Yasuni Nakanuma

Shizuoka Cancer Center, Sizuoka, Shizuoka, Japan

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Publications (926)3221.3 Total impact

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    ABSTRACT: Glycoform of mucin 1 (MUC1) in cancerous cells changes markedly with cell differentiation, and thus qualitative detection and verification of the MUC1 glycosylation changes have potential diagnostic value. We have developed an ultrasensitive method to detect the changes in cholangiocarcinoma (CC), which produces MUC1, and applied it in the diagnostics development. The focused glycan analysis using 43-lectin-immobilized microarray could obtain the glycan profiles of sialylated MUC1 in 5 μL of sera. The high-throughput analysis detected disease-specific alterations of glycosylation, and the statistical analysis confirmed that use of Wisteria floribunda agglutinin (WFA) alone produced a diagnostic score sufficient for discriminating 33 CC cases from 40 hepatolithiasis patients and 48 normal controls (p < 0.0001). The CC-related glycosylation change was verified by the lectin-antibody sandwich ELISA with WFA in two cohorts: (1) 78 Opisthorchis viverrini infected patients without CC and 78 with CC, (2) 33 CC patients and 40 hepatolithiasis patients (the same cohort used for the above lectin microarray). The WFA positivity distinguished patients with CC (opisthorchiasis: p < 0.0001, odds ratio = 1.047; hepatolithiasis: p = 0.0002, odds ratio = 1.018). Sensitive detection of qualitative alterations of sialylated MUC1 glycosylation is indispensable for the development of our glycodiagnostic test for CC.
    Analytical Chemistry 06/2015; DOI:10.1021/acs.analchem.5b01329 · 5.83 Impact Factor
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    ABSTRACT: A rare case of an intrahepatic multicystic tumor is described. A 26-year-old man visited our hospital because of abdominal discomfort. Contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography revealed a 10 × 7 cm multicystic tumor of the bile duct in the right side of the liver. The gross appearance of the tumor resembled an intraductal papillary neoplasm of the bile duct, and right hepatectomy with regional lymphadenectomy was performed. Histologically, these cystic lesions were composed of variably and irregularly dilated duct structures lined by columnar epithelium resembling bile duct lining. There were no atypical cells and no papillary growth of the epithelial cells. Interestingly, the dilated ducts contained inspissated bile, and the inter-cystic parenchyma contained variable but irregularly distributed and hamartomatous hepatic parenchyma with an abnormal lobular pattern. Though it had atypical features of a hamartoma in some aspects (age, smooth muscle), this case could finally be regarded as a variant of multicystic biliary hamartoma.
    Clinical Journal of Gastroenterology 05/2015; DOI:10.1007/s12328-015-0574-y
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    ABSTRACT: Given that pancreatic ductal adenocarcinoma (PDAC) is among the most fatal malignancies with an extremely poor prognosis, the objectives of this study were to provide a detailed understanding of PDAC pathophysiology in view of the host immune response. We examined the PDAC tissues, sera, and peripheral blood cells of PDAC patients using immunohistochemical staining, the measurement of cytokine/chemokine concentrations, gene expression analysis, and flow cytometry. PDAC tissues were infiltrated by macrophages, especially CD33+CD163+ M2 macrophages and CD4+ T cells that concomitantly express programmed cell death-1 (PD-1). Concentrations of interleukin (IL)-6, IL-7, IL-15, monocyte chemotactic protein-1, and interferon-inducible protein-1 in the sera of PDAC patients were significantly elevated. The gene expression profile of CD14+ monocytes and CD4+ T cells was discernible between PDAC patients and healthy volunteers, and the differentially expressed genes were related to activated inflammation. Intriguingly, PD-1 was significantly up-regulated in the peripheral blood CD4+ T cells of PDAC patients. Correspondingly, the frequency of CD4+PD-1+ T cells increased in the peripheral blood cells of PDAC patients, and this increase correlated to chemotherapy resistance. In conclusion, inflammatory condition in both the PDAC tissue and peripheral blood cells in PDAC patients were prominent, highlighting monocytes/macrophages as well as CD4+ T cells with influence of the clinical prognosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Cancer Science 04/2015; 106(6). DOI:10.1111/cas.12663 · 3.53 Impact Factor
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    ABSTRACT: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations. Clinical questions (CQs) were proposed in seven topics. Recommendation, grade of recommendation and statement for each CQ were discussed and finalized by evidence-based approach. Recommendation was graded to grade 1 (strong) and 2 (weak) according to the concept of GRADE system. The 29 CQs covered seven topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, (6) radiation therapy, and (7) pathology. In 27 CQs, 19 recommendations were rated strong and 11 recommendations weak. Each CQ included the statement of how the recommendation was graded. This guideline provides recommendation for important clinical aspects based on evidence. Future collaboration with cancer registry will be a key for assessment of the guidelines and establishment of new evidence. Free full-text articles and a mobile application of this guideline are available via http://www.jshbps.jp/en/guideline/biliary-tract2.html. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
    Journal of Hepato-Biliary-Pancreatic Sciences 03/2015; 22(4). DOI:10.1002/jhbp.233 · 2.31 Impact Factor
  • Yasuni Nakanuma, Yuko Kakuda
    Nippon rinsho. Japanese journal of clinical medicine 03/2015; 73 Suppl 3:471-6.
  • Yasuni Nakanuma, Yuko Kakuda
    Nippon rinsho. Japanese journal of clinical medicine 03/2015; 73 Suppl 3:455-60.
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    ABSTRACT: Alteration in intrahepatic microcirculation of IPH has been poorly understood. This study aimed to characterize altered intrahepatic microcirculation of idiopathic portal hypertension (IPH) focusing on the expression pattern of glutamine synthetase (GS). Immunohistochemical staining of GS was performed using liver sections of IPH (n = 28). Serial section analysis was performed to determine microcirculatory disturbances of IPH. Paraportal shunt vessels were observed in 20 cases of IPH, and they were divided into two types according to the GS staining pattern; hepatocytes surrounding the vessels were negative for GS (Type 1) and positive for GS (Type 2). All 20 cases had one or more Type 1 vessels within a section, and 10 cases were further associated with Type 2 vessels. The cases with Type 2 vessels showed infrequent symptoms of esophageal varices. Regarding the GS staining as an indicator of hepatic veins, some of Type 2 vessels were supposed to represent portovenous shunts. Isolated arteries in hepatic parenchyma were present in 21 cases, and they were located around terminal hepatic venules in 6 cases, corresponding to centrizonal arteries. Broad hepatocellular GS staining in hyperplastic lesions was noted in 5 cases, whereas nodular regenerative hyperplasia lacked GS expression. GS immunostaining revealed microcirculatory disturbances of IPH that were associated with abnormalities in both venous and arterial vessels. This article is protected by copyright. All rights reserved.
    Hepatology Research 02/2015; DOI:10.1111/hepr.12506 · 2.22 Impact Factor
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    ABSTRACT: The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html. © Japanese Society of Hepato-Biliary-Pancreatic Surgery.
    Journal of Hepato-Biliary-Pancreatic Sciences 02/2015; 22(3). DOI:10.1002/jhbp.211
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    ABSTRACT: Purpose To identify the imaging features of hepatocellular carcinoma (HCC) associated with β-catenin mutation and their relationship to pathologic findings. Materials and Methods Institutional ethics committee approval and informed consent were obtained. One hundred thirty-eight surgically resected HCCs were analyzed in this study. Immunohistochemical expression of β-catenin and its transcriptional product, glutamine synthetase (GS), were graded and classified into three groups: the β-catenin positive and GS positive group (HCC with β-catenin mutation), the β-catenin negative and GS positive group (intermediate HCC), and the β-catenin negative and GS negative group (HCC without β-catenin mutation). Clinical, pathologic, and imaging findings from dynamic computed tomography (CT) and gadoxetic acid-enhanced magnetic resonance (MR) imaging (T1-weighted, T2-weighted, diffusion-weighted, and hepatobiliary phase imaging) were evaluated. Correlations among immunohistochemical expression of β-catenin, GS, and organic anion transporting polypeptide 1B3 (uptake transporter of gadoxetic acid) were evaluated. The χ(2), Kruskal-Wallis, and Spearman correlation tests were used. Results HCCs with β-catenin mutation (n = 27) showed a lower median contrast-to-noise ratio at diffusion-weighted imaging than did intermediate HCCs (n = 23) and HCCs without β-catenin mutation (n = 84) (13.2, 24.4, and 27.0, respectively; P = .02), higher apparent diffusion coefficient (1.33, 1.13, and 1.12, respectively; P < .0001), higher contrast-to-noise ratio (0.58, -28.7, and -45.0, respectively; P < .0001) and higher enhancement ratio during the hepatobiliary phase (0.90, 0.50, and 0.42, respectively; P < .0001). At pathologic examination, HCCs with β-catenin mutation showed pseudoglandular proliferation and bile production with a higher grade of differentiation (P = .04, .001, and .005, respectively). There were significant positive correlations among expression of β-catenin, GS, and organic anion transporting polypeptide 1B3 (P < .0001). Conclusion HCCs with β-catenin mutation showed a higher grade of differentiation with frequent pseudoglandular patterns and bile production, and characteristic imaging findings included a high enhancement ratio at gadoxetic acid-enhanced MR imaging and a high apparent diffusion coefficient at diffusion-weighted imaging. (©) RSNA, 2015 Online supplemental material is available for this article.
    Radiology 02/2015; 275(3):141315. DOI:10.1148/radiol.14141315 · 6.21 Impact Factor
  • Yasuni Nakanuma, Yuko Kakuda
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    ABSTRACT: Herein, we propose a new pathologic classification of cholangiocarcinoma (CCA) based on recent progress in studies of preinvasive CCA lesions and the relationship of CCA to hepatic progenitor cells, as well as a new concept with respect to the pathologic similarities between biliary and pancreatic neoplasms. Depending on anatomical location, CCA is classifiable as intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). iCCA is classifiable as the conventional type and the bile ductular type, whereas pCCA and dCCA mainly present as conventional adenocarcinoma. In addition, these three CCAs may present as the intraductal neoplasm type or rare variants. Bile ductular CCA resembles proliferating bile ductules and expressing hepatic progenitor cell phenotypes. Four types of preinvasive lesions are proposed: flat, papillary, tubular lesion, and cystic lesion. These lesions are eventually followed by invasive CCA. Interestingly, these preinvasive lesions have pancreatic counterparts. This CCA classification may introduce a new field of CCA research. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 02/2015; 29(2). DOI:10.1016/j.bpg.2015.02.006 · 3.28 Impact Factor
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    ABSTRACT: Deregulated autophagy followed by cellular senescence in biliary epithelial cells (BECs) may be closely related to the abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in primary biliary cirrhosis (PBC). We examined an involvement of endoplasmic reticulum (ER) stress in the deregulated autophagy and cellular senescence in PBC. We examined the degree of ER stress using markers; glucose-regulated protein 78 (GRP78) and protein disulfide isomerases (PDI), autophagy and cellular senescence in cultured BECs treated with an ER stress inducer, tunicamycin (TM), glycochenodeoxycholic acid (GCDC), and palmitic acid (PA), and the effect of pretreatment with tauroursodeoxycholic acid (TUDCA). We examined the expression of PDI and GRP78 in livers taken from the patients with PBC (n = 43) and 75 control livers. The expression of ER stress markers was significantly increased in cultured BECs treated with TM, GCDC or PA in BECs (p < 0.05), and pretreatment with TUDCA significantly suppressed the induced ER stress (p < 0.05). Autophagy, deregulated autophagy, and cellular senescence were induced in BECs treated with TM, GCDC, or PA. Pretreatment with TUDCA further increased autophagy in BECs treated with PA and suppressed cellular senescence caused by treatments with TM, GCDC, or PA (p < 0.05). A granular expression of PDI and GRP78 was significantly more extensive in small bile ducts in PBC, compared with control livers (p < 0.05). The expression of GRP78 was seen in senescent BECs in PBC. ER stress may play a role in the pathogenesis of deregulated autophagy and cellular senescence in biliary epithelial lesions in PBC.
    Journal of Gastroenterology 01/2015; DOI:10.1007/s00535-014-1033-0 · 4.02 Impact Factor
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    ABSTRACT: We thank Dr. Tapan and Sertoglu for their interest in our study and their comments. In the letter to the Editor, they recommend to measure fatty acid composition after excluding patients with type 2 diabetes mellitus (T2DM) because the activity of the desaturase enzymes regulating especially polyunsaturated fatty acids can be affected by T2DM and correlates with the level of fasting plasma glucose and insulin resistance [1]. In our study, HbA1c levels are 7.1±0.2% and 7.1±0.3% for simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) groups, respectively, and the patients with T2DM are included in both SS and NASH groups. The number of patients with T2DM was 42/63 (66.7%) and 29/40 (72.5%) for SS and NASH groups, respectively, and there was no statistically significant difference in the rate of T2DM between SS and NASH groups. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 12/2014; DOI:10.1111/liv.12755 · 4.41 Impact Factor
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    ABSTRACT: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occurring after liver transplantation is a relatively rare complication but it often takes a life-threatening course. However, the detailed etiology and mechanism of VOD/SOS after liver transplantation (LT) remains unclear. We report two cases with rapidly progressive VOD/SOS after ABO-identical LT resistant to various therapies. In case 1, in which the patient underwent deceased-donor LT, the first episode of acute allograft rejection was triggered VOD/SOS, and the presence of donor non-specific anti-HLA antibodies was confirmed. The recipient died with graft failure on day 46 after transplantation. Case 2, in which the patient underwent living-donor LT from the mother, had neither rejection nor mechanical venous obstruction, but condition of the patient rapidly worsened and he died on day 13 after transplantation. This recipient's direct cross-match test for the donor's B lymphocyte was strongly positive, but that for T lymphocyte was negative. In both cases, neither stenosis of hepatic vein outflow tract nor C4d deposition in post-transplantation liver biopsy specimens and autopsy specimen was found. On the other hand, in both cases, the patient was transfusion unresponsive thrombocytopenia and hyperbilirubinemia persisted postoperatively, and glycoprotein Ⅰ bα was strongly stained in the neighboring centrilobular area (zone 3), especially in the space of Disse, and platelet phagocytosis was observed in Kupffer cells and hepatocytes around zone 3 such as clinical xenotransplantation of the liver in post-transplantation liver biopsy specimens. From the viewpoint of graft injury, VOD/SOS was considered that sustained sinusoidal endothelial cells injury resulted in bleeding in the space of Disse and led to around centrilobular hemorrhagic necrosis, and the fundamental cause was damage around centrilobular area including sinusoid by acute cellular rejection, antibody-mediated rejection or ischemic reperfusion injury. The extrasinusoidal platelet activation, aggregation, and phagocytosis of platelets were some of the main reasons for VOD/SOS and transfusion-resistant thrombocytopenia. Copyright © 2014 Elsevier Inc. All rights reserved.
    Transplantation Proceedings 12/2014; 46(10):3523-35. DOI:10.1016/j.transproceed.2014.09.110 · 0.95 Impact Factor
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    Yasuni Nakanuma, Motoko Sasaski, Kenichi Harada
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    ABSTRACT: Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC, and deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology. Copyright © 2014. Published by Elsevier B.V.
    Journal of Hepatology 11/2014; 62(4). DOI:10.1016/j.jhep.2014.11.027 · 10.40 Impact Factor
  • Yuko Kakuda, Kenichi Harada, Yasuni Nakanuma
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    ABSTRACT: The canals of Hering (CoH), which are the most peripherally located bile drainage pathway, are considered a niche of hepatic progenitor cells. Recently, CoH loss has been described as an early feature of primary biliary cirrhosis (PBC). We investigated the correlation between CoH loss and the histopathological variables of PBC. Liver biopsy specimens from 62 PBC patients (M:F=8:54, age=58±12 years) were evaluated prior to ursodeoxycholic acid treatment. Liver biopsies of patients with normal liver (n=11), chronic viral hepatitis (n=36) and non-alcoholic fatty liver disease (n=13) were used as controls. The number of CoH per definite area of hepatic parenchyma (c to p ratio) was calculated in individual cases. We compared the c to p ratios of PBC patients with that of controls and analysed the correlations with histological variables and clinical features. The c to p ratios in PBC patients with mild and extensive fibrosis were lower than those in controls with each degree of fibrosis. The c to p ratios were negatively correlated with stage, fibrosis, bile duct loss, orcein-positive granule deposition and hepatitis activities in PBC (p<0.01) and with alkaline phosphatase and total bilirubin levels at liver biopsies (p<0.05). The number of CoH was low in early stages and further decreased with stage progression in PBC. CoH loss, reflecting a reduced supply of progenitor cells to the biliary tree, may be involved in the histological progression of PBC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of Clinical Pathology 11/2014; 68(2). DOI:10.1136/jclinpath-2014-202417 · 2.55 Impact Factor
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    ABSTRACT: Background Cholangiocarcinoma has been reported in workers exposed to chlorinated organic solvents and has consequently been classified as an occupational disease (occupational cholangiocarcinoma) by the Japanese Ministry of Health, Labour and Welfare. This study aimed to identify the characteristics of nine workers newly diagnosed with occupational cholangiocarcinoma.Methods This study was a retrospective study conducted in 13 hospitals and three universities. Clinicopathological findings of nine occupational cholangiocarcinoma patients from seven printing companies in Japan were investigated and compared with 17 cholangiocarcinoma patients clustered in a single printing company in Osaka.ResultsPatient age at diagnosis was 31–57 years. Patients were exposed to 1,2-dichloropropane and/or dichloromethane. Serum γ-glutamyl transpeptidase activity was elevated in all patients. Regional dilatation of the intrahepatic bile ducts without tumor-induced obstruction was observed in two patients. Four patients developed intrahepatic cholangiocarcinoma and five developed hilar cholangiocarcinoma. Biliary intraepithelial neoplasia and/or intraductal papillary neoplasm of the bile duct was observed in four patients with available operative or autopsy specimens.Conclusions Most of these patients with occupational cholangiocarcinoma exhibited typical findings, including high serum γ-glutamyl transpeptidase activity, regional dilatation of the bile ducts, and precancerous lesions, similar to findings previously reported in 17 occupational cholangiocarcinoma patients in Osaka.
    Journal of Hepato-Biliary-Pancreatic Sciences 11/2014; 21(11). DOI:10.1002/jhbp.137 · 2.31 Impact Factor
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    ABSTRACT: The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here, we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in approximately 15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n = 70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n = 109). Conclusion: This non-invasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease. (Hepatology 2014;).
    Hepatology 11/2014; 60(5). DOI:10.1002/hep.27093 · 11.19 Impact Factor
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    ABSTRACT: Similar to the pancreatic carcinoma sequence model, cholangiocarcinoma reportedly follows a stepwise carcinogenesis process via the precursor lesion biliary intraepithelial neoplasia (BilIN). Given that autophagy plays an important role in the occurrence and development of carcinomas, we examined the involvement of autophagy in multistep cholangiocarcinogenesis. Thirty-six patients with hepatolithiasis associated with BilIN and/or cholangiocarcinoma, 7 with intrahepatic cholangiocarcinoma, 8 with intraductal papillary neoplasm of the bile duct (IPNB) and 6 with control livers were surveyed. Their lesions were categorized as follows: invasive carcinoma (n = 16), IPNB (n = 8), BIlN-3 (n = 16), BilIN-1/2 (n = 40), non-neoplastic large bile duct (LBD) (n = 55) and peribiliary gland (PBG) (n = 55). We examined the immunohistochemical expression of autophagy-related proteins, microtubule-associated proteins light chain 3β (LC3), beclin-1 and p62/sequestosome-1 (p62), as well as tumor suppressor gene product p53. The extent of expression was semiquantitatively assessed. The status of KRAS mutations at codons 12 and 13 was examined in selected cases of BilIN-1/2. The expression of LC3 (cytoplasmic), beclin-1 (cytoplasmic) and p62 (cytoplasmic and nuclear) was significantly higher in BilIN-1/2, BilIN-3, IPNB and invasive carcinoma than in LBD and PBG (p < 0.01). KRAS mutation was detected in 6 of 15 BilIN-1/2 (40%) and there was no correlation between the status of KRAS mutation and the expression of autophagy-related proteins. In conclusion, this study is the first to disclose that the expression of autophagy-related proteins, LC3, beclin-1 and p62, was increased at an early stage of multistep cholangiocarcinogenesis in hepatolithiasis. Autophagy, probably deregulated autophagy, may be related to the occurrence and development of cholangiocarcinoma.
    Human pathology 10/2014; 46(2). DOI:10.1016/j.humpath.2014.09.016 · 2.81 Impact Factor
  • Motoko Sasaki, Yasuni Nakanuma
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    ABSTRACT: A subgroup of intrahepatic cholangiocarcinoma and combined hepatocellular- cholangiocarcinoma contain a component of cholangiolocellular carcinoma, which is composed of small bile ductular cells. Ductular reaction, a reactive lesion at the portal tract interface comprising increased bile ductules, is frequently seen in chronic advanced liver diseases. Bile duct adenoma, a benign tumor/tumorous lesion is also composed of bile ductular cells. Differential diagnosis among these bile ductular tumors/lesions is sometimes difficult. Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile ductular tumors/lesions. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, while it was not observed in bile duct adenomas or ductular reactions. In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas. A borderline between cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a. In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile ductular tumors/lesions.
    Histology and histopathology 10/2014; 30(3). · 2.24 Impact Factor
  • Kenichi Harada, Yasuni Nakanuma
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    ABSTRACT: IgG4-related diseases including IgG4-related sclerosing cholangitis are characterized by the increased level of serum IgG4 and the marked infiltration of IgG4+ plasma cells in affected organs. However, several cases of extrahepatic biliary cancers often accompany the significant infiltration of IgG4+ cells. IL-10 is an important regulatory cytokine associated with the differentiation of IgG4-producing plasma cells and the IgG4 reaction in biliary cancers shows a negative correlation with CD8+ cytotoxic T cells, suggesting that the IgG4 reaction in biliary cancers is associated with the evasion of the tumor-related immune surveillance. Moreover, cancer cells could play a role of regulatory functions by themselves directly and indirectly via a production of IL-10. To clarify the association with IgG4 reaction in the carcinogenesis of cholangiocarcinoma, we examined the IgG4 reaction in its precursor lesion biliary intraepithelial neoplasia (BilIN). Consequently, although a few or none IgG4+ cells were found in BilIN1 and BilIN2 lesions, several or many positive cells were scattered around the large bile ducts showing BilIN3, irrespective of the degree of periductal inflammation. These findings suggest that IgG4 reaction reflects the regulatory cytokine milieu associated with the extrahepatic biliary cancers and also its carcinogenesis, especially the development from BilIN2 to BilIN3.
    Pathology 10/2014; 46 Suppl 2:S23. DOI:10.1097/01.PAT.0000454130.89458.ab · 2.62 Impact Factor

Publication Stats

20k Citations
3,221.30 Total Impact Points


  • 2014–2015
    • Shizuoka Cancer Center
      Sizuoka, Shizuoka, Japan
  • 1979–2015
    • Kanazawa University
      • • School of Medicine
      • • Department of Gastroenterology
      • • Department of Internal Medicine
      Kanazawa, Ishikawa, Japan
  • 1987–2014
    • Kanazawa Medical University
      • • Department of Pathology
      • • Department of Radiology
      Kanazawa, Ishikawa, Japan
  • 2013
    • North Internal Medicine
      Bartlett, Tennessee, United States
    • Osaka City University
      • Department of Hepato-Biliary-Pancreatic Surgery
      Ōsaka, Ōsaka, Japan
  • 2009
    • King's College London
      Londinium, England, United Kingdom
  • 2008
    • Japanese Red Cross
      Edo, Tōkyō, Japan
    • Ishikawa Prefectural Central Hospital
      Ishiza, Okinawa, Japan
  • 2003
    • NHO Nagasaki Medical Center
      Nagasaki, Nagasaki, Japan
  • 1997
    • Tottori University
      • Faculty of Medicine
      Tottori, Tottori-ken, Japan
  • 1993–1997
    • University of California, Davis
      • Division of Rheumatology/Allergy/Clinical Immunology
      Davis, California, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1994
    • Fukui Prefectural University
      Hukui, Fukui, Japan
  • 1986
    • Rancho Los Amigos Rehabilitation Center
      Downey, California, United States