Yasuni Nakanuma

Shizuoka Cancer Center, Sizuoka, Shizuoka, Japan

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Publications (960)3428.11 Total impact

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    ABSTRACT: On the basis of the similarities in the histopathologic findings and the clinical-biologic behaviors of select biliary and pancreatic conditions, a new disease concept, "biliary diseases with pancreatic counterparts," has been proposed. Both nonneoplastic and neoplastic pathologic conditions of the biliary tract have their counterparts in the pancreas. Immunoglobulin G4 (IgG4)-related sclerosing cholangitis is the biliary manifestation of IgG4-related sclerosing disease, and type 1 autoimmune pancreatitis is its pancreatic counterpart. People with chronic alcoholism can develop peribiliary cysts and fibrosis as well as pancreatic fibrosis and chronic pancreatitis simultaneously. Pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm are considered pancreatic counterparts for the biliary neoplasms of extrahepatic cholangiocarcinoma, intraductal papillary neoplasm of the biliary tract, and hepatic mucinous cystic neoplasm, respectively. The anatomic proximity of the biliary tract and the pancreas, the nearly simultaneous development of both organs from the endoderm of the foregut, and the presence of pancreatic exocrine acini within the peribiliary glands surrounding the extrahepatic bile ducts are suggested as causative factors for these similarities. Interestingly, these diseases show "nearly" identical findings at cross-sectional imaging, an observation that further supports this new disease concept. New information obtained with regard to biliary diseases can be used for evaluation of pancreatic abnormalities, and vice versa. In addition, combined genetic and molecular studies may be performed to develop novel therapeutic targets. For both biliary and pancreatic diseases, imaging plays a pivotal role in initial diagnosis, evaluation of treatment response, efficacy testing of novel drugs, and long-term surveillance. (©)RSNA, 2016.
    No preview · Article · Jan 2016 · Radiographics
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    ABSTRACT: Intraductal papillary neoplasm of bile duct (IPNB) is a papillary tumor covered by well-differentiated neoplastic epithelium with fine fibrovascular cores in the dilated bile ducts. It reportedly shows similarities to intraductal papillary mucinous neoplasm of pancreas (IPMN), to various degrees. Herein, IPNB was pathologically analyzed by classifying 52 cases into four groups based on the histopathological similarities to IPMN: group A (identical to IPMN, 19 cases), group B (similar to but slightly different from IPMN, 18 cases), group C (vaguely similar to IPMN, 5 cases), and group D (different from IPMN, 10 cases). In group A, intrahepatic and perihilar regions were mainly affected, a majority of cases were of low/intermediate or high grade without invasion, and gastric type was the most common phenotype, followed by oncocytic and intestinal types. In groups C and D, perihilar and distal bile ducts were affected, almost all cases were of high grade with invasion, and a majority of them were of intestinal and pancreatobiliary phenotypes. Most group B cases were of intestinal phenotype and all were of high grade with or without invasion. In conclusion, these four groups of IPNB showed unique pathological features and behaviors. Group A cases were less aggressive and shared many features with IPMN, while group C and D cases were more aggressive and mainly found in perihilar and distal bile ducts. Group B resembling IPMN was intermediate between them. This classification may be useful in clinical practice and holds promise for a novel approach to analyze IPNB tumorigenesis.
    No preview · Article · Jan 2016 · Human pathology
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    Full-text · Dataset · Jan 2016
  • Yasuni Nakanuma

    No preview · Article · Jan 2016 · Gastroentérologie Clinique et Biologique
  • Motoko Sasaki · Yasuni Nakanuma
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    ABSTRACT: Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. "Oncogene-induced" and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future.
    No preview · Article · Dec 2015 · Expert review of gastroenterology & hepatology
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    ABSTRACT: Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4+ and CD8+ T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH.
    Preview · Article · Nov 2015 · Scientific Reports
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    ABSTRACT: Background: We aimed to identify the pathological characteristics of occupational cholangiocarcinoma. Methods: We examined the location and distribution of the carcinomas; atypical epithelium including biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB); and chronic bile duct injuries in operative or autopsy liver specimens from 16 patients. We examined the detailed pathological findings and diagnostic imaging of 3 patients. Immunohistochemical analysis using primary antibodies against γH2AX and S100P was performed. Results: BilIN and chronic bile duct injury were observed in 16 patients, and IPNB or invasive IPNB was observed in 11 patients. BilIN, IPNB, and/or chronic bile duct injury were observed in almost all the large bile ducts. Regional dilatation of the bile ducts without tumor-induced obstruction revealed such pathological changes. Highly positive results for the γH2AX and S100P markers were noted in invasive carcinoma, BilIN, and IPNB, whereas positive results for γH2AX and negative results for S100P were noted in non-neoplastic biliary epithelium. Conclusions: The carcinogenic process of occupational cholangiocarcinoma comprised chronic bile duct injury and DNA damage in almost all the large bile ducts, along with induction of precancerous lesions and development of invasive carcinoma. Such pathological findings reflected radiological changes on diagnostic imaging. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Journal of Hepato-Biliary-Pancreatic Sciences
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    ABSTRACT: The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated ( κ = 0.60 ). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C ( p < 0.05 ). While hepatocellular type was coincided in a majority of cases by histological and DDW-J scale evaluation, cholestatic type was not well coincided. In conclusion, biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.
    Preview · Article · Nov 2015 · Mediators of Inflammation
  • Yasuni Nakanuma · Takashi Miyata · Tsuneyuki Uchida
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    ABSTRACT: Cholangiocarcinomas (CCAs) are anatomically classified into intrahepatic, perihilar, and distal types. The gross pathological classification of intrahepatic CCAs divides them into mass-forming, periductal-infiltrating, and intraductal-growth types; and perihilar/distal CCAs into flat- and nodular-infiltrating and papillary types. Unique preinvasive lesions appear to precede individual gross types of CCA. Biliary intraepithelial neoplasia, a flat lesion, precedes periductal-, flat-, and nodular-infiltrating CCAs, whereas intraductal papillary neoplasm of the bile duct (IPNB) precedes the intraductal-growth and papillary type of CCAs. IPNBs are heterogeneous in their histological and pathological profiles along the biliary tree. Hepatobiliary cystadenomas/adenocarcinomas are reclassified as cystic IPNBs and hepatic mucinous cystic neoplasms. Peribiliary glands may participate in the development of CCAs. These latest findings present a new challenge for understanding the pathology of CCAs.
    No preview · Article · Oct 2015 · Expert review of gastroenterology & hepatology
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    Susumu Tazuma · Yasuni Nakanuma
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    ABSTRACT: Background: Hepatolithiasis is a calculus disease of the liver with no known cause that is relatively uncommon, and is characterized by a refractory nature and high frequency of recurrence. Hepatolithiasis is one of the diseases listed by the Ministry of Health, Labour and Welfare of Japan under Research on Intractable Diseases, and it requires further research on the pathogenesis as well as the therapeutic strategy. It is also included in the clinical guidelines for cholelithiasis of the Japanese Society of Gastroenterology, which suggest guiding principles for the treatment of hepatolithiasis. Methods: we performed questionnaire surveys of hepatolithiasis twice in 2010 and in 2012. Verification of the evidence-based clinical practice guidelines a questionnaire survey of 22 facilities in 2010 and 25 facilities in 2012 across Japan that provided cooperation, which enabled us to assess 210 new cases over a two-year period. Conclusions: Comparison with two surveys that have been carried out previously revealed the main factor associated with hepatolithiasis was a history of biliary tract surgery, which was noted in the majority of cases. In addition, there was an increase of patients in whom balloon endoscopy was performed using transduodenal approach. This method is not included in the treatment options of the current clinical guidelines for cholelithiasis, so there may be a need to take it into consideration when the guidelines are revised.
    Preview · Article · Oct 2015 · Lipids in Health and Disease
  • Motoko Sasaki · Yasuni Nakanuma
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    ABSTRACT: This chapter reviews a new type of hepatocellular neoplasm, serum amyloid A-positive hepatocellular neoplasm (SAA-HN), which arises in patients with advanced alcoholic liver disease such as cirrhosis. SAA-HNs share histological and immunohistochemical features with inflammatory hepatocellular adenoma, for example, a strong immunoreactivity for SAA. Clinicopathological features and issues regarding SAA-HN are reviewed with emphasis regarding its potential to develop into hepatocellular carcinoma.
    No preview · Article · Sep 2015 · Digestive Diseases
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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.
    No preview · Article · Sep 2015 · Journal of Gastroenterology
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    ABSTRACT: Intraductal papillary or tubular neoplasms of the bile duct have recently been proposed as one of the pre-invasive lesions of cholangiocarcinoma. Herein, a total of 50 cases of intraluminal polypoid neoplasms of the bile ducts experienced in Khon Kaen University Hospital in Thailand were pathologically examined. These cases presumably had a history of infection of Opisthorchis viverrini. These neoplasms were histologically composed of high-grade intraepithelial neoplasm showing a tubular and/papillary pattern without invasion (20 cases), and with minimal and considerable invasion (15 and 15 cases, respectively). They were histologically classifiable into papillary type (10 cases), tubular type (20 cases) and papillotubular type (20 cases), and were phenotypically classifiable into gastric (17 cases), intestinal (17 cases) and pancreatobiliary types (16 cases). It was found that cases of papillary type and gastric or intestinal phenotype were less invasive, while those of tubular or papillotubular type and pancreatobiliary phenotype were more invasive. In conclusion, intraductal polypoid neoplasms in Thailand were well-differentiated papillary and/or tubular neoplasms including those with no or minimal invasion, and histological and phenotypic subclassifications seem to be useful for evaluation of the aggressive pathological behaviors of these neoplasms.
    No preview · Article · Sep 2015 · International journal of clinical and experimental pathology
  • Motoko Sasaki · Maylee Hsu · Matthew M Yeh · Yasuni Nakanuma
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    ABSTRACT: In biliary epithelial lesions in primary biliary cirrhosis (PBC), mitochondrial proteins associated with deregulated autophagy are abnormally expressed. We examined whether this could be used as a diagnostic marker for end-stage PBC and recurrent PBC after liver transplantation. We examined the expression of the mitochondrial protein pyruvate dehydrogenase complex-E2 component and cytochrome c oxidase, subunit I (CCO), the autophagy-related marker microtubule-associated protein-light chain 3 (LC3), and p62/sequestosome-1 and the senescence markers p16(Ink4a) and p21(WAF1/Cip1) in small bile ducts and bile ductules in explanted livers from patients with PBC (n = 20) in comparison with liver tissue from control patients (n = 21) and post-transplant samples including recurrent PBC and cellular rejection (n = 28). Intense granular expression of mitochondrial proteins was significantly more frequent in small bile ducts in explanted livers with PBC than in control livers (p < 0.05). Post-transplant samples comprised of three groups: group A (positive for mitochondrial proteins, n = 7), group B (positive for either autophagy-related or senescence markers but negative for mitochondrial proteins, n = 7), and group C (all negative, n = 14). All but one case of group A were clinically and histologically diagnosed as recurrent PBC. In contrast, all cases of group B were diagnosed as cellular rejection. This study suggests that the expression of mitochondrial proteins in small bile ducts may be a useful diagnostic marker for end-stage PBC and recurrent PBC after liver transplantation.
    No preview · Article · Aug 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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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.
    Full-text · Article · Jun 2015 · Analytical Chemistry
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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.
    No preview · Article · May 2015 · Clinical Journal of Gastroenterology
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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.
    Full-text · Article · Apr 2015 · Cancer Science
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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.
    Full-text · Article · Mar 2015 · Journal of Hepato-Biliary-Pancreatic Sciences
  • Yasuni Nakanuma · Yuko Kakuda

    No preview · Article · Mar 2015 · Nippon rinsho. Japanese journal of clinical medicine
  • Yasuni Nakanuma · Yuko Kakuda

    No preview · Article · Mar 2015 · Nippon rinsho. Japanese journal of clinical medicine

Publication Stats

26k Citations
3,428.11 Total Impact Points


  • 2014-2015
    • Shizuoka Cancer Center
      Sizuoka, Shizuoka, Japan
  • 1978-2015
    • Kanazawa University
      • School of Medicine
      Kanazawa, Ishikawa, Japan
  • 1980-2014
    • Kanazawa Medical University
      • • Department of Radiology
      • • Department of Gastroenterology
      • • Department of Pathology
      Kanazawa, Ishikawa, Japan
  • 2008
    • Japanese Red Cross
      Edo, Tōkyō, Japan
    • Ishikawa Prefectural Central Hospital
      Ishiza, Okinawa, Japan
  • 1998
    • Virginia Commonwealth University
      • Department of Pathology
      Ричмонд, Virginia, United States
  • 1995-1997
    • University of California, Davis
      • Division of Rheumatology/Allergy/Clinical Immunology
      Davis, California, United States
  • 1996
    • University of California, San Francisco
      San Francisco, California, United States
  • 1994
    • Fukui Prefectural University
      Hukui, Fukui, Japan
  • 1986
    • Rancho Los Amigos Rehabilitation Center
      Downey, California, United States