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| 1.
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Kobayashi, Mio ; Kakuda, Yuko ; Harada, Kenichi ; Sato, Yasunori ; Sasaki, Motoko ; Ikeda, Hiroko ; Terada, Mitsuhiro ; Mukai, Munenori ; Kaneko, Shuichi ; Nakanuma, Yasuni ; 小林, 水緒 ; 原田, 憲一 ; 佐藤, 保則 ; 佐々木, 素子 ; 池田, 博子 ; 金子, 周一 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />AIM: To investigate histological and immunohistochemical differences in hepatitis between autoimmune
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hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. METHODS: 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. RESULTS: 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/IgGequal, and IgG-predominant types, with the latter sharing several features with AIH. CONCLUSION: These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
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| 2.
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Onishi, Ichiro ; Kitagawa, Hirohisa ; Harada, Kenichi ; Maruzen, Syogo ; Sakai, Seisyo ; Makino, Isamu ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Takamura, Hiroyuki ; Fujimura, Takashi ; Kayahara, Masato ; Ikeda, Hiroko ; Ohta, Tetsuo ; Nakanuma, Yasuni ; 北川, 裕久 ; 原田, 憲一 ; 牧野, 勇 ; 林, 泰寛 ; 中川原, 寿俊 ; 田島, 秀浩 ; 高村, 博之 ; 藤村, 隆 ; 萱原, 正都 ; 池田, 博子 ; 太田, 哲生 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />We present the first case of an intraductal papillary neoplasm of the bile duct (IPNB) accompanying
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a mixed adenoneuroendocrine carcinoma (MANEC). A 74-yearold woman presented with fever of unknown cause. Laboratory data revealed jaundice and liver injury. Contrast-enhanced computed tomography revealed a 20 mm polypoid tumor in the dilated distal bile duct, which exhibited early enhancement and papillary growth. Upper gastrointestinal endoscopy revealed mucus production from the papilla of Vater, characterized by its protruding and dilated orifice. Endoscopic ultrasonography visualized the polypoid tumor in the distal bile duct, but no invasive region was suggested by diagnostic imaging. Therefore, the initial diagnosis was IPNB. After endoscopic nasobiliary drainage, a pylorus-preserving pancreaticoduodenectomy was performed. Pathological examination of the resected bile duct revealed papillary proliferation of biliary-type cells with nuclear atypia, indicating pancreaticobiliary-type IPNB. In addition, solid portions comprised of tumor cells with characteristic salt-and-pepper nuclei were evident. Immunohistochemistry revealed expression of the neuroendocrine marker synaptophysin in this solid component, diagnosing it as a neuroendocrine tumor (NET). Furthermore, the MIB-1 proliferation index of NET was higher than that of IPNB, and microinvasion of the NET component was found, indicating neuroendocrine carcinoma (NET G3). This unique case of MANEC, comprising IPNB and NET, provides insight into the pathogenesis of biliary NET. © 2013 Baishideng. All rights reserved.
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| 3.
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Wakisaka, Naohiro ; Endo, Kazuhira ; Kitazawa, Tomohiro ; Shimode, Yuzo ; Kato, Koroku ; Moriyama-Kita, Makiko ; Koda, Wataru ; Ikeda, Hiroko ; Ishikawa, Kazuya ; Ueno, Takayoshi ; Nakanishi, Yosuke ; Kondo, Satoru ; Sugimoto, Hisashi ; Yoshimura, Kenichi ; Tsujii, Hiroyuki ; Kawashiri, Shuichi ; Omoto, Kiyoshi ; Yoshizaki, Tomokazu ; 脇坂, 尚宏 ; 遠藤, 一平 ; 加藤, 広禄 ; 喜多, 万紀子 ; 香田, 渉 ; 池田, 博子 ; 石川, 和也 ; 上野, 貴雄 ; 中西, 庸介 ; 近藤, 悟 ; 杉本, 寿史 ; 吉村, 健一 ; 川尻, 秀一 ; 吉崎, 智一
概要:
金沢大学医薬保健研究域医学系<br />Background: In sentinel lymph node (SLN) biopsy for head and neck cancers, the radioisotope method h
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as been the gold standard. However, this method has several problems, such as unavoidable radiation exposure and requirements of expensive equipment. Aims/Objectives: To overcome these problems, we evaluated the contrast-enhanced ultrasonography (CEUS)-guided SLN-detection method, and predicted the SLN metastatic status using novel ultrasound technology, superb microvascular imaging (SMI). Methods: Ten patients (6 with oral and 4 with oropharyngeal cancers) without neck lymph node metastasis were enrolled in this study. Ultrasound contrast agent, Sonazoid ™ , was infiltrated into the mucosa at the primary site to observe the lymphatic ducts and SLNs in the neck field. The detected SLNs were examined for blood flow using SMI to categorize the SLNs metastases-positive or negative. Results: SLNs were successfully detected in 8 out of 10 cases. In 7 out of the 8 cases, in whom SLNs were successfully detected, the metastatic status of SLNs was correctly diagnosed with SMI. Conclusions and significance: Although more clinical data are needed based on a larger cohort, establishing the CEUS-guided SLN-detection and criteria for the accurate diagnosis of SLN-metastases using SMI would be valuable as an alternative to radioisotope method, in oral and oropharyngeal cancers. © 2019, © 2019 Acta Oto-Laryngologica AB (Ltd).<br />Embargo Period 12 months<br /># This study was approved by the Bioethics Committee of Kanazawa University (Nos.2016-037 and 2017-015). The clinical study protocol was explained in detail to patients eligible for the study. Written consent was obtained from all patients who agreed to participate.# This work was supported by a grant-in-aid from The Public Trust Fund For Clinical Cancer Research.
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| 4.
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池田, 博子 ; Ikeda, Hiroko
概要:
近年，日本国民の約2人に1人は生涯のうちにがんに罹患すると推計されている．日本ではがん対策基本法に基づき，癌に対する取り組みが進められている．1990年に始まったヒトゲノム計画ではヒト1人分の全ゲノム解析に，13年の歳月と30億ドルの費用を
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要していたが，目覚ましい技術進歩により，2016年には解析期間は1週間以下にまで短縮し，費用は約1000ドルにまで低廉化してきた．こうした技術革新により，次世代シークエンシング法 (next-generation sequencing; NGS) を用いたゲノム解析が，研究のみならず，患者の診断･治療といった診療にも拡がってきている．政府はがんゲノム医療の計画的な推進を提唱し，2017年には厚生労働省主導のがんゲノム医療推進コンソーシアム懇談会が立ち上げられ，当該医療の推進に必要な薬事承認や保険適用の制度設計などが議論されている1)． 悪性腫瘍の病理組織・細胞検体を用いた体細胞遺伝子検査は急増しており，今後は次世代シークエンシング法 (NGS) などの新規技術を用いたゲノム診断 (遺伝子パネル検査) の臨床導入が見込まれている．日常の病理組織診断では，生検もしくは手術などにより採取･切除された組織のホルマリン固定パラフィン包埋 (formalin-fixed, paraffin-embedded; FFPE) 検体が主として用いられ，形態診断に加え，核酸やタンパクなどの検索を目的とした分子診断に供される．ゲノム解析では生体内環境に近い新鮮検体の利用が望ましいが，現況では治療法選択などにおいて腫瘍の病理診断は必須である．今後は形態診断，免疫組織化学法を用いた分子診断，ゲノム診断，いずれの利用にも耐えうる一定水準以上の病理検体の品質が求められるようになり，病理検査室ではその対応が急務となっている． 本稿では，がんゲノム医療の国内動向と遺伝子パネル検査の現状を概説し，ゲノム診療，研究のための病理組織検体取扱い規定を紹介する．
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| 5.
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Tajima, Hidehiro ; Takamura, Hiroyuki ; Kitagawa, Hirohisa ; Nakayama, Akira ; Shoji, Masatoshi ; Watanabe, Toshifumi ; Tsukada, Tomoya ; Nakanuma, Shinichi ; Okamoto, Koichi ; Sakai, Seisho ; Kinoshita, Jun ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Oyama, Katsunobu ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Miyashita, Tomoharu ; Ninomiya, Itasu ; Fushida, Sachio ; Fujimura, Takashi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Ikeda, Hiroko ; Ohta, Tetsuo ; 田島, 秀浩 ; 高村, 博之 ; 北川, 裕久 ; 中村, 信一 ; 岡本, 浩一 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 尾山, 勝信 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 二宮, 致 ; 若山, 友彦 ; 藤村, 隆 ; 井関, 尚一 ; 池田, 博子 ; 太田, 哲生
概要:
金沢大学医薬保健研究域医学系<br />A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and mult
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iple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved.<br />Embargo Period 6 months
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| 6.
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Sasaki, Motoko ; Ikeda, Hiroko ; Sawada, Seiko ; Sato, Yasunori ; Nakanuma, Yasuni
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金沢大学医薬保健研究域医学系<br />Background: Primary biliary cirrhosis (PBC) is an autoimmune liver disease targeting the intrahepati
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c small bile ducts showing chronic non-suppurative destructive cholangitis (CNSDC). Recent studies suggest that naturally-occurring CD4+CD25high regulatory T cells (Tregs) expressing Forkhead box P3 (Foxp3) play an active role in immunological self-tolerance. Aims: To investigate whether Foxp3+Tregs are involved in the pathogenesis of PBC. Methods: Foxp3+Tregs was detected immunohistochemically in livers from patients with PBC (n = 27), chronic viral hepatitis (CVH) (n = 15), and normal subjects (n = 10). The distribution of Tregs in portal tracts was semi-quantitatively evaluated in each groups. Levels of Foxp3, IL-10, TGFβ, IFNγ and TNFα mRNA was evaluated in PBC (n= 15) and control livers (n = 21) using semi-quantitative reverse transcriptase-PCR. Results: In PBC and CVH livers, the amounts of infiltrating Foxp3+Tregs in portal tracts were in parallel with the degree of portal inflammation irrespective of disease. The infiltration of Foxp3+Tregs into portal tracts with CNSDC in PBC was foremost in comparison with inflamed portal tracts in CVH or those without CNSDC in PBC (p<0.05). Focally, Tregs infiltrated into the biliary epithelial layer at the site of CNSDC. The level of Foxp3, IL-10 and TGFβ mRNA expression was high in PBC compared with normal livers (p<0.05). IFNγ and TNFα mRNA was high in early PBC and CVH livers. Conclusion: Results of this evaluation of Foxp3+Tregs do not suggest that the reduced regulatory function accounts for the development of CNSDC in PBC.
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| 7.
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Harada, Kenichi ; Chiba, Mayumi ; Okamura, Atsushi ; Hsu, Maylee ; Sato, Yasunori ; Igarashi, Saya ; Ren, Xiang Shan ; Ikeda, Hiroko ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Nakanuma, Yasuni
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金沢大学医薬保健研究域医学系<br />Aims: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate
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cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. Copyright Article author (or their employer) 2011.
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| 8.
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Sasaki, Motoko ; Ikeda, Hiroko ; Kataoka, Hiroaki ; Nakanuma, Yasuni
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金沢大学大学院医学系研究科<br />The repair system of damaged biliary mucosa was not fully clarified so far in primary biliary cirrhos
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is (PBC). Given that related factors of the hepatocyte growth factor (HGF) such as HGF activator (HGFA) and HGFA inhibitor type 1 (HAI-1) participate in the repair of injured gastrointestinal mucosa, we investigated the involvement of the HGF/HGFA/HAI-1 system in PBC and control livers. The expression of HGFA, HAI-1, and c-Met was examined in PBC livers (n=24), diseased livers (control, n=30), and normal livers (n=15) by immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction. We examined the expression of HGFA, HAI-1, and c-Met, and the effect of HGF administration on cell proliferation and wound healing, and HAI expression in cultured mouse biliary epithelial cells (BECs). HAI-1 expression was faint in control livers, whereas it was significantly augmented in damaged small bile ducts, bile ductules, and periportal hepatocytes in PBC (p<0.05). HGFA and c-Met were homogeneously expressed in BECs in PBC and control livers. HAI-1 expression was increased at the front of wound healing and the treatment with HGF-enhanced HAI-1 expression, cell proliferation, and wound healing in cultured BECs. HGF/HGFA/HAI-1 system may participate in biliary mucosal repair as reported in gastrointestinal mucosal repair. © Springer-Verlag 2006.
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| 9.
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Sasaki, Motoko ; Ikeda, Hiroko ; Nakanuma, Yasuni ; 佐々木, 素子 ; 中沼, 安二
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金沢大学大学院医学系研究科がん細胞学<br />Mucin secreted by mucosal epithelial cells plays a role in the protection of the mucosal surface
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and also is involved in pathological processes. So far, MUC1-4, 5AC, 5B, 6-8, 11-13 and 15-17 genes coding the backbone mucin core protein have been identified in humans. Their diverse physiological distribution and pathological alterations have been reported. We have studied the expression profiles of MUC genes in the intrahepatic biliary system in developmental, normal and diseased livers using immunohistochemistry and in situ hybridization. Fetal intrahepatic bile ducts and ductal plates frequently express MUC1, while intrahepatic large bile ducts after birth express mainly MUC3 mucin. In hepatolithiasis, MUC5AC (gastric foveolar epithelial type) and MUC6 (pyloric gland type) mucins are newly expressed in surface epithelial cells and proliferated peribiliary glands, respectively, and the expression of gel-forming mucin may play a role in lithogenesis. Most biliary epithelial dysplasias and cholangiocarcinomas associated with hepatolithiasis expressed MUC5AC, suggesting that intrahepatic bile ducts express the gastric foveolar phenotype during carcinogenesis. In addition, intestinal metaplasia, intraductal papillary tumor and mucinous carcinoma, characterized by MUC2 expression, are occasionally associated with hepatolithiasis in a CDX2 homeobox gene-dependent manner. These findings may suggest the presence of intestinal metaplasia-related carcinogenesis in the intrahepatic biliary system as in the stomach.
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| 10.
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Kakuda, Yuko ; Harada, Kenichi ; Sawada-Kitamura, Seiko ; Ikeda, Hiroko ; Sato, Yasunori ; Sasaki, Motoko ; Okafuji, Hirofumi ; Mizukoshi, Eishiro ; Terasaki, Shuichi ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Kaizaki, Yasuharu ; Kaneko, Shuichi ; Nakanuma, Yasuni
概要:
Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) tha
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t takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved.
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