Y Nakanuma

Kanazawa Medical University, Kanazawa, Ishikawa, Japan

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Publications (834)3054.88 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgG-equal, and IgG-predominant types, with the latter sharing several features with AIH. These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.
    World Journal of Gastroenterology 04/2014; 20(13):3597-608. · 2.55 Impact Factor
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    ABSTRACT: BackgroundsCombined hepatocellular-cholangiocarcinoma (cHC-CC), a malignant liver tumor with poor prognosis, is composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and diverse components with intermediate features between HCC and CC, which correspond to hepatic progenitor cells.AimsAccording to the WHO classification 2010, we surveyed the prevalence and clinicopathological significance of each subtype with stem cell features (SC subtype; typical subtype [TS], intermediate cell subtype [INT] and cholangiolocellular type [CLC]) in cHC-CC and HCC.Methods Sixty-two patients with cHC-CC (19 women and 43 men) and 26 patients with HCC (all men) were examined. The prevalence of each component was histologically assessed with assistance of mucin and immunohistochemical stainings.ResultsSC subtypes were observed in all cHC-CCs in various amount and combination. The prevalence of each SC subtype in cHC-CC was as follows; TS, 10 (16.1%); INT, 53 (83.9%); and CLC, 44 (71.0%). The proportion of INT was significantly correlated to gender (female-dominant) (p<0.05), tumor size (p<0.05), histological grading of HCC (p<0.01) and inversely correlated to the degree of stromal fibrosis (p<0.05). The proportion of CLC was significantly correlated to the degree of fibrosis (p<0.01) and inflammation (p<0.01), and inversely correlated to tumor size (p<0.01) and histological grading of HCC (p<0.05). The proportion of TS was significantly inversely correlated to the degree of inflammation (p<0.01). Histological diversity score was significantly correlated to vascular invasion and the positivity for α-fetoprotein.Conclusion The proportion of each SC subtype was significantly associated with certain clinicopathological factors, suggesting different properties of each SC subtypes.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 04/2014; · 3.87 Impact Factor
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    ABSTRACT: Oestrogen has been speculated to play an important role in the pathogenesis of primary biliary cirrhosis (PBC), which mainly affects middle-aged and old-aged females because biliary epithelial cells (BECs) are known to express oestrogen receptors (ERs). Oestrogen-related receptors (ERRs) are constitutively active without oestrogen and competitively inhibit the ER-dependent effects of oestrogen. We clarified the effects of oestrogen and the significance of ERRs along with their association with the pathogenesis of cholangiopathy in PBC. We investigated the expression of ERs and ERRs and the apoptosis-related cell kinetics in BECs using cultured human BECs and human liver specimens. Although cultured human BECs and the interlobular bile ducts in the liver expressed ERβ, in cultured BECs, oestrogen treatment did not induce significant cell proliferation but increased the expression of a negative cell proliferation regulator (14-3-3σ protein). The cultured BECs constantly expressed ERRα and ERRγ, and oestrogen downregulated the ERRγ expression. Furthermore, the ERRγ expression was determined in the intrahepatic bile ducts and was stronger in the middle-aged and old-aged females, particularly those with PBC, than in the younger females. The ERRγ ligand activated a transcription factor, SP1, and enhanced the expression of the pro-apoptotic Bcl-2 family molecules and Bcl-2 inhibitor-induced apoptosis in cultured BECs. Although oestrogen downregulates the ERRγ expression, the increased ERRγ expression under oestrogen-deficient conditions increases the susceptibility to Bcl-2 family-mediated apoptosis in cultured human BECs of females, particularly those with PBC. Understanding the oestrogen-mediated cell kinetics is important for elucidating the pathogenesis of cholangiopathy in PBC.
    Journal of clinical pathology 03/2014; · 2.43 Impact Factor
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    ABSTRACT: Cholangiolocellular carcinoma (CoCC) has distinct pathological characteristics, and CoCC is considered to originate from hepatic progenitor or stem cells. However, the surgical outcome of CoCC has not been clarified in detail. We retrospectively studied 275 patients with intrahepatic cholangiocarcinoma (ICC) who underwent hepatectomy between 1990 and 2011. Surgical outcomes were compared between 29 patients with CoCC and 130 patients with mass-forming (MF) type ICC since all patients with CoCC showed MF type on macroscopic findings. The number of patients with chronic liver disease was significantly higher in the CoCC group than in the ICC group. The number of patients with abnormal levels of CA19-9 was significantly lower in the CoCC group than in the ICC group. Portal vein invasion and intrahepatic metastasis were significantly lower in patients with CoCC group than in the ICC group. In the CoCC group, 15 of 28 patients survived for more than 5 years after curative surgery whereas 15 of 102 patients with ICC survived for more than 5 years after curative surgery. The 5-year survival rate was significantly higher in patients with CoCC (75 %) than in patients with ICC (33 %, p = 0.0005). Multivariate analysis showed CoCC, absence of portal vein invasion or hepatic vein invasion, and absence of intrahepatic metastasis to be significant independent prognostic factors for overall survival in patients with MF-type ICC and CoCC. CoCC is rare, but patients with CoCC had special characteristics with favorable long-term survival due to its less invasive histopathologic characteristics.
    Annals of Surgical Oncology 03/2014; · 4.12 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 02/2014; · 12.00 Impact Factor
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    ABSTRACT: Intrahepatic cholangiocarcinoma arising in chronic advanced liver disease sometimes contains a component of cholangiolocellular carcinoma. Bile duct adenoma, a benign tumor/tumorous lesion and ductular reaction, is also composed of bile ductular cells, and the differential diagnosis is sometimes difficult. We have previously reported that cholangiolocellular carcinoma showed overexpression of a polycomb group protein EZH2, which participates in bypass/escape from cellular senescence during carcinogenesis. In contrast, the ductular reaction showed high expression of senescence-associated p16. In this study, we examined whether immunostaining for EZH2 and p16 is useful for differential diagnosis among cholangiolocellular carcinoma, bile duct adenoma, and ductular reactions. Subjects included 33 patients with intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma with components of cholangiolocellular carcinoma and 16 patients with bile duct adenoma. The expressions of EZH2 and p16 were examined immunohistochemically. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, but it was not observed in bile duct adenomas and ductular reactions, which were seen around carcinomas in 80% of cases. The extensive expression of p16 was seen only in 4 cases of cholangiolocellular carcinomas (12%). In contrast, the expression of p16 was seen in 13 cases (81%) of bile duct adenomas and in all cases of ductular reactions. The borderline between the component of cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16 in 69% of cases. In conclusion, immunostaining for EZH2 and p16 may be useful for differential diagnosis among cholangiolocellular carcinomas, bile duct adenomas, and ductular reactions.
    The American journal of surgical pathology 01/2014; · 4.06 Impact Factor
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    ABSTRACT: A tumorigenic role of peribiliary glands (PBGs) has been suggested recently. This study was performed to clarify the histological characteristics of PBGs showing cystic and micropapillary epithelial changes. From histological sections of a total of 938 autopsy livers, cases with cystic and micropapillary changes of the epithelial cells of intrahepatic PBGs were collected. PBGs with cystic change that lacked micropapillary epithelial changes were referred to as cystic lesion. Mucin staining and immunohistochemical analysis were performed, and the results were compared between cystic and micropapillary (C-P) lesions and cystic lesions. C-P and cystic lesions were observed in 9 (1 %) and 40 (4 %) , respectively. The atypia of micropapillary epithelium was usually mild, but in a single case, invasive adenocarcinoma accompanied a C-P lesion. Abundant mucin expression was observed in all cases of C-P lesion, which was similar to mucinous acini of normal PBGs rather than serous acini. Immunohistochemical analysis showed that MUC5AC was more frequently expressed in C-P lesions than in cystic lesions. Immunohistochemical expression of cyclin D1 and S100P was characteristically found in C-P lesions. Mean Ki-67 labeling index of C-P lesions was significantly higher than that of cystic lesions. The immunoprofile of C-P lesions was similar to that of the branch-type intraductal papillary mucinous neoplasm of the pancreas. These results suggest that C-P lesions may have neoplastic features and might represent a precursor of biliary epithelial neoplasms, including branch-type intraductal papillary neoplasm of the bile duct as well as mucin-producing cholangiocarcinoma, a concept that we have recently proposed.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2014; · 2.68 Impact Factor
  • Yasuni Nakanuma, Yasunori Sato
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    ABSTRACT: Routine experiences suggest that cholangiocarcinomas (CCAs) show different clinicopathological behaviors along the biliary tree, and hilar CCA apparently resembles pancreatic duct adenocarcinoma (PDAC). Herein, the backgrounds for these similarities were reviewed. While all cases of PDAC, hilar CCA, intrahepatic CCA (ICCA) and CCA components of combined hepatocellular-cholangiocarcinoma (cHC-CCA) were adenocarcinomas, micropapillary patterns and columnar carcinoma cells were common in PDAC and hilar CCA, and trabecular components and cuboidal carcinoma cells were common in ICCA and CCA components of cHC-CCA. Anterior gradient protein-2 and S100P were frequently expressed in perihilar CCA and PDAC, while neural cell adhesion molecule and luminal epithelial membrane antigen were common in CCA components of c-HC-CCA. Pdx1 and Hes1 were frequently and markedly expressed aberrantly in PDAC and perihilar CCA, although their expression was rare and mild in CCA components in cHC-CCA and ICCA. Hilar CCA showed a similar postoperative prognosis to PDAC but differed from ICCA and cHC-CCA. Taken together, hilar CCA may differ from ICCA and CCA components of cHC-CCA but have a similar development to PDAC. These similarities may be explained by the unique anatomical, embryological and reactive nature of the pancreatobiliary tract. Further studies of these intractable malignancies are warranted.
    Journal of hepato-biliary-pancreatic sciences. 01/2014;
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    ABSTRACT: Serum antimitochondrial antibodies are characteristic in most patients with primary biliary cirrhosis (PBC); however, the significance of antimitochondrial antibodies in the pathogenesis of PBC remains unclear. We examined the extent and types of mitochondrial protein-expressing inflammatory cells and its association with deregulated autophagy of mitochondria in biliary epithelial lesions in PBC. We examined the expression of pyruvate dehydrogenase complex-E2 component and a mitochondrial protein cytochrome c oxidase, subunit I in inflammatory cells in livers taken from patients with PBC (n=35) and control livers (n=64) including primary sclerosing cholangitis. Mitochondrial protein-expressing inflammatory cells were characterised by double immunofluorescence with surface markers. Infiltration of mitochondrial protein-expressing inflammatory cells was mainly observed in portal tracts and in the biliary epithelial layer and around the damaged small bile ducts in PBC. The extent of infiltration in portal tracts was significantly higher in PBC and early stage of chronic viral hepatitis than normal livers. The extent of infiltration around bile ducts and in biliary epithelial layer was significantly higher in early stage of PBC than control livers. Mitochondrial protein-expressing inflammatory cells included (1) CD68 and/or myeloperoxidase -positive monocytes/macrophages and (2) CD79a, CD38, CD138, IgM-positive and/or IgG-positive plasma cells. Colocalised expression of pyruvate dehydrogenase complex-E2 component and autophagy marker light chain 3β was observed in the inflammatory cells. Mitochondrial protein-expressing inflammatory cells infiltrating around the damaged bile ducts and in biliary epithelial layers may be closely associated with the pathogenesis of bile duct lesion in PBC.
    Journal of clinical pathology 01/2014; · 2.43 Impact Factor
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    ABSTRACT: The polycystic kidney (PCK) rat is an animal model of Caroli's disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte proliferation of the PCK rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell proliferative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell proliferative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell proliferative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat, and inhibition of the pathway can reduce cholangiocyte proliferation via the mechanism involving apoptosis and/or autophagy.
    PLoS ONE 01/2014; 9(1):e87660. · 3.73 Impact Factor
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    ABSTRACT: Adenoviruses are increasingly recognized as important pathogens following allogeneic stem cell transplantation. We herein report two cases of disseminated adenovirus infection that presented with nodular shadows on chest X-ray after allogeneic bone marrow transplantation from unrelated donors. Both patients died of respiratory failure. Autopsies revealed adenovirus infection of multiple organs. Adenovirus infection should be suspected when nodular lung lesions of unknown origin appear in allogeneic stem cell transplant recipients.
    Internal Medicine 01/2014; 53(5):499-503. · 0.97 Impact Factor
  • Yasuni Nakanuma
    Clinics and Research in Hepatology and Gastroenterology. 01/2014; 38(1):e1–e2.
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    ABSTRACT: To investigate the hemodynamics and progression of a hypervascular focus (HF) in a borderline lesion by dual-phase CT during hepatic arteriography (CTHA) and reveal the process of the transformation to hypervascular overt hepatocellular carcinoma (HCC). This study was performed with the approval of our institutional ethics committee, and informed consent for the retrospective usage of clinical materials was obtained from all the patients. The 121 nodules in 76 consecutive patients with liver cirrhosis and chronic hepatitis showing an HF in a borderline lesion on angiography-assisted CT were analyzed. Hemodynamic changes were observed in 24 patients who underwent repeated angiography-assisted CT. Histopathological analysis was conducted in eight nodules. HF was classifiable into type A (stain disappeared), B (stain prolonged), C (stain was washed out and corona-like drainage into the outer nodule was seen) and D (stain was washed out and corona-like drainage into the whole outer nodule was seen) on the late phase of CTHA and was seen to progress in this order on follow-up observation. Histopathologically, de-differentiated foci showed significantly higher expression of sinusoidal capillarization and unpaired arteries than background nodules and showed pseudocapsule, compressive and replacing growth at the border of the background nodule. HF showed multi-step progression and transformation to hypervascular overt HCC.
    Japanese journal of radiology 12/2013; · 0.73 Impact Factor
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    ABSTRACT: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic non-suppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRα) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRα axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRα axis to clarify PDC dysfunction in CNSDC of PBC. The expression of PGC-1α, Bcl-3, ERRα, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). The nuclear expression of PGC-1α, Bcl-3 and ERRα was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reverse-transcription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. In CNSDC of PBC, the activation of the ERRα-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.
    Journal of clinical pathology 11/2013; · 2.43 Impact Factor
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    ABSTRACT: Senescent cells can alter local tissue environments by secretion of various senescence-associated secretory phenotypes (SASP), such as cytokines and chemokines. Given senescent biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show increased expression of chemokines CCL2 and CX3CL1 as SASP, we further examined an involvement of CCL2/CCR2 and CX3CL1/CX3CR1 systems in the pathogenesis of PBC. We examined immunohistochemically the expression of CCR2, CX3CR1, CCL2 and CX3CL1 in livers taken from the patients with PBC (n = 45) and control livers (n = 78), such as chronic viral hepatitis (CVH; n = 39). CCR2 or CX3CR1-expressing cells were characterized by double immunofluorescence with CD3, CD4, CD8, CD56 or CD68. CCR2 is expressed in round cells, epithelioid cells and dendritic cells and most CCR2-positive cells were CD68-positive. Infiltration of CCR2-positive cells in the intraepithelial layer or around small bile ducts was significantly more extensive in PBC than CVH and normal liver (p < 0.05) and was significantly correlated with the expression of CCL2 in BECs (p < 0.01). Most CX3CR1-expressing inflammatory cells were CD3-positive T cells (CD8 > CD4). Infiltration of CX3CR1-positive cells in the intraepithelial layer and around small bile ducts was significantly more extensive in PBC than control livers (p < 0.05) and was significantly correlated with the expression of CX3CL1 in BECs (p < 0.05). CCL2 and CX3CL1 produced by senescent BECs may promote infiltration of corresponding CCR2 and CX3CR1-expressing cells and further aggravate inflammation in bile duct lesion in PBC.
    Digestive Diseases and Sciences 11/2013; · 2.26 Impact Factor
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    ABSTRACT: The biliary tract and pancreas are located closely anatomically, and both develop from the endoderm foregut almost at the same time. Interestingly, the lining epithelia of the bile duct and main pancreatic duct show similar morphologies and phenotypes, and both are accompanied by periductal glands. Furthermore, the exocrine pancreatic acini are remnantly found in the biliary glands. Based on these findings, it seems plausible that the biliary tract has features of pancreatic elements in addition to the duct system, which is specialized for the drainage of bile secreted by hepatic parenchyma, particularly, hepatocytes. Interestingly, some pancreatic and biliary diseases show similar pathological features and even biological behaviors. For example, extrahepatic cholangiocarcinoma and ductal adenocarcinoma of the pancreas share many clinicopathological features. Both of them are hypothesized to arise from similar preneoplastic and early neoplastic intraepithelial lesions. Intraductal papillary tumors, with frequent mucin hyperproduction, develop in the pancreas (intraductal papillary mucinous neoplasm) and also in the biliary tract (intraductal papillary neoplasm of the bile duct). IgG4-related disease affects the biliary tract (IgG4-related sclerosing cholangitis) and autoimmune pancreatitis in the same patients, with both showing similar morphologies. Herein, we propose that these non-neoplastic and neoplastic biliary diseases showing similarities to corresponding pancreatic diseases could be included in a new disease concept "biliary diseases with pancreatic counterparts". Based on this new concept, information obtained in biliary tract diseases could be applied to the analysis of pancreatic disease and vice versa, and also novel therapeutical strategies and molecular and genetic studies on pancreatic and biliary diseases may be developed with a unified approach.
    Histology and histopathology 10/2013; · 2.28 Impact Factor
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    ABSTRACT: A 77-year-old woman complained of epigastralgia, and a tumor (5 cm in diameter) of the gallbladder neck was detected by image analysis. Following cholecystectomy, the tumor was pathologically diagnosed as intraductal papillary neoplasm (IPN), gastric type, with associated invasive carcinoma. About 10 mo later, intraluminal multiple masses (3 foci, up to 1.8 cm) were noted in the extrahepatic bile duct, and the resected specimen showed that all tumors had similar gross and microscopic features as seen in gallbladder IPN without invasion, and they were synchronous multiple lesions. This case showed a papillary tumor of the gallbladder of gastric phenotype, and confirmed that the gallbladder is a target of IPN in addition to the bile ducts.
    World Journal of Gastroenterology 09/2013; 19(36):6125-6126. · 2.55 Impact Factor
  • Kenichi Harada, Yasuni Nakanuma
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    ABSTRACT: Primary biliary cirrhosis (PBC) tends to affect females more than males. PBC selectively damages intrahepatic small bile ducts, particularly interlobular bile ducts. The clinical presentation of PBC has changed according to recent advances in clinicobiological diagnosis and improvements in therapeutic effects and prognosis. In particular, we encounter PBC patients with hepatocellular carcinoma (HCC), and the number of these patients appears to have increased. The precise reason for the increased number of PBC patients with HCC in recent decades remains unknown, but recognizing the current status of carcinogenesis in PBC patients, identifying the associated clinicopathological risk factors, and understanding how the pathogenesis of PBC is directly associated with HCC, is important. In this review, we summarize the data from two nationwide surveys undertaken in Japan as well as recent data from Japanese and international studies.
    Hepatology Research 09/2013; · 2.07 Impact Factor
  • Yasuni Nakanuma
    Gastroentérologie Clinique et Biologique 09/2013; · 0.80 Impact Factor
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    ABSTRACT: Objectives: To examine the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (HC-CC), which the World Health Organization (WHO) proposed classifying into 2 types, and the expression of delta-like 1 homolog (DLK1), as well as putative stem cell markers, such as NCAM/CD56 and CD133. Methods: In this study we examined the expression of stem cell markers using immunohistochemistry. Results: Thirty-six cases of combined HC-CC were subclassified into 24 cases, with more than 5% stem cell features (group B) and 12 cases with less than 5% stem cell areas (group A). The postoperative overall survival rate was worse for group B than for group A. DLK1 was frequently expressed in group B cases compared with group A, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma cases. Conclusions: The 2010 WHO classification seems important for elucidating the pathogenesis of stem cell-related liver cancers.
    American Journal of Clinical Pathology 09/2013; 140(3):329-40. · 2.88 Impact Factor

Publication Stats

14k Citations
3,054.88 Total Impact Points


  • 1987–2014
    • Kanazawa Medical University
      • • Department of Radiology
      • • Department of Gastroenterology
      • • Department of Pathology
      • • Department of Internal Medicine (III)
      Kanazawa, Ishikawa, Japan
  • 1979–2014
    • Kanazawa University
      • • Department of Gastroenterology
      • • Department of Disease Control and Homeostasis
      • • School of Medicine
      • • Department of Radiology
      • • Department of Internal Medicine
      Kanazawa, Ishikawa, Japan
  • 2013
    • North Internal Medicine
      Bartlett, Tennessee, United States
    • Tohoku University
  • 2009–2013
    • King's College London
      • Department of Immunobiology
      Londinium, England, United Kingdom
  • 2012
    • Tokyo Women's Medical University
      • Institute of Gastroenterology
      Edo, Tōkyō, Japan
    • University of Toyama
      • Graduate School of Medicine and Pharmaceutical Science for Education
      Toyama-shi, Toyama-ken, Japan
    • Toyama University
      Kanazawa, Ishikawa, Japan
  • 2008–2012
    • Kyoto Prefectural University of Medicine
      • Graduate School of Medical Science
      Kioto, Kyōto, Japan
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
    • Kyushu University
      • Graduate School of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2011
    • Sungkyunkwan University
      • Department of Radiology
      Seoul, Seoul, South Korea
  • 2004–2011
    • Kyoto University
      • Department of Diagnostic Pathology
      Kyoto, Kyoto-fu, Japan
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
  • 1988–2008
    • Ishikawa Prefectural Central Hospital
      Ishiza, Okinawa, Japan
  • 2006
    • National Cancer Center, Japan
      • Department of Diagnostic Radiology
      Edo, Tōkyō, Japan
  • 2003
    • State University of New York Downstate Medical Center
      • Department of Pathology
      Brooklyn, NY, United States
  • 1993–2002
    • University of California, Davis
      • Division of Rheumatology/Allergy/Clinical Immunology
      Davis, CA, United States
    • University of California, San Francisco
      • Department of Pathology
      San Francisco, CA, United States
  • 1988–1999
    • Nagai Internal Medicine Clinic
      Okayama, Okayama, Japan
  • 1997
    • Tottori University
      • Faculty of Medicine
      Tottori, Tottori-ken, Japan