]
  • 鑑別診断において造影超音波が有用であった多血性の肝内胆管癌(腫瘤形成型)の1例
    友岡 瑞樹; 盛田 真弘; 南 康範; 依田 広; 南 知宏; 青木 智子; 田北 雅弘; 萩原 智; 上嶋 一臣; 西田 直生志; 工藤 正俊
    肝臓 (一社)日本肝臓学会 60 (Suppl.3) A926 - A926 0451-4203 2019/11 [Refereed]
  • Kudo Masatoshi; Ueshima Kazuomi; Chan Stephen L; Minami Tomohiro; Chishina Hirokazu; Aoki Tomoko; Takita Masahiro; Hagiwara Satoru; Minami Yasunori; Ida Hiroshi; Takenaka Mamoru; Sakurai Toshiharu; Watanabe Tomohiro; Morita Masahiro; Ogawa Chikara; Wada Yoshiyuki; Ikeda Masafumi; Ishii Hiroshi; Izumi Namiki; Nishida Naoshi
    HEPATOLOGY 70 133A - 134A 0270-9139 2019/10 [Refereed]
  • 難治性腹水に対して行われたデンバーシャント術の報告
    青木 智子; 田北 雅弘; 大塚 康生; 南 知宏; 萩原 智; 南 康範; 依田 広; 上嶋 一臣; 西田 直生志; 鶴崎 正勝; 工藤 正俊
    日本門脈圧亢進症学会雑誌 (一社)日本門脈圧亢進症学会 25 (3) 146 - 146 1344-8447 2019/09 [Refereed]
  • Minami Y; Minami T; Takita M; Hagiwara S; Ida H; Ueshima K; Nishida N; Kudo M
    Hepatology research : the official journal of the Japan Society of Hepatology 1386-6346 2019/07 [Refereed]
  • Hagiwara S; Nishida N; Ida H; Ueshima K; Minami Y; Takita M; Komeda Y; Kudo M
    Journal of medical virology 0146-6615 2019/06 [Refereed]
  • Ueshima K; Nishida N; Hagiwara S; Aoki T; Minami T; Chishina H; Takita M; Minami Y; Ida H; Takenaka M; Sakurai T; Watanabe T; Morita M; Ogawa C; Hiraoka A; Johnson P; Kudo M
    Cancers MDPI 11 (5) pii: E952.  2019 [Refereed]
     
    Background: This study investigated the impact of baseline liver function according to the Child-Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child-Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child-Pugh score 5 and ALBI grade 1 (group 1), (2) Child-Pugh score 5 and ALBI grade 2 (group 2), (3) Child-Pugh score 6 (group 3), and (4) Child-Pugh score >= 7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child-Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.
  • Kudo M; Ueshima K; Chan S; Minami T; Chishina H; Aoki T; Takita M; Hagiwara S; Minami Y; Ida H; Takenaka M; Sakurai T; Watanabe T; Morita M; Ogawa C; Wada Y; Ikeda M; Ishii H; Izumi N; Nishida N
    Cancers 11 (8) pii: E1084  2019 [Refereed]
  • Ultrasound-ultrasound image overlay fusion improves real-time control of radiofrequency ablation margin in the treatment of hepatocellular carcinoma
    Minami Y; Minami T; Hagiwara S; Ida H; Ueshima K; Nishida N; Murakami T; Kudo M
    Eur Radiol 28 (5) 1986 - 1993 2018/05 [Refereed]
  • 南 康範; 南 知宏; 千品寛和; 田北雅弘; 萩原 智; 依田 広; 上嶋一臣; 西田直生志; 工藤正俊
    肝胆膵 (株)アークメディア 77 (6) 1139 - 1144 0389-4991 2018 [Refereed]
  • Hagiwara S; Nishida N; Watanabe T; Ida H; Sakurai T; Ueshima K; Takita M; Komeda Y; Nishijima N; Osaki Y; Kudo M
    Antivir Ther 23 513 - 521 2018 [Refereed]
  • Nishida N; Nishimura T; Kaido T; Minaga K; Yamao K; Kamata K; Takenaka M; Ida H; Hagiwara S,MinamiY; Sakurai T; Watanabe T; Kudo M
    Cancers MDPI 10 (10) 367 - 367 2072-6694 2018 [Refereed]
     
    Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for TP53, CTNNB1, and TERT promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients.
  • Tomohiro Watanabe
    Intern Med JAPAN SOC INTERNAL MEDICINE 57 (17) 2505 - 2509 0918-2918 2018 [Refereed]
     
    A 27-year-old man bearing an erythropoietic protoporphyria (EPP)-associated ferrochelatase (FECH) mutation was admitted to our hospital for general malaise and marked elevation of the serum levels of hepatobiliary enzymes and bilirubin. Initial treatment with plasma exchange did not reduce the blood protoporphyrin or serum liver enzyme levels, so phlebotomy was started. Surprisingly, weekly phlebotomy normalized the serum levels of liver enzymes, accompanied by a marked reduction in the blood protoporphyrin levels. The clinical course of this case strongly suggests that phlebotomy may be a suitable treatment option for EPP-related hepatopathy.
  • Nishida N; Arizumi T; Hagiwara S; Ida H; Sakurai T; Kudo M
    Liver Cancer KARGER 6 (2) 113 - 125 2235-1795 2017/02 [Refereed]
     
    Background: Several studies suggest the role of circulating microRNAs (miRNAs) as biomarkers of hepatocellular carcinoma (HCC). However, the serum miRNA profile associated with the response to sorafenib remains to be elucidated. The aim of this study was to clarify the specific miRNAs in serum that could predict the early response of HCC to sorafenib treatment. Summary: Analyzing the sera from 16 HCC patients, we selected five miRNAs that showed differences in serum levels between patients with and without tumor responses among 179 known secretory miRNAs by using locked nucleic acid probe -based quantitative PCR. Through further analysis using a validation cohort that included 53 HCC patients who underwent sorafenib treatment and 8 healthy control subjects, we found that miR-181a-5p and miR-3395p showed significant differences in serum levels among patients with partial response (PR), stable disease (SD), and progressive disease (PD), where PR patients showed the highest and PD the lowest levels. We also analyzed the factors associated with disease control (DC; PR or SD) 3 months after the initiation of sorafenib treatment; patients with DC showed a significantly higher level of serum miR-181a-5p than non -DC patients or healthy control subjects (p = 0.0349 and 0.0180 for DC vs. non -DC and control vs. non -DC by Tukey-Kramer test, respectively). We further conducted multivariate analysis among HCC patients with Barcelona Clinic Liver Cancer stage C using extrahepatic metastasis, serum decarboxyprothrombin, and miR-181a-5p levels as covariables; serum miR-181a-5p was the only independent factor for achieving DC (p = 0.0092, odds ratio 0.139, and 95% confidence interval 0.011-0.658). In addition, miR-181a-5p level was also the only independent factor affecting overall survival (p = 0.0194, hazard ratio 0.267, and 95% confidence interval 0.070-0.818). Key Messages: A high serum level of miR-181a-5p before treatment is associated with DC after the initiation of sorafenib. (C) 2016 S. Karger AG, Basel
  • Serum microRNA profile that predict initial effect of sorafenib in patients with advanced hepatocellular carcinoma
    Nishida N; Arizumi T; Hagiwara S; Ida H; Sakurai T; Kudo M
    Liver Cancer 6 113 - 125 2017 [Refereed]
  • Ida H; Hagiwara S; Kono M; Minami T; Chishina H; Arizumi T; Takita M; Yada N; Minami Y; Ueshima K; Nishida N; Kudo M
    Digest Dis 35 (6) 565 - 573 0257-2753 2017 [Refereed]
  • Umehara Y; Hagiwara S; Nishida N; Sakurai T; Ida H; Minami Y; Takita M; Minami T; Chishina H; Ueshima K; Komeda Y; Arizumi T; Watanabe T; Kudo M
    Digest Dis 35 (6) 548 - 555 0257-2753 2017 [Refereed]
  • Kono M; Minami Y; Iwanishi M; Minami T; Chishina H; Arizumi T; Komeda Y; Sakurai T; Takita M; Yada N; Ida H; Hagiwara S; Ueshima K; Nishida N; Kudo M
    Oncology 92 29 - 34 0030-2414 2017 [Refereed]
  • Yada N; Sakurai T; Minami T; Arizumi T; Takita M; Hagiwara S; Ida H; Ueshima K; Nishida N; Kudo M
    Oncology 92 10 - 15 0030-2414 2017 [Refereed]
  • Kono M; Nishida N; Hagiwara S; Minami T; Chishina H; Arizumi T; Minaga K; Kamata K; Komeda Y; Sakurai T; Takenaka M; Takita M; Yada N; Ida H; Minami Y; Ueshima K; Watanabe T; Kudo M
    Digestive diseases (Basel, Switzerland) 35 (6) 556 - 564 0257-2753 2017 [Refereed]
  • Tomohiro Watanabe; Kouhei Yamashita; Yasuyuki Arai; Kosuke Minaga; Ken Kamata; Tomoyuki Nagai; Yoriaki Komeda; Mamoru Takenaka; Satoru Hagiwara; Hiroshi Ida; Toshiharu Sakurai; Naoshi Nishida; Warren Strober; Masatoshi Kudo
    JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 198 (10) 3886 - 3896 0022-1767 2017 [Refereed]
     
    In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-alpha. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-beta 1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-alpha and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.
  • Hagiwara S; Nishida N; Watanabe T; Sakurai T; Ida H; Minami Y; Takita M; Minami T; Iwanishi M; Chishina H; Ueshima K; Komeda Y; Arizumi T; Kudo M
    Oncology 92 (Suppl 1) 3 - 9 2017
  • Arizumi T; Ueshima K; Iwanishi M; Minami T; Chishina H; Kono M; Takita M; Yada N; Hagiwara S; Minami Y; Ida H; Komeda Y; Takenaka M; Sakurai T; Watanabe T; Nishida N; Kudo M
    Liver Cancer 6 (3) 227 - 235 2017 [Refereed]
  • Kwok WY; Hagiwara S; Nishida N; Watanabe T; Sakurai T; Ida H; Minami Y; Takita M; Minami T; Iwanishi M; Chishina H; Kono M; Ueshima K; Komeda Y; Arizumi T; Enoki E; Nakai T; Kumabe T; Nakashima O; Kondo F; Kudo M
    Oncology 92 (Suppl 1) 16 - 28 2017
  • Arizumi T; Minami T; Chishina H; Kono M; Takita M; Yada N; Hagiwara S; Minami Y; Ida H; Ueshima K; Kamata K; Minaga K; Komeda Y; Takenaka M; Sakurai T; Watanabe T; Nishida N; Kudo M
    Dig Dis 35 (6) 583 - 588 2017
  • Arizumi T; Minami T; Chishina H; Kono M; Takita M; Yada N; Hagiwara S; Minami Y; Ida H; Ueshima K; Kamata K; Minaga K; Komeda Y; Takenaka M; Sakurai T; Watanabe T; Nishida N; Kudo M
    Dig Dis 35 (6) 589 - 597 2017
  • Kwok WY; Hagiwara S; Nishida N; Watanabe T; Sakurai T; Ida H; Minami Y; Takita M; Minami T; Iwanishi M; Chishina H; Kono M; Ueshima K; Komeda Y; Arizumi T; Enoki E; Nakai T; Kumabe T; Nakashima O; Kondo F; Kudo M
    Oncology 92 Suppl 1 16 - 28 0030-2414 2016/12 [Refereed]
  • Ishizu S; Setoyama T; Ueo T; Ueda Y; Kodama Y; Ida H; Kawaguchi Y; Yoshizawa A; Chiba T; Miyamoto S
    Pancreas 45 (6) e24 - 5 0885-3177 2016/07 [Refereed]
  • Arizumi T; Ueshima K; Iwanishi M; Minami T; Chishina H; Kono M; Takita M; Kitai S; Inoue T; Yada N; Hagiwara S; Minami Y; Ida H; Sakurai T; Kitano M; Nishida N; Kudo M
    Digestive diseases (Basel, Switzerland) 34 (6) 671 - 678 0257-2753 2016 [Refereed]
  • Nishida N; Kono M; Minami T; Chishina H; Arizumi T; Takita M; Yada N; Ida H; Hagiwara S; Minami Y; Ueshima K; Sakurai T; Kudo M
    Digestive diseases (Basel, Switzerland) 34 (6) 632 - 639 0257-2753 2016 [Refereed]
  • Yada N; Sakurai T; Minami T; Arizumi T; Takita M; Hagiwara S; Ida H; Ueshima K; Nishida N; Kudo M
    Digest Dis 34 (6) 650 - 653 0257-2753 2016 [Refereed]
  • Minami Y; Minami T; Chishina H; Kono M; Arizumi T; Takita M; Yada N; Hagiwara S; Ida H; Ueshima K; Nishida N; Kudo M
    Digest Dis 34 (6) 687 - 691 0257-2753 2016 [Refereed]
  • Takita M; Iwanishi M; Minami T; Kono M; Chishina K; Arizumi T; Yada N; Hagiwara S; Minami Y; Ida H; Ueshima K; Nishida N; Kudo M
    Digest Dis 34 (6) 654 - 658 0257-2753 2016 [Refereed]
  • Hagiwara S; Nishida N; Chishina H; Ida H; Sakurai T; Komeda Y; Kitano M; Kudo M
    Internal medicine (Tokyo, Japan) JAPAN SOC INTERNAL MEDICINE 55 (22) 3273 - 3277 0918-2918 2016 [Refereed]
     
    The patient was a 67-year-old female with liver cirrhosis due to hepatitis C. She was administered furosemide at 20 mg/day and spironolactone at 25 mg/day, but the ascites did not improve. Despite the additional administration of tolvaptan at 3.75 mg/day, the response to ascites was still poor. While the dose of tolvaptan was thereafter increased to 7.5 mg/day on the 7th hospital day, the ascites still persisted. However, she continued to receive tolvaptan (7.5 mg/day) because the worsening of her subjective symptoms was mild and she wished to do so. The ascites was later found to have almost completely disappeared on computed tomography (CT) at 6 months.
  • Nagai T; Arao T; Nishio K; Matsumoto K; Hagiwara S; Sakurai T; Minami Y; Ida H; Ueshima K; Nishida N; Sakai K; Saijo N; Kudo K; Kaneda H; Tamura D; Aomatsu K; Kimura H; Fujita Y; Haji S; Kudo M
    Dig Dis KARGER 34 (6) 702 - 707 0257-2753 2016 [Refereed]
     
    Background: Epithelial-mesenchymal transition (EMT) is considered to play a critical role in cancer progression and metastasis. However, the impact of EMT on the prognosis of hepatocellular carcinoma (HCC) is still elusive. In this study, we examined the relationship between the expression of EMT markers and recurrence-free survival (RFS) and overall survival (OS) in HCC patients after hepatic resection. Summary:The mRNA expression of 15 genes related to EMT was assessed by quantitative real-time polymerase chain reaction in cancerous tissues from 72 patients who underwent hepatic resection of HCC between January 2005 and December 2010 at our hospital. The upregulation of TWIST and the downregulation of tight junction protein ZO-1 (TJP1) were significantly associated with shorter RFS as well as OS. Increased levels of TWIST and decreased levels of TJP1 should be predictive markers for poor prognosis in patients with HCC after hepatectomy; those could serve as potential biomarkers for the treatment of HCC. Key Messages: A low level of TJP1 and high level of TWIST expression were prognostic factors predicting HCC after hepatic resection. (C) 2016 S. Karger AG, Basel
  • Chishina H; Hagiwara S; Nishida N; Ueshima K; Sakurai T; Ida H; Minami Y; Takita M; Kono M; Minami T; Iwanishi M; Umehara Y; Watanabe T; Komeda Y; Arizumi T; Kudo M
    Dig Dis 34 (6) 659 - 664 0257-2753 2016
  • Hagiwara S; Nishida N; Watanabe T; Sakurai T; Ida H; Minami Y; Takita M; Minami T; Iwanishi M; Chishina H; Ueshima K; Komeda Y; Arizumi T; Kudo M
    Dig Dis 34 (6) 620 - 626 0257-2753 2016
  • Nishida N; Iwanishi M; Minami T; Chishina H; Arizumi T; Takita M; Kitai S; Yada N; Ida H; Hagiwara S; Minami Y; Ueshima K; Sakurai T; Kitano M; Kudo M
    Digest Dis 33 (6) 708 - 714 0257-2753 2015/10 [Refereed]
  • Nishida N; Iwanishi M; Minami T; Chishina H; Arizumi T; Takita M; Kitai S; Yada N; Ida H; Hagiwara S; Minami Y; Ueshima K; Sakurai T; Kitano M; Kudo M
    Digest Dis KARGER 33 (6) 745 - 750 0257-2753 2015/10 [Refereed]
     
    Objectives: Several studies revealed that the proportion of hepatocellular carcinoma (HCC) without hepatitis virus infection (NBNC-HCC) is increasing. On the other hand, epigenetic alterations are reportedly responsible for HCC development. Here, we identified HCC risk factors that are associated with DNA methylation in the background liver tissue of NBNC-HCC patients. Methods: We performed methylation analysis in 37 pairs of virus-positive and 22 pairs of NBNC-HCC and non-cancerous livers using a HumanMethylation450 BeadChip array. After the selection of differentially methylated CpGs (DM-CpGs) in cancerous and non-cancerous livers, we analyzed DNA methylation of DM-CpGs within the adjacent non-cancerous liver tissue that is affected by specific HCC risk factors. Results: A total of 38,331 CpGs were selected as DM-CpGs using the following criteria: difference of beta-value between HCC and non-cancerous liver and false discovery rate (FDR) q < 1.0E-12. We subsequently selected the DM-CpGs that had methylation differences with the background liver tissue (that has FDR q < 0.35). Among the virus-positive patients, the type of hepatitis virus was mostly associated with differences in methylation within the background liver tissues. However, we found that background methylation patterns were most significantly associated with aging in NBNC patients. Interestingly, age-related methylation differences in DM-CpGs were also observed in NBNC-HCC tissues. Conclusions: Hepatitis viruses affect the methylation profiles within background liver tissues. However, difference in background methylation was mostly associated with age in NCBC-HCC patients; some age-related methylation events could contribute to emergence of NBNC-HCC in elderly individuals. (C) 2015 S. Karger AG, Basel
  • Arizumi T; Ueshima K; Iwanishi M; Chishina H; Kono M; Takita M; Kitai S; Inoue T; Yada N; Hagiwara S; Ida H; Minami Y; Sakurai T; Nishida N; Kitano M; Kudo M
    Digest Dis 33 (6) 728 - 734 0257-2753 2015/10 [Refereed]
  • Yamada A; Horimatsu T; Okugawa Y; Nishida N; Honjo H; Ida H; Kou T; Kusaka T; Sasaki Y; Yagi M; Higurashi T; Yukawa N; Amanuma Y; Kikuchi O; Muto M; Ueno Y; Nakajima A; Chiba T; Boland CR; Goel A
    Clinical cancer research : an official journal of the American Association for Cancer Research AMER ASSOC CANCER RESEARCH 21 (18) 4234 - 4242 1078-0432 2015/09 [Refereed]
     
    Purpose: Circulating microRNAs (miRNA) are emerging as promising diagnostic biomarkers for colorectal cancer, but their usefulness for detecting early colorectal neoplasms remains unclear. This study aimed to identify serum miRNA biomarkers for the identification of patients with early colorectal neoplasms.Experimental Design: A cohort of 237 serum samples from 160 patients with early colorectal neoplasms (148 precancerous lesions and 12 cancers) and 77 healthy subjects was analyzed in a three-step approach that included a comprehensive literature review for published biomarkers, a screening phase, and a validation phase. RNA was extracted from sera, and levels of miRNAs were examined by real-time RT-PCR.Results: Nine miRNAs (miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-24, miR-29a, miR-92, and miR-125b) were selected as candidate biomarkers for initial analysis. In the screening phase, serum levels of miR-21, miR-29a, and miR-125b were significantly higher in patients with early colorectal neoplasm than in healthy controls. Elevated levels of miR-21, miR-29a, and miR-125b were confirmed in the validation phase using an independent set of subjects. Area under the curve (AUC) values for serum miR-21, miR-29a, miR-125b, and their combined score in discriminating patients with early colorectal neoplasm from healthy controls were 0.706, 0.741, 0.806, and 0.827, respectively. Serum levels of miR-29a and miR-125b were significantly higher in patients who had only small colorectal neoplasms (<= 5 mm) than in healthy subjects.Conclusions: Because serum levels of miR-21, miR-29a, and miR-125b discriminated patients with early colorectal neoplasm from healthy controls, our data highlight the potential clinical use of these molecular signatures for noninvasive screening of patients with colorectal neoplasia. (C) 2015 AACR.
  • Yada N; Sakurai T; Minami T; Arizumi T; Takita M; Hagiwara S; Ueshima K; Ida H; Nishida N; Kudo M
    Oncology 89 53 - 59 0030-2414 2015 [Refereed]
  • Arizumi T; Ueshima K; Iwanishi M; Minami T; Chishina H; Kono M; Takita M; Kitai S; Inoue T; Yada N; Hagiwara S; Ida H; Minami Y; Sakurai T; Nishida N; Kitano M; Kudo M
    Oncology 89 4 - 10 0030-2414 2015 [Refereed]
  • Arizumi T; Ueshima K; Iwanishi M; Minami T; Chishina H; Kono M; Takita M; Kitai S; Inoue T; Yada N; Hagiwara S; Ida H; Minami Y; Sakurai T; Kitano M; Nishida N; Kudo M
    Oncology 89 47 - 52 0030-2414 2015 [Refereed]
  • Naoshi Nishida; Tadaaki Arizumi; Masahiro Takita; Tonnoyuki Nagai; Satoshi Kitai; Norihisa Yada; Satoru Hagiwara; Tatsuo Inoue; Yasunori Minami; Kazuonni Ueshima; Toshiharu Sakurai; Hiroshi Ida; Masatoshi Kudo
    ONCOLOGY KARGER 84 82 - 87 0030-2414 2013 [Refereed]
     
    Objectives: Hepatocellular carcinoma (HCC) is one of the common cancers worldwide. Accurate diagnosis of tumor progression is critical for the appropriate management of HCC. Here, we established a sensitive assay to detect and quantify tumor-derived DNA in the serum of HCC patients. Methods: Aberrant methylation of the APC gene was quantified in 23 HCC patients and 8 healthy volunteers using 100 mu l of serum. For sensitive detection and accurate quantification of tumor DNA, we combined seminested polymerase chain reaction (PCR) with TaqMan PCR, which could amplify the APC gene regardless of the methylation status and detect the methylated and unmethylated sequences separately. The ratio of methylated to unmethylated sequences was quantified. Results: The methylated APC gene was detected in all HCC patients examined, but no healthy volunteers showed amplification of methylated sequences in serum. HCC patients with portal vein thrombosis showed a significantly higher methylated to unmethylated APC gene ratio in serum than those without portal vein thrombosis (p = 0.0029). Conclusions: Considering the strong association between the ratio of the methylated to unmethylated APC sequences in serum and the presence of portal vein thrombosis, methylation status of APC sequences could be a promising marker for improving HCC management. Copyright (C) 2013 S. Karger AG, Basel
  • Naoshi Nishida; Shinichi Iwamura; Hiroshi Ida; Satoshi Hagiwara; Yoshinori Kagioka; Yasunori Minami; Yoji Maetani; Kyo Itoh; Masatoshi Kudo
    DIGESTIVE DISEASES KARGER 31 (5-6) 408 - 414 0257-2753 2013 [Refereed]
     
    Budd-Chiari syndrome (BCS) is a rare condition characterized by hepatic venous outflow obstruction. In this report, we present 4 cases of BCS with complete and incomplete obstruction of the inferior vena cava (IVC) and hepatic vein (HV). Each case showed different and unique features of liver damage, which were attributed to the site and degree of obstruction. Interestingly, improved liver functions such as increased serum albumin levels, decreased hyaluronic acid levels and a normal indocyanine green clearance test were evident within 1 month of the balloon angioplasty. Pericellular fibrosis and hypervascular regenerative nodules were also reversible after obstruction removal. Therefore, it is very important to manage this rare disease before it progresses to liver cirrhosis. (C) 2013 S. Karger AG, Basel
  • Seiji Shio; Yuzo Kodama; Hiroshi Ida; Masahiro Shiokawa; Koji Kitamura; Etsuro Hatano; Shinji Uemoto; Tsutomu Chiba
    CANCER SCIENCE WILEY-BLACKWELL 102 (4) 776 - 783 1347-9032 2011/04 [Refereed]
     
    RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region frequently inactivated through hypermethylation, histone modulation, and other processes in various human tumors. In this study, to elucidate a causal link between RUNX3 expression and biliary tract cancer, we investigated 17 human biliary cancer specimens. In addition, to examine roles of RUNX3 in biliary tract cancer, we restored silenced RUNX3 in the human biliary cancer cell line Mz-ChA-2 using a histone deacetylase inhibitor. Thirteen of 17 human cancer specimens exhibited suppressed RUNX3 expression compared with normal biliary ducts. Moreover, the decreased RUNX3 expression was related to a lower accumulation of acetylated histone H3 associated with RUNX3. In in vitro experiments, vorinostat, a member of a new class of highly potent histone deacetylase inhibitors, restored RUNX3 expression in Mz-ChA-2 cells. Furthermore, vorinostat-induced RUNX3 significantly enhanced p21 expression and growth inhibition of Mz-ChA-2 cells through restoration of TGF-beta signaling. These data suggest the significance of histone deacetylation-associated suppression of RUNX3 expression in biliary tract carcinogenesis. Furthermore, vorinostat might hold promise for treating biliary tract cancer through enhancement of TGF-beta signaling by restoration of RUNX3. (Cancer Sci 2011; 102: 776-783)
  • Manabu Fukuhara; Tomohiro Watanabe; Taro Ueo; Hiroshi Ida; Yuzo Kodama; Tsutomu Chiba
    RHEUMATOLOGY OXFORD UNIV PRESS 49 (8) 1602 - 1604 1462-0324 2010/08 [Refereed]
  • Reiko Akitake; Tomohiro Watanabe; Chikage Zaima; Norimitsu Uza; Hiroshi Ida; Shinsuke Tada; Naoshi Nishida; Tsutomu Chiba
    GUT B M J PUBLISHING GROUP 59 (4) 542 - 545 0017-5749 2010/04 [Refereed]
     
    We report a case of immunoglobulin G4 (IgG4)-related sclerosing disease involving the pancreas, liver and salivary glands. Massive infiltration of IgG4-expressing plasma cells was seen in the liver and submandibular lymph nodes. Interestingly, accumulation of IgG4-expressing plasma cells was also seen in the colon and terminal ileum. Peripheral blood mononuclear cells (PBMCs) isolated from this patient exhibited enhanced production of IgG4 and interleukin-10 upon stimulation with Toll-like receptor (TLR) ligands as compared with those from a healthy control. In contrast, production of tumour necrosis factor alpha and interferon gamma by PBMCs from this patient was markedly reduced. Since colonic mucosa is always exposed to TLR ligands derived from commensal organisms, the results of immunological studies suggest that enhanced T helper type 2 responses to intestinal microflora may underlie the immunopathogenesis in this patient with IgG4-related sclerosing disease.
  • Kosuke Ueda; Hiroyuki Matsui; Tomohiro Watanabe; Junya Seki; Tatsuo Ichinohe; Yoshihisa Tsuji; Kayoko Matsumura; Yugo Sawai; Hiroshi Ida; Yoshihide Ueda; Tsutomu Chiba
    INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 49 (7) 653 - 657 0918-2918 2010 [Refereed]
     
    Extramedullary plasmacytoma of the liver is rare. Here, we report a case presenting with rupture of extramedullary plasmacytoma of the liver. She had a past history of multiple myeloma with IgA. type. Her serum was positive for hepatitis C virus infection and exhibited elevated levels of serum protein induced by vitamin K absence or antagonist-II. She was initially diagnosed as rupture of hepatocellular carcinoma (HCC) and then treated with transarterial chemoembolization (TACE) since bloody ascites and formation of hematoma were seen around hyper-vascular liver tumors on computed tomography. However, the clinical course of this case after TACE was atypical for HCC rupture, as shown by the development of a huge intra-abdominal abscess extending from the liver tumor. Immuno-histochemical analysis of the tumor biopsy specimen revealed massive infiltration of plasma cells expressing IgA and. chain. To our knowledge, this is the first case of rupture of extramedullary liver plasmacytoma.
  • Chouhei Sakakura; Takuo Hamada; Koji Miyagawa; Minoru Nishio; Atushi Miyashita; Hiroyuki Nagata; Hiroshi Ida; Shujiro Yazumi; Eigo Otsuji; Tsutomu Chiba; Kosei Ito; Yoshiaki Ito
    ANTICANCER RESEARCH INT INST ANTICANCER RESEARCH 29 (7) 2619 - 2625 0250-7005 2009/07 [Refereed]
     
    Purpose and Experimental Design: Using real-time quantitative methylation-specific PCR (RTQ-MSP), methylated RUNX3 sequences were quantified and the fractional concentrations of circulating tumor DNA in serum were determined, along with peripheral blood cells collected preoperatively, intraoperatively and postoperatively from 65 patients with gastric cancer. Results: RTQ-MSP was sufficiently sensitive to detect RUNX3 methylation. Quantitative MSP data were expressed in terms of the methylation index, which was defined as the relative amount of methylated RUNX3 sequences divided by the concentration of methylated actin. High levels of methylated RUNX3 sequences were detected in the peripheral circulation of 29% (19 of 65) of the gastric cancer patients. The RUNX3 methylation index was concordant with cancer stage, histology, lymphatic and vascular invasion, and was more sensitive than carcinoembryonic antigen (CEA) as a biomarker. Twenty-nine percent (19 out of 65) of preoperative serum samples had methylated RUNX3 sequences, ranging from 5.2 to 1625955 (median quantity=43 m-index, sensitivity 95.5%, specificity 62.5%, AUC 0.8651). After surgical resection, the median RUNX3 methylation index in serum significantly decreased. These results demonstrate the clinical usefulness and effectiveness of peripheral blood RTQ-MSP for detecting and monitoring gastric cancer after treatment. Furthermore, 5 out of the 30 preoperative control samples of benign disease (cases of panperitonitis due to acute appendicitis or cholecystitis) showed transient RUNX3 methylation which decreased after the operation in accordance with recovery. Conclusion: Quantification of epigenetic changes in serum RUNX3 methylation using RTQ-MSP is useful for the detection and monitoring of gastric cancer.
  • Kenji Ueno; Tomohiro Watanabe; Yukiko Kawata; Tomoyuki Gotoh; Yoshihisa Tsuji; Hiroshi Ida; Shinsuke Tada; Shujiro Yazumi; Tsutomu Chiba
    EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LIPPINCOTT WILLIAMS & WILKINS 20 (11) 1118 - 1121 0954-691X 2008/11 [Refereed]
     
    We report a case of autoimmune pancreatitis involving the colonic mucosa. Although serum level of IgG4 was normal, computed tomography and endoscopic retrograde cholangiopancreatography showed diffuse enlargement of the pancreas and irregular narrowing of the pancreatic ducts, respectively. Colonoscopy revealed a polypoidal lesion in the ascending colon. A lymphoplasmacytic infiltration was seen both in the pancreas and in the polypoidal lesion of the colon. Furthermore, immunohistochemical analysis showed abundant IgG4-positive plasma cells in these lesions. This is the first case report of a simultaneous occurrence of autoimmune pancreatitis and a colonic polypoidal lesion, both of which are characterized with increased IgG4 responses. Eur J Gastroenterol Hepatol 20:1118-1121 (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.
  • Akio Ido; Akihiro Moriuchi; Hiroyuki Marusawa; Kazuki Ikeda; Masatsugu Numata; Naohisa Yamaji; Hitoshi Setoyama; Hiroshi Ida; Makoto Oketani; Tsutomu Chiba; Hirohito Tsubouchi
    HEPATOLOGY RESEARCH WILEY-BLACKWELL PUBLISHING, INC 38 S88 - S92 1386-6346 2008/11 [Refereed]
     
    Hepatocyte growth factor (HGF) is a potential therapeutic agent for fatal liver diseases, including fulminant hepatic failure (FHF). After performing a number of preclinical tests with recombinant human HGF (rh-HGF), we started a phase I/II study in September 2005 of patients with FHF or late-onset hepatic failure (LOHF), to examine the safety and clinical efficacy of rh-HGF. We first administered rh-HGF (0.6 mg/m(2)/day) for 13 days to a 67-year-old Japanese man with FHF. All data from this patient were reviewed by the independent data monitoring committee, and the safety of rh-HGF was recognized. Finally, a clinical trial of rh-HGF was approved to be continued. As of August 2007, we have administered rh-HGF to four patients with FHF or LOHF. All patients showed a moderate decrease in systolic blood pressure during rh-HGF administration, while the urinary excretion of albumin did not increase in all cases. In the first and third patients, hepatic failure gradually progressed, and they died 66 and 29 days, respectively, after encephalopathy occurred. The second and fourth patients are presently still alive. In conclusion, we started a clinical trial that examined the effects of rh-HGF in patients with FHF or LOHF, and in the four patients with FHF or LOHF enrolled in this study, repeated doses of rh-HGF did not produce any severe side effects.
  • Seiji Shio; Shujiro Yazumi; Kohei Ogawa; Kazunori Hasegawa; Yoshihisa Tsuji; Masaya Kida; Junichi Yamauchi; Hiroshi Ida; Shinsuke Tada; Shinji Uemoto; Tsutomu Chiba
    AMERICAN JOURNAL OF GASTROENTEROLOGY NATURE PUBLISHING GROUP 103 (6) 1393 - 1398 0002-9270 2008/06 [Refereed]
     
    OBJECTIVES: With the increasing number of living donor liver transplantations, biliary complications in donors have emerged as a major postoperative problem. The aim of the present study was to characterize the features of the biliary complications that occur in donors. METHODS: The study subjects comprised 731 consecutive patients who donated liver grafts (434 right-lobe and 297 left-lobe grafts) for transplantation at Kyoto University Hospital from July 1999 to December 2006. Donors whose biliary complications could not be cured by conservative therapy were referred for endoscopic treatment. RESULTS: Postoperative biliary complications occurred in 55 (7.5%) donors. Initially, 48 of these 55 donors had biliary leakage and 7 had biliary stricture. Subsequently, 5 of 48 donors with leakage developed biliary stricture. The respective incidences of biliary leakage and overall biliary complications were significantly higher among donors of right-lobe grafts (9.9% and 11.1%) than among donors of left-lobe grafts (1.7% and 2.4%). Among 55 donors with biliary complications, 24 were cured by conservative therapy, and 1 was converted to surgical repair due to ileus. Endoscopic treatment was successful in 24 of 30 (80%) donors treated by endoscopic retrograde cholangiography, while the remaining 6 (20%) patients underwent surgery due to difficulties with cannulation (N = 2), excessive biliary leakage (N = 2), or complete biliary obstruction (N = 2). CONCLUSIONS: Donors of right-lobe grafts have a significantly higher incidence of biliary complications than donors of left-lobe grafts. When conservative therapy fails, endoscopic treatment is effective for these complications, and should be attempted as the first-line therapy before surgical repair.
  • Sing-Huang Tan; Hiroshi Ida; Quek-Choon Lau; Boon-Cher Goh; Wei-Shieng Chieng; Marie Loh; Yoshiaki Ito
    ONCOLOGY REPORTS SPANDIDOS PUBL LTD 18 (5) 1225 - 1230 1021-335X 2007/11 [Refereed]
     
    The purpose was to validate the use of RUNX3 as a potential biomarker for detection of cancer in serum samples and to determine its sensitivity alone and in combination with p16, RASSF1A and CDH1 using methylation-specific polymerase chain reaction (MSP). We examined the promoter methylation status of RUNX3, p16, RASSF1A and CDH1 by MSP using the serum of 70 metastatic breast, non-small cell lung, gastric, pancreatic, colorectal or hepatocellular carcinomas. The DNA from 10 healthy serum controls was used to determine the specificity of methylation. According to our results, promoter hyper-methylation of RUNX3 was detected in the serum of 44 patients comprising breast 9/19 (47%), non-small cell lung 11/20 (55%), gastric 4/4 (100%), pancreatic 2/2 (100%), colorectal 11/17 (65%) and liver 7/8 (88%) carcinomas. Comparative figures for the other genes were as follows: p16 - 39/70 (7/19, 10/20, 2/4, 0/2, 12/17, 8/8); RASSF1A - 24/70 (8/19, 6/20, 1/4, 1/2, 4/17, 4/8); CDH1 - 10/70 (0/19, 4/20, 1/4, 1/2, 3/17, 1/8). Using a panel of four genes, hypermethylation of one or more genes was found in 62/70 samples (15/19, 19/20, 4/4, 2/2, 14/17, 8/8). A panel of three genes omitting RUNX3 detected hypermethylation in only 50/70 samples. No methylation was detected in the 10 healthy serum controls. Thus, RUNX3 can be detected in the serum of a high proportion of advanced cancers. This suggests that serum hypermethylation of RUNX3 is at least as, or possibly more sensitive a marker, than other tumor suppressor genes currently under investigation. Inclusion of RUNX3 in gene panels can potentially increase the sensitivity of such panels for serum diagnosis of malignancies and warrants further study.
  • C. Sakakura; K. Miyagawa; K. I. Fukuda; S. Nakashima; T. Yoshikawa; S. Kin; Y. Nakase; H. Ida; S. Yazumi; H. Yamagishi; T. Okanoue; T. Chiba; K. Ito; A. Hagiwara; Y. Ito
    ONCOGENE NATURE PUBLISHING GROUP 26 (40) 5927 - 5938 0950-9232 2007/08 [Refereed]
     
    Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor ( TGF)-beta-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression ( P < 0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-beta and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2'-deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.
  • Junichi Yamauchi; Shujiro Yazumi; Masaya Kida; Seiji Shio; Shinsuke Tada; Hiroshi Ida; Mohamed Shawkat; Daisuke Harada; Tsutomu Chiba
    DIGESTIVE ENDOSCOPY BLACKWELL PUBLISHING 19 S126 - S128 0915-5635 2007/07 [Refereed]
     
    A 66-year-old woman who had a repeated history of cholangitis since undergoing choledocho-jejunostomy for post-cholecystectomy common bile duct stricture, was referred to Kyoto University Hospital for further examination of the stricture of left intrahepatic biliary duct (IHBD). Endoscopic retrograde cholangiography (ERC) showed obstruction of the left IHBD with slightly protruding lesion. Peroral cholangioscopy (POCS) with narrow band imaging (NBI) demonstrated that a protruding lesion with papillary surface had neither tumor vessels on the surface of the tumor nor microvessel in each papillary projection. Biopsy presented only inflammation. Pathological analysis of the resected left lobe also showed only inflammatory change. NBI-videocholangioscopy appears to be useful for diagnosing biliary disease by evaluating the tumor vessels including microvessel in papillary projection.
  • Kazunori Hasegawa; Shujiro Yazumi; Manabu Wada; Toshiharu Sakurai; Masaya Kida; Junichi Yamauchi; Hiroshi Hisatsune; Shinsuke Tada; Hiroshi Ida; Yuenn Nakase; Chohei Sakakura; Akeo Hagiwara; Tsutomu Chiba
    CANCER SCIENCE BLACKWELL PUBLISHING 98 (6) 838 - 843 1347-9032 2007/06 [Refereed]
     
    RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region commonly inactivated by deletion and methylation in various human tumors. To elucidate the role of RUNX3 in transforming growth factor (TGF)-beta signaling in biliary tract cancer, we transfected Mz-ChA-2 cells, which do not express RUNX3 but have intact TGF-beta type II receptor and SMAD4 genes, with the RUNX3 expression plasmid pcDNA3.1/RUNX3 or with the vector pcDNA3.1 as a control. Four Mz-ChA-2/RUNX3 clones and one control clone were obtained. Although TGF-beta 1 only slightly inhibited growth of the control cells, growth inhibition and TGF-beta-dependent G(1) arrest were significantly enhanced in the RUNX3-transfected clones. None of the clones, however, exhibited apoptosis. The slightly increased TGF-beta 1-induced p21 expression in the control clone was strongly enhanced in the RUNX3-transfected clones, and was accompanied by augmented decreases in the expression of cyclins D1 and E. When RUNX3 small interfering RNA was added, TGF-beta-dependent induction of p21 was reduced in the RUNX3-transfected clones. Xenografts of the clones in nude mice demonstrated that tumorigenicity was significantly decreased in the RUNX3-transfected clones in inverse proportion to the expression levels of RUNX3. Based on these results, RUNX3 is involved in TGF-beta-induced expression of p21 and the resulting induction of TGF-beta-dependent G(1) arrest.
  • Canhua Huang; Hiroshi Ida; Kosei Ito; Haiyuan Zhang; Yoshiaki Ito
    BIOCHEMICAL PHARMACOLOGY PERGAMON-ELSEVIER SCIENCE LTD 73 (7) 990 - 1000 0006-2952 2007/04 [Refereed]
     
    Vorinostat (suberoylanilide hydroxamic acid, SAHA) represents a new class of highly potent histone deacetylase (HDAC) inhibitors that cause growth arrest, differentiation, and apoptosis of many tumor types in vitro and in vivo. RUNX3, a gastric tumor suppressor, is epigenetically silenced in gastric cancer cells. This study investigates the role of RUNX3 in vorinostat-induced suppression of gastric cancer cell growth. RUNX3 was up-regulated by vorinostat in gastric cancer cell lines not expressing RUNX3. In terms of cell viability, the mean IC50 of vorinostat in RUNX3-negative cells was significantly lower than that seen in RUNX3-positive cells, indicating that the former are more sensitive to vorinostat in terms of growth arrest than are RUNX3-positive lines. The mechanism underlying this difference was found to be reactivation of RUNX3 expression by vorinostat and concomitant increase in acetylated histone H3 in the promoter region of RUNX3. Using three RUNX3-negative cell lines, we determined the contribution of RUNX3 reactivation to growth inhibition and induction of apoptosis following treatment of cells with vorinostat and found that up-regulated RUNX3 was significantly responsible for tumor suppressive activities. (c) 2007 Elsevier Inc. All rights reserved.
  • Lena Motoda; Motomi Osato; Namiko Yamashita; Bindya Jacob; Lynnette Q. Chen; Masatoshi Yanagida; Hiroshi Ida; Hee-Jun Wee; Alfred X. Sun; Ichiro Taniuchi; Dan Littman; Yoshiaki Itoa
    STEM CELLS WILEY-BLACKWELL 25 (12) 2976 - 2986 1066-5099 2007 [Refereed]
     
    The RUNX1/AML1 gene encodes a transcription factor essential for the generation of hematopoietic stem cells and is frequently targeted in human leukemia. In human RUNX1-related leukemias, the RAS pathway is often concurrently mutated, but the mechanism of the synergism remains elusive. Here, we found that inactivation of Runx1 in mouse bone marrow cells results in an increase in the stem/progenitor cell fraction due to suppression of apoptosis and elevated expression of the polycomb gene Bmi-1, which is important for stem cell self-renewal. Introduction of oncogenic N-RAS into wild-type cells, in contrast, reduced the stem/progenitor cell fraction because of senescence, apoptosis, and differentiation. Such detrimental events presumably occurred because of the cellular fail-safe program, although hyperproliferation was initially induced by an oncogenic stimulus. Runx1 insufficiency appears to impair such a fail-safe mechanism, particularly in the stem/progenitor cells, thereby supporting the clonal maintenance of leukemia-initiating cells expressing an activated oncogene.
  • Sing-Huang Tan; Hiroshi Ida; Boon-Cher Goh; Wenson Hsieh; Marie Loh; Yoshiaki Ito
    ANTICANCER RESEARCH INT INST ANTICANCER RESEARCH 26 (6B) 4287 - 4292 0250-7005 2006/11 [Refereed]
     
    Background: Aberrant methylation of cytosine in promoter CpG islands is a recognized contributory process to carcinogenesis. This study explores the methylation profile of RUNX3 in combination with p16, RASSF1A, CDH1 and hMLH1 in nasopharyngeal carcinoma (NPC) patients. Materials and Methods: Genomic DNA was extracted from 19 fresh frozen NPC biopsies, which were then subjected to bisulfite conversion and methylation-specific PCR for analysis of promoter hypermethylation for the five respective genes. Three cell lines, SNU1, RKO and LS174T, were used as controls. Results: The incidences of promoter methylation were as follows: RUNX3 0/19 (0%), p16 6/19 (32%), RASSF1A 13/19 (68%), CDH1 9/19 (47%) and hMLH1 4/19 (21%). Ninety-five percent of the tumor specimens displayed aberrant methylation in at least one of these genes. No significant correlation between methylation status of these genes and clinical parameters was found. Conclusion: Methylation of multiple genes is involved in critical pathways for cancer development in NPC. Promoter hypermethylation for RUNX3 was, however, not present.
  • Kouji Miyagawa; Chouhei Sakakura; Susumu Nakashima; Tetsuji Yoshikawa; Shuichi Kin; Yuenn Nakase; Kosei Ito; Hisakazu Yamagishi; Hiroshi Ida; Shujiro Yazumi; Tsutomu Chiba; Yoshiaki Ito; Akeo Hagiwara
    ANTICANCER RESEARCH INT INST ANTICANCER RESEARCH 26 (5B) 3633 - 3643 0250-7005 2006/09 [Refereed]
     
    Background: Our previous studies suggested that deficient function of RUNX3 protein is causally related to development and progression of human gastric cancer. RUNX3 is mapped to 1p36, which is frequently deleted in hepatocellular carcinomas (HCC), therefore, these tumors were investigated for expression and copy number changes of RUNX3 and other Runt-related genes, RUNX1, RUNX2, and their co-factor CBF. Similarly nearby uninvolved liver showing cirrhosis or normal histology was investigated in conjunction with various clinicopathological factors. Materials and Methods: Copy number change and expression change of RUNX family genes in 35 hepatocellular carcinoma specimens and adjoining liver with cirrhosis (LC) or normal histology were estimated using quantitative reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization.
  • T Yano; K Ito; H Fukamachi; XZ Chi; HJ Wee; K Inoue; H Ida; P Bouillet; A Strasser; SC Bae; Y Ito
    MOLECULAR AND CELLULAR BIOLOGY AMER SOC MICROBIOLOGY 26 (12) 4474 - 4488 0270-7306 2006/06 [Refereed]
     
    Genes involved in the transforming growth factor beta (TGF-beta) signaling pathway are frequently altered in several types of cancers, and a gastric tumor suppressor RUAW3 appears to be an integral component of this pathway. We reported previously that apoptosis is notably reduced in Runx3(-/-) gastric epithelial cells. In the present study, we show that a proapoptotic gene Bim was transcriptionally activated by RUNX3 in the gastric cancer cell lines SNU16 and SNU719 treated with TGF-beta. The human Bim promoter contains RUNX sites, which are required for its activation. Furthermore, a dominant negative form of RUNX3 comprised of amino acids I to 187 increased tumorigenicity of SNU16 by inhibiting Bim expression. In Runx3(-/-) mouse gastric epithelium, Bim was down-regulated, and apoptosis was reduced to the same extent as that in Bim(-/-) gastric epithelium. We confirmed comparable expression of TGF-beta I and TGF-beta receptors between wild-type and Runx3(-/-) gastric epithelia and reduction of Bim in TGF-beta 1(-/-) stomach. These results demonstrate that RUNX3 is responsible for transcriptional up-regulation of Bim in TGF-beta-induced apoptosis.
  • K Ito; Q Liu; M Salto-Tellez; T Yano; K Tada; H Ida; C Huang; N Shah; M Inoue; A Rajnakova; KC Hiong; BK Peh; HC Han; T Ito; M Teh; KG Yeoh; Y Ito
    CANCER RESEARCH AMER ASSOC CANCER RESEARCH 66 (6) 3345 - 3345 0008-5472 2006/03 [Refereed]
  • Y Yamamura; WL Lee; K Inoue; H Ida; Y Ito
    JOURNAL OF BIOLOGICAL CHEMISTRY AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC 281 (8) 5267 - 5276 0021-9258 2006/02 [Refereed]
     
    The transcription factor RUNX3, which mediates apoptosis and cell growth inhibition in gastric epithelial cells, is a candidate tumor suppressor that is frequently lost in gastric cancer cells. Here, we found that restoration of RUNX3 expression in the cell line not expressing RUNX3 induced apoptosis and that it physically interacted with the Forkhead transcription factor FoxO3a/FKHRL1, known to be an important regulator of apoptosis and the cell cycle. Active unphosphorylated FoxO3a/FKHRL1 was expressed in the gastric cancer cell lines. RUNX3-induced apoptosis depended on the expression of Bim, a proapoptotic BH3-only protein, and both RUNX3 and FoxO3a/FKHRL1 were required for induction of Bim expression. Furthermore, we showed that interaction of RUNX3 and FoxO3a/FKHRL1 was also indispensable for Bim expression and apoptosis in mouse embryonic fibroblasts. In the Bim promoter, RUNX3 bound to two conserved RUNX-binding elements (RBE1 and RBE2), with RBE1 being immediately downstream of a FoxO-binding element. The physical interaction of RUNX3 and FoxO3a/FKHRL1 on the Bim promoter activated transcription of Bim. These findings show that RUNX3 cooperates with FoxO3a/FKHRL1 to participate in the induction of apoptosis by activating Bim and may play an important role in tumor suppression in gastric cancer.
  • K Ito; Q Liu; M Salto-Tellez; T Yano; K Tada; H Ida; CH Huang; N Shah; M Inoue; A Rajnakova; KC Hiong; BK Peh; HC Han; T Ito; M Teh; KG Yeoh; Y Ito
    CANCER RESEARCH AMER ASSOC CANCER RESEARCH 65 (17) 7743 - 7750 0008-5472 2005/09 [Refereed]
     
    Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-beta is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.
  • M Wada; S Yazumi; S Takaishi; K Hasegawa; M Sawada; H Tanaka; H Ida; C Sakakura; K Ito; Y Ito; T Chiba
    ONCOGENE NATURE PUBLISHING GROUP 23 (13) 2401 - 2407 0950-9232 2004/03 [Refereed]
     
    RUNX3, a Runt domain transcription factor involved in TGF-beta signaling, is a candidate tumor-suppressor gene localized in 1p36, a region commonly deleted in a wide variety of human tumors, including those of the stomach, bile duct, and pancreas. Recently, frequent inactivation of RUNX3 has been demonstrated in human gastric carcinomas. In this study, to examine the involvement of RUNX3 abnormalities in tumorigenesis of bile duct as well as pancreatic cancers, we investigated not only the expression but also methylation status of RUNX3 in 10 human bile duct and 12 pancreatic cancer cell lines. Seven (70%) of the bile duct and nine (75%) of the pancreatic cancer cell lines exhibited no expression of RUNX3 by both Northern blot analysis and the reverse transcriptase polymerase chain reaction. All of the 16 cell lines that did not express RUNX3 also showed methylation of the promoter CpG island of the gene, whereas the six cell lines that showed RUNX3 expression were not methylated or only partially methylated in the RUNX3 promoter region. Moreover, treatment with the methylation inhibitor 5'-aza-2'-deoxycitidine activated RUNX3 mRNA expression in all of 16 cancer cell lines that originally lacked RUNX3 expression. Finally, hemizygous deletion of RUNX3, as detected by fluorescence in situ hybridization, was found in 15 of the 16 cancer cell lines that lacked RUNX3 expression. These data suggest that the inactivation of RUNX3 plays an important role in bile duct and pancreatic carcinogenesis, and that methylation is a common mechanism by which the gene is inactivated.

MISC

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2009 -2010 
    Author : IDA Hiroshi
     
    Detection of methylation of RUNX3 in bile juice was developed. Expression of RUNX3 in bile duct cancer cells was restored by the treatment with a new histone deacethylase inhibitor. Anti-tumor effect by the drug was revealed. Analysis of RUNX3 histone acethylation as well as DNA methylation can be a prognostic marker of bile duct cancer.

Other link

researchmap


Copyright © MEDIA FUSION Co.,Ltd. All rights reserved.