Papers - akihide Tanimoto

Kitazono Ikumi, Murakami Miki, Takeda Aya, Noguchi Hirotsugu, Tasaki Takashi, Kirishima Mari, Higashi Michiyo, Ueda Kazuhiro, Tanimoto Akihide .  Pulmonary pleomorphic carcinoma: A rare case showing arterial carcinomatosis mimicking pulmonary artery intimal sarcoma(タイトル和訳中) .  Pathology International75 ( 2 ) 114 - 120   2025.2Reviewed

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Yanazume Shintaro, Kobayashi Yusuke, Kirita Yukari, Kitazono Ikumi, Nagata Chikako, Kozai Ayumi, Tanimoto Akihide, Kobayashi Hiroaki .  A potential inflammatory biomarker for advanced endometrial cancer treated with lenvatinib plus pembrolizumab(タイトル和訳中) .  The Journal of Obstetrics and Gynaecology Research51 ( 1 ) jog.16182 - jog.16182   2025.1Reviewed

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Tasaki Takashi, Baba Naoko, Noguchi Hiroyuki, Murakami Miki, Kitazono Ikumi, Higashi Michiyo, Tanimoto Akihide .  A skin biopsy case of Mpox virous infection .  Japanese Journal of Diagnostic Pathology42 ( 2 ) 146 - 149   2025Reviewed

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Language：Japanese   Publisher：The Japanese Society of Pathology  

<p>We report a case of Mpox virus infection in 30s-year-old man.　He had sexual contact with a multiple sex partner one month ago.　He had a fever and skin rash （erythema, papules or pseudopustules） on his chest, forearms, palms, and penis.　Microscopic examination of the skin biopsied specimen from his chest revealed epidermal necrosis with shadow cells, balloon cell degeneration, and exocytosis of neutrophils.　Eosinophilic inclusion bodies were observed in keratinocytes.　A final diagnosis of Mpox virus infection was confirmed by PCR.　As the histopathological features are not specific for Mpox virus infection, it is necessary to interactively diagnose in combination with patient’s history and clinical findings.</p>

DOI： 10.69281/jspjjdp.2024_11_0048

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Tasaki Takashi, Noguchi Hiroyuki, Murakami Miki, Kitazono Ikumi, Higashi Michiyo, Tanimoto Akihide .  A case of pleomorphic adenoma with tyrosine rich crystalloids .  Japanese Journal of Diagnostic Pathology42 ( 3 ) 200 - 203   2025Reviewed

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Language：Japanese   Publisher：The Japanese Society of Pathology  

<p>Pleomorphic adenoma is the most common salivary gland tumor.　Tyrosine-rich crystalloids （TRCs） are rarely seen in the chondromyxoid stromal component of this tumor.　We report a case of pleomorphic adenoma with TRCs in 70s-year-old woman.　The tumor was 65 mm in diameter and located in the right parotid gland.　Microscopic examination revealed numerous floret-like TRCs in abundant myxoid stroma and myoepithelial nests.　TRCs were more clearly observed by Giemsa stain.　TRCs are most frequently seen in pleomorphic adenoma, however, they are also known to be seen in other salivary gland tumors, including malignant tumors, and non-neoplastic tissues.　TRCs should not be a diagnostic clue for pleomorphic adenoma.</p>

DOI： 10.69281/jspjjdp.2025_01_0003

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Nozomi Furuzono, Shinichi Togami, Ikumi Kitazono, Takuro Nishikawa, Akihide Tanimoto, Hiroaki Kobayashi .  Malignant peripheral nerve sheath tumor of the cervix in an adolescent with neurofibromatosis type 1: A case report and review of literature. .  The journal of obstetrics and gynaecology research50 ( 12 ) 2372 - 2376   2024.12Reviewed International journal

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Malignant peripheral nerve sheath tumors (MPNSTs) of the cervix are rare, particularly in patients with neurofibromatosis type 1 (NF1). This report describes a cervical MPNST in an 18-year-old patient with no history of sexual activity, abnormal vaginal discharge, and prolonged menstruation. She had more than six café-au-lait spots on her body since birth and was diagnosed with NF1 at 2 years of age. Positron emission tomography-computed tomography revealed a large pelvic mass and lung and bone metastases. Biopsy confirmed MPNST. Immunohistochemical staining showed diffuse positivity for CD10, approximately 30% positivity for cyclin D1, partial positivity for α-SMA, desmin, and MyoD1, and negativity for myogenin, S-100, and SOX-10. A cancer gene panel identified several genetic abnormalities, but none were actionable mutations. Despite systemic chemotherapy, the tumor progressed rapidly, and the patient died 8 weeks post-admission. Early diagnosis of MPNST is crucial. In patients with NF1, even mild symptoms can indicate MPNST.

DOI： 10.1111/jog.16139

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Furuzono Nozomi, Togami Shinichi, Kitazono Ikumi, Nishikawa Takuro, Tanimoto Akihide, Kobayashi Hiroaki .  Malignant peripheral nerve sheath tumor of the cervix in an adolescent with neurofibromatosis type 1: A case report and review of literature(タイトル和訳中) .  The Journal of Obstetrics and Gynaecology Research50 ( 12 ) 2372 - 2376   2024.12Reviewed

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Nonaka Yuto, Yanagi Masakazu, Sakagami Yuri, Ohnou Nobuhito, Tanimoto Akihide, Ueda Kazuhiro .  A Case of Intravascular Large B-cell Lymphoma That Was Overlooked due to Nonspecific Symptoms During Combination Immunotherapy for Left Upper Lobe Lung Adenocarcinoma .  Haigan64 ( 6 ) 872 - 877   2024.10

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Language：Japanese   Publisher：The Japan Lung Cancer Society  

<p><b><i>Background. </i></b>Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma characterized by selective lymphoma cell growth in the lumina of vessels, mainly capillaries. We report a case of IVLBCL that was overlooked due to nonspecific symptoms during combination immune checkpoint inhibitor (ICI) therapy for lung cancer. <b><i>Case. </i></b>The patient was a 68-year-old man who was on maintenance therapy (pembrolizumab+PEM) for left upper lobe lung adenocarcinoma (cT2a (PL1) N0M1c (bone marrow, spleen) stage IVB). The patient was admitted to hospital with complaints of general fatigue and dyspnea and was treated for immune-related adverse events (irAE) because of pancytopenia and hypothyroidism. However, the symptoms did not improve. Multiple bone marrow punctures were performed to investigate the possibility of malignant lymphoma or recurrent bone marrow metastasis; however, no malignant cells were found. The patient was diagnosed with IVLBCL based on a random skin biopsy. <b><i>Conclusion. </i></b>IVLBCL is a malignant lymphoma that occurs without lymph node enlargement, and which has limited specific findings. Aggressive additional tests are important to distinguish IVLBCL from irAE during the administration of ICI therapy.</p>

DOI： 10.2482/haigan.64.872

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野中 裕斗, 柳 正和, 坂上 友梨, 大納 伸人, 谷本 昭英, 上田 和弘 .  左上葉肺腺癌に対する複合免疫療法中に非特異的所見のため鑑別困難であった血管内大細胞型B細胞リンパ腫の1例 .  肺癌64 ( 6 ) 872 - 877   2024.10Reviewed

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

背景.血管内大細胞型B細胞リンパ腫(intravascular large B-cell lymphoma:IVLBCL)は血管,主に毛細血管内腔でリンパ腫細胞が増殖する節外性大細胞型B細胞リンパ腫の稀なタイプである.今回肺癌に対する免疫チェックポイント阻害薬(immune checkpoint inhibitor:ICI)併用薬物療法中に,鑑別困難であったIVLBCLの1例を経験したので報告する.症例.68歳男性.左上葉肺腺癌(cT2a(PL1)N0M1c(骨髄,脾臓)stage IVB)に対する維持療法中に全身倦怠感・呼吸困難感を認め,入院した.甲状腺機能低下などを認めたため,免疫関連副作用(immune-related adverse events:irAE)として加療するも改善しなかった.悪性リンパ腫や骨髄転移の再発を考慮し複数回骨髄穿刺を行うも悪性細胞は認めず,ランダム皮膚生検でIVLBCLの診断を得た.結論.IVLBCLはリンパ節腫大を認めない,特異的所見が乏しい悪性リンパ腫である.ICI投与中にはirAEとの鑑別に挙げ,積極的な検査の追加が重要である.(著者抄録)

Nayuta Higa, Toshiaki Akahane, Mari Kirishima, Hajime Yonezawa, Ryutaro Makino, Hiroyuki Uchida, Seiya Yokoyama, Tomoko Takajo, Ryosuke Otsuji, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Hitoshi Yamahata, Nobuhiro Hata, Nobutaka Horie, Masamichi Kurosaki, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya .  All-in-one bimodal DNA and RNA next-generation sequencing panel for integrative diagnosis of glioma. .  Pathology, research and practice263   155598 - 155598   2024.9Reviewed International journal

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Previously, we constructed a DNA-based next-generation sequencing (NGS) panel for an integrated diagnosis of gliomas according to the 2021 World Health Organization classification system. The aim of the current study was to evaluate the feasibility of a modified panel to include fusion gene detection via RNA-based analysis. Using this bimodal DNA/RNA panel, we analyzed 210 cases of gliomas and others to identify fusion genes in addition to gene alterations, including TERT promoter (TERTp) mutation and 1p/19q co-deletion, in formalin-fixed paraffin-embedded tissues. Of the 210 patients, fusion genes were detected in tumors of 35 patients. Eighteen of 112 glioblastomas (GBs) harbored fusion genes, including EGFR and FGFR3 fusions. In IDH-mutant astrocytoma, 6 of 30 cases showed fusion genes such as MET and NTRK2 fusions. Eleven molecular GBs and 20 not-elsewhere-classified cases harbored no gene fusions. Other 11 tumors including ependymoma, pilocytic astrocytoma, diffuse hemispheric glioma, infant-type hemispheric glioma, and solitary fibrous tumors exhibited diagnostic fusion genes. Overall, our results suggest that the all-in-one bimodal DNA/RNA panel is reliable for detecting diagnostic gene alterations in accordance with the latest WHO classification. The integrative pathological and molecular strategy could be valuable in confirmation of diagnosis and selection of treatment options for brain tumors.

DOI： 10.1016/j.prp.2024.155598

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Mitsuho Hirahara, Masatoyo Nakajo, Ikumi Kitazano, Megumi Jinguji, Atsushi Tani, Koji Takumi, Kiyohisa Kamimura, Akihide Tanimoto, Takashi Yoshiura .  Usefulness of the Primary Tumor Standardized Uptake Value of Iodine-123 Metaiodobenzylguanidine for Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma. .  Molecular imaging and biology26 ( 6 ) 1005 - 1015   2024.9Reviewed International journal

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PURPOSE: To examine the usefulness of semi-quantitative analysis using the standardized uptake value (SUV) of iodine-123 metaiodobenzylguanidine ([123I]-MIBG) for predicting metastatic potential in patients with pheochromocytoma (PHEO) and paraganglioma (PGL). PROCEDURES: This study included 18 PHEO and 2 PGL patients. [123I]-MIBG visibility and SUV-related parameters (SUVmax, SUVmean, tumor volume of [123I]-MIBG uptake [TV_MIBG], and total lesion [123I]-MIBG uptake) were compared with the pathological grading obtained using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), which are used to predict metastatic potential. The PASS scores were categorized as < 4 and ≥ 4. Based on the GAPP scores, PHEOs/PGLs were categorized as follows: well, moderately, and poorly differentiated tumors. The Mann-Whitney U test or Spearman's rank correlation was used to assess differences or associations between two quantitative variables. RESULTS: All PHEOs/PGLs were visualized on [123I]-MIBG scintigraphy. There were 16 PASS < 4 and 4 PASS ≥ 4 tumors. Moreover, 11 and 9 tumors were well and moderately differentiated, respectively. The uptake scores and SUV-related parameters significantly differed between tumors with a PASS score of < 4 and those with a PASS score of ≥ 4 (each, p > 0.05). Moderately differentiated tumors had significantly higher uptake scores and SUV-related parameters except TV_MIBG than well-differentiated tumors (each, p < 0.05). The GAPP score was positively correlated with the uptake scores and SUV-related parameters (each, p < 0.05) except TV_MIBG. CONCLUSIONS: The primary tumor [123I]-MIBG uptake assessed using SUV-related parameters can be an imaging tool for predicting metastatic potential in patients with PHEO/PGL.

DOI： 10.1007/s11307-024-01952-8

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Yuki Tanaka, Manabu Natsumeda, Masayuki Ohashi, Rie Saito, Nayuta Higa, Toshiaki Akahane, Hideki Hashidate, Junko Ito, Satoshi Fujii, Atsushi Sasaki, Akihide Tanimoto, Ryosuke Hanaya, Kei Watanabe, Makoto Oishi, Hiroyuki Kawashima, Akiyoshi Kakita .  Primary spinal cord gliomas: Pathologic features associated with prognosis. .  Journal of neuropathology and experimental neurology83 ( 12 ) 1010 - 1019   2024.7Reviewed International journal

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Primary spinal cord gliomas are rare and are associated with high mortality. Unlike brain tumors, the clinicopathological features of spinal cord gliomas are not well defined. We analyzed clinical, histopathology, and immunohistochemical features and overall survival (OS) of 25 patients with primary spinal cord gliomas treated between 1994 and 2023 at 4 institutions. IDH1 R132H, H3K27M, and p53 were assessed by immunohistochemistry (IHC). Four (16%), 5 (20%), 2 (8%), and 13 (52%) patients were diagnosed as having grades 1, 2, 3, and 4 gliomas according to the World Health Organization (WHO) 2021 classification, respectively. One case (4%), with a circumscribed diffuse midline glioma, H3K27-altered, had a rare molecular profile and could not be graded. IHC demonstrated H3K27M positivity, indicative of H3F3A K27M or HIST1H3B K27M mutation, in 9 (36%) patients. H3K27me3-loss was evident in 13 (52%) patients. In one patient with a grade 1 tumor that showed negative staining for H3K27M and H3K27me3 loss, numbers of EZHIP-positive cells were increased, suggesting diffuse midline glioma, H3K27-altered (WHO grade 4). H3K27me3 loss, frequency of p53 positive cells (≥10%), MIB-1 index (≥10%), and high histopathological grades significantly correlated with poor OS. These results indicate the pathological and immunohistochemical characteristics of primary spinal cord gliomas that impact prognosis.

DOI： 10.1093/jnen/nlae084

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寺原 航, 田崎 貴嗣, 霧島 茉莉, 北薗 育美, 村上 未樹, 田畑 和宏, 東 美智代, 野元 祐輔, 白濱 浩, 谷本 昭英 .  第2期梅毒疹の2症例 .  診断病理41 ( 3 ) 281 - 285   2024.7Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

症例1は30代男性,頭痛と全身に1cm大の紅斑や丘疹を認めた。症例2は30代女性,後頸部や両手掌,外陰に2cm大までの鱗屑を伴う紅斑や丘疹を認めた。皮膚生検ではいずれも過角化,不全角化と表皮内の好中球浸潤,基底層の空胞変性,真皮浅層から深層におよぶリンパ球,形質細胞や好中球の浸潤を認めた。免疫組織化学的にT.pallidumの菌体を認め,第2期梅毒と診断した。単一の炎症性皮膚疾患のカテゴリーに入れ難い,多彩な組織像を呈する皮疹には,第2期梅毒を鑑別することが重要である。(著者抄録)

寺原 航, 田崎 貴嗣, 霧島 茉莉, 北薗 育美, 村上 未樹, 田畑 和宏, 東 美智代, 谷本 昭英 .  Low grade non-intestinal-type sinonasal adenocarcinomaの1例 .  診断病理41 ( 3 ) 255 - 259   2024.7Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

症例は30代男性。左鼻腔を充満し鼻中隔に基部を持つ有茎性病変を認めた。組織学的には,異型に乏しい類円形核を有する腫瘍細胞がback-to-back構造を示す小型の腺管を形成して密に増殖しており,間質の介在はわずかであった。腫瘍細胞はCK7,S-100,SOX10にびまん性に陽性,CDX2が部分的に陽性,DOG-1は管腔内側を縁取る陽性像を認め,low grade non-intestinal-type sinonasal adenocarcinomaと診断した。本腫瘍は鼻腔・副鼻腔に発生する稀な腫瘍であり,腺房細胞癌,漿粘液腺過誤腫などが鑑別となるが,いずれも鼻腔内でポリープ状を呈するため,組織学的検索により鑑別することが重要である。(著者抄録)

霧島 茉莉, 村上 未樹, 野口 紘嗣, 田崎 貴嗣, 北薗 育美, 田畑 和宏, 東 美智代, 谷本 昭英 .  上縦隔進展と左胸腔への突出を伴う脊髄血管芽腫の1例 .  診断病理41 ( 3 ) 267 - 273   2024.7Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

血管芽腫は腫瘍性間質細胞と豊富な血管からなる腫瘍である。縦隔進展を伴う稀な脊髄血管芽腫を経験したので報告する。70代女性で,胸髄から上縦隔へ進展し,左胸腔へ突出するダンベル型腫瘤を認めた。組織学的には淡明な細胞質を有する腫瘍細胞のシート状配列と豊富な血管網を認め,免疫組織化学的に腫瘍細胞はα-inhibinとS100蛋白に陽性であった。稀ではあるが縦隔や胸腔に及ぶ脊髄腫瘍の鑑別に血管芽腫を挙げることは重要であり,脊髄血管芽腫ではvon Hippel-Lindau病の精査と経過観察が必要である。(著者抄録)

中島 真由美, 秋山 大成, 高浪 浩太, 徳村 祐太, 槌田 紋子, 南新 洋美, 中村 敬夫, 東 美智代, 谷本 昭英 .  神経内分泌腫瘍との鑑別が困難であった肺原発悪性黒色腫の1例 .  日本臨床細胞学会九州連合会雑誌55   37 - 40   2024.7Reviewed

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 肺の悪性黒色腫のほとんどは他臓器からの転移であり,肺原発の症例は極めて稀である.今回,神経内分泌腫瘍との鑑別に苦慮した肺原発悪性黒色腫の一例を経験したので報告する.症例 80代,男性.右肺上葉の充実性結節に対して気管支鏡検査が施行された.気管支洗浄細胞診では,粗顆粒状の核クロマチンを有する裸核状の小型異型細胞集塊を認めた.核小体は目立たず,索状やロゼット様の配列と思われる部分を認め,神経内分泌腫瘍が示唆された.異型細胞の内外に褐色色素を散見し,核内封入体を有する異型細胞も認められた.気管支生検では,大小不同の目立つ類円形核と広い胞体を有した腫瘍細胞を認めた.免疫組織化学では,HMB-45およびMelan A陽性であり悪性黒色腫と診断した.全身検索の結果,原発巣を示唆する部位は他に認められず,肺原発の悪性黒色腫と考えられた.結語 メラニン顆粒などの色素顆粒を鑑別し,顆粒含有細胞の形態を注意深く観察することで,特徴的な細胞所見に乏しい症例においても,悪性黒色腫を鑑別診断に挙げることが可能であると考えられた.(著者抄録)

Ikumi Kitazono, Toshiaki Akahane, Hiromi Sasaki, Yasuyo Ohi, Yoshiaki Shinden, Tomoko Takajo, Takashi Tasaki, Michiyo Higashi, Hirotsugu Noguchi, Masanori Hisaoka, Akihide Tanimoto .  Malignant phyllodes tumor with EGFR variant III mutation: A rare case report with immunohistochemical and genomic studies. .  Pathology, research and practice259   155389 - 155389   2024.7Reviewed International journal

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A female in her 60's presented with a left-sided breast mass. A core needle biopsy specimen showed diffuse proliferation of a round cell tumor, which was positive for vimentin, NKX2.2, BCOR, and focal CD99 on immunohistochemistry (IHC). No fusion genes of the Ewing family sarcomas were detected. With a tentative diagnosis of primary breast sarcoma (PBS), total mastectomy was performed after chemotherapy. The resected tissues showed proliferation of round or spindle-shaped tumor cells with a high nuclear-to-cytoplasmic ratio, exhibiting solid and fascicular arrangements but no epithelial component or organoid pattern. While IHC indicated no particular histological diagnosis, genomic examination revealed gene alterations in MED12 p.G44D, MLL2 (KMT2D) p.T1496fs*27, and EGFR variant III (vIII). Moreover, a retrospective IHC study showed overexpression of EGFRvIII. A malignant phyllodes tumor (PT) with extensive sarcomatous overgrowth was indicated as an integrative diagnosis. This is a rare case of a malignant PT harboring EGFRvIII. The present case provides an importance of accurate diagnosis and genomic analysis of rare breast tumors, as malignant PT and PBS are different in its treatment strategy and prognosis.

DOI： 10.1016/j.prp.2024.155389

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Lynne Takada, Takafumi Kawano, Keisuke Yano, Yumiko Iwamoto, Masato Ogata, Chihiro Kedoin, Masakazu Murakami, Koshiro Sugita, Shun Onishi, Mitsuru Muto, Mari Kirishima, Akihide Tanimoto, Satoshi Ieiri .  Ovarian endometrioma: a report of a pediatric case diagnosed prior to menstruation. .  Surgical case reports10 ( 1 ) 152 - 152   2024.6Reviewed International journal

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BACKGROUND: Ovarian endometriomas (OEs) are rarely found in the pediatric population, especially before menstruation. We report a 6-year-old girl who was postoperatively diagnosed with OE before menstruation. CASE PRESENTATION: A 6-year-old girl presented to a local pediatrician with abdominal pain and vomiting. Abdominal ultrasonography revealed a multilocular cystic lesion to the left of the bladder. Magnetic resonance imaging (MRI) revealed similar findings, with the contents of the cyst showing a low signal on T1-weighted imaging and a high signal on T2-weighted imaging. The patient was referred to our institution for further examination. Enhanced computed tomography (CT) showed a multilocular cystic lesion sized 56 × 44 × 30 mm with partial calcification. The left ovarian vein was dilated, suggesting the origin of the tumor to be the left ovary. Extirpation of the lesion was performed under laparoscopic assistance. Pathological findings indicated an ovarian endometrioma. To our knowledge, this is the youngest report of an OE diagnosed in a patient prior to menstruation. CONCLUSIONS: OEs in children before menstruation are extremely rare; thus, the long-term prognosis is yet to be determined.

DOI： 10.1186/s40792-024-01951-5

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Takada Lynne, Kawano Takafumi, Yano Keisuke, Iwamoto Yumiko, Ogata Masato, Kedoin Chihiro, Murakami Masakazu, Sugita Koshiro, Onishi Shun, Muto Mitsuru, Kirishima Mari, Tanimoto Akihide, Ieiri Satoshi .  Ovarian endometrioma: a report of a pediatric case diagnosed prior to menstruation(タイトル和訳中) .  Surgical Case Reports10   s40792 - 024   2024.6Reviewed

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Language：English   Publisher：Springer Berlin Heidelberg  

Hideyuki Oi, Yuto Hozaka, Toshiaki Akahane, Kosuke Fukuda, Tetsuya Idichi, Kiyonori Tanoue, Yoichi Yamasaki, Yota Kawasaki, Yuko Mataki, Hiroshi Kurahara, Michiyo Higashi, Akihide Tanimoto, Takao Ohtsuka .  Genetic assessment of IPMN for predicting concomitant pancreatic ductal adenocarcinoma. .  Pancreas53 ( 10 ) e790 - e795   2024.5Reviewed International journal

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OBJECTIVE: Krüppel-like transcription factor 4(KLF4) mutations are more frequently observed in low-grade lesions than in high-grade lesions of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. However, the role of KLF4 mutations in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study clarified the rate and effect of KLF4 mutations in IPMN with concomitant PDAC. METHODS: DNA was extracted from 65 formalin-fixed and paraffin-embedded samples from 52 patients including 13 IPMN with concomitant PDAC and 39 IPMN alone. A comprehensive screening was performed using next-generation sequencing (NGS) for the 5 IPMNs with concomitant PDAC and 5 IPMNs alone, followed by targeted sequencing for KLF4, GNAS, and KRAS mutations. RESULTS: In NGS screening, KRAS mutations were observed in all samples except for one, GNAS mutation in two IPMNs with concomitant PDAC, and a KLF4 mutation in one IPMN with concomitant PDAC. Targeted sequence detected KLF4 mutations in 11 of the 52 IPMNs. Concomitant PDAC developed only in the non-intestinal, non-invasive, and branch duct IPMN cases, and KLF4 mutations were more frequent in this IPMN type than in the other type (36% vs. 10%, p = 0.04). For this IPMN type with KLF4 mutation, PDAC-prediction sensitivity, specificity, and accuracy were 63%, 82%, and 79%, respectively. CONCLUSION: For selected IPMNs with non-intestinal, non-invasive, and branch duct, genetic assessment might be a helpful tool for predicting the possible development of concomitant PDAC, although a prospective validation study using a larger study population is needed.

DOI： 10.1097/MPA.0000000000002373

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大西 俊平, 山崎 文之, Jeet Amatya Vishwa, 米澤 潮, 比嘉 那優大, 赤羽 俊章, 谷本 昭英, 武島 幸男, 花谷 亮典, 堀江 信貴 .  Astrocytoma,IDH-mutant with primitive neuronal componentの一例 .  Brain Tumor Pathology41 ( Suppl. ) 146 - 146   2024.5Reviewed

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赤羽 俊章, 比嘉 那優大, 霧島 茉莉, 米澤 大, 牧野 隆太郎, 内田 裕之, 山本 淳考, 吉本 幸司, 花谷 亮典, 谷本 昭英 .  WHO新分類(WHO2021)の課題とその克服2:脳腫瘍病理形態診断と分子診断の融合の可能性 脳腫瘍診断用カスタムパネルによるNot Elsewhere Classified(NEC)の再分類 .  Brain Tumor Pathology41 ( Suppl. ) 088 - 088   2024.5Reviewed

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比嘉 那優大, 赤羽 俊章, 米澤 大, 横山 勢也, 牧野 隆太郎, 内田 裕之, 霧島 茉莉, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  WHO新分類(WHO2021)の課題とその克服2:脳腫瘍病理形態診断と分子診断の融合の可能性 グリオーマに特化したカスタムDNA/RNAパネルを用いたクリニカルシーケンス .  Brain Tumor Pathology41 ( Suppl. ) 087 - 087   2024.5Reviewed

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牧野 隆太郎, 比嘉 那優大, 赤羽 俊章, 米澤 大, 内田 裕之, 高城 朋子, 霧島 茉莉, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  WHO新分類(WHO2021)の課題とその克服1:脳腫瘍病理形態診断と分子診断の融合の可能性 Molecular Glioblastomaの臨床学的特徴 .  Brain Tumor Pathology41 ( Suppl. ) 076 - 076   2024.5Reviewed

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霧島 茉莉, 寺原 航, 村上 未樹, 北薗 育美, 信澤 純人, 米永 理法, 中川 俊輔, 上村 清央, 義岡 孝子, 谷本 昭英 .  EWSR1::BEND2融合遺伝子を有する脊髄/脳幹Astroblastomaの1例 .  診断病理41 ( 2 ) 145 - 151   2024.4Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

Astroblastomaは大脳に好発する境界明瞭なグリア系腫瘍で,WHO分類第5版ではAstroblastoma,MN1-alteredとして記載されている。脊髄や脳幹のAstroblastomaはMN1再構成ではなくEWSR1::BEND2融合遺伝子を有する頻度が高い。6歳女児の頸髄から延髄に境界明瞭で嚢胞変性を伴う腫瘍を認めた。組織学的には,血管壁や間質の硝子化を伴って腫瘍細胞がastroblastic pseudorosetteや偽乳頭状構造を示して増殖し,免疫組織化学ではEMA,GFAP,Olig2陽性を示し,Fluorescence in situ hybridizationでEWSR1::BEND2融合遺伝子を確認した。大脳のAstroblastomaと異なる融合遺伝子を有する稀な脊髄/脳幹のAstroblastomaの診断にはependymomaやpiloytic astrocytoma等の鑑別と共に,特徴的なEWSR1::BEND2融合遺伝子の検索が重要である。(著者抄録)

霧島 茉莉, 寺原 航, 村上 未樹, 北薗 育美, 信澤 純人, 米永 理法, 中川 俊輔, 上村 清央, 義岡 孝子, 谷本 昭英 .  EWSR1::BEND2融合遺伝子を有する脊髄/脳幹Astroblastomaの1例 .  診断病理41 ( 2 ) 145 - 151   2024.4Reviewed

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Astroblastomaは大脳に好発する境界明瞭なグリア系腫瘍で,WHO分類第5版ではAstroblastoma,MN1-alteredとして記載されている。脊髄や脳幹のAstroblastomaはMN1再構成ではなくEWSR1::BEND2融合遺伝子を有する頻度が高い。6歳女児の頸髄から延髄に境界明瞭で嚢胞変性を伴う腫瘍を認めた。組織学的には,血管壁や間質の硝子化を伴って腫瘍細胞がastroblastic pseudorosetteや偽乳頭状構造を示して増殖し,免疫組織化学ではEMA,GFAP,Olig2陽性を示し,Fluorescence in situ hybridizationでEWSR1::BEND2融合遺伝子を確認した。大脳のAstroblastomaと異なる融合遺伝子を有する稀な脊髄/脳幹のAstroblastomaの診断にはependymomaやpiloytic astrocytoma等の鑑別と共に,特徴的なEWSR1::BEND2融合遺伝子の検索が重要である。(著者抄録)

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比嘉 那優大, 赤羽 俊章, 米澤 大, 横山 勢也, 牧野 隆太郎, 内田 裕之, 霧島 茉莉, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  脳腫瘍1 小児脳腫瘍におけるカスタムDNA/RNAパネルを用いたクリニカルシーケンス .  小児の脳神経49 ( 2 ) 168 - 168   2024.4Reviewed

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Takuya Yoshimura, Yuka Hirano, Taiji Hamada, Seiya Yokoyama, Hajime Suzuki, Hirotaka Takayama, Hirono Migita, Takayuki Ishida, Yasunori Nakamura, Masahiro Ohsawa, Akihiro Asakawa, Kiyohide Ishihata, Akihide Tanimoto .  Exercise Suppresses Head and Neck Squamous Cell Carcinoma Growth via Oncostatin M. .  Cancers16 ( 6 )   2024.3Reviewed International journal

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Major advances have been made in cancer treatment, but the prognosis for elderly cancer patients with sarcopenia and frailty remains poor. Myokines, which are thought to exert preventive effects against sarcopenia, have been reported to be associated with the prognosis of various cancers, but their effect on head and neck squamous cell carcinoma (HNSCC) is unknown. The aim of this study was to clarify the influence of exercise on the control of HNSCC and to examine the underlying mechanism involved. Mice were injected with HSC-3-M3 cells, a human cell line of highly metastatic and poorly differentiated tongue cancer, at the beginning of the study. Just prior to transplantation, blood was collected from the mice, and the levels of myokines were measured by ELISA. Oncostatin M (OSM), a selected myokine, was added to HSC-3-M3 cells, after which the cell proliferation ability, cell cycle, and protein expression were analyzed in vitro. Tumor cell viability was lower (control: 100%, exercise: 75%), tumors were smaller (control: 26.2 mm3, exercise: 6.4 mm3), and survival was longer in the exercise group than in the control group in vivo. OSM inhibited HSC-3-M3 cell proliferation in a concentration-dependent manner in vitro. The addition of OSM increased the proportion of cells in the G0/G1 phase, decreased the proportion of cells in the G2/M phase, and increased the expression of the CDK inhibitors p21 and p27. These results indicate that exercise may directly inhibit the proliferation of HNSCC cell lines via OSM.

DOI： 10.3390/cancers16061187

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Seiya Yokoyama, Kei Matsuo, Akihide Tanimoto .  Methylation-Specific Electrophoresis .  Methods in Molecular Biology2763   259 - 268   2024.2Reviewed International journal

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Methylation of CpG sites in the promoter region of genomic DNA is an important epigenetic modification that plays a critical role in gene regulation, particularly in gene silencing. Epigenetic abnormalities, along with genetic alterations, are implicated in carcinogenesis and cancer progression. Numerous studies have investigated the role of epigenetics in cancer using various tools to assess DNA methylation. However, conventional analysis methods for DNA methylation require a large amount of DNA but lack higher sensitivity, making them unsuitable for analysis of samples with high heterogeneity, such as tumor tissues. In this study, we introduce a novel electrophoresis method named "methylation-specific electrophoresis (MSE)," which utilizes a denaturing gradient acrylamide gel. We demonstrate the applicability of the MSE method for DNA methylation analysis of the mucin gene as an example.

DOI： 10.1007/978-1-0716-3670-1_22

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霧島 茉莉, 赤羽 俊章, 横山 勢也, 比嘉 那優大, 米澤 大, 内田 裕之, 花谷 亮典, 吉本 幸司, 谷本 昭英 .  膠芽腫の細胞形態とゲノム変化による予後推定の試み .  日本病理学会会誌113 ( 1 ) 435 - 436   2024.2Reviewed

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保坂 優斗, 福田 皓祐, 内野 祥徳, 後藤 雄一, 大井 秀之, 佐竹 霜一, 伊地知 徹也, 山崎 洋一, 田上 聖徳, 川崎 洋太, 又木 雄弘, 蔵原 弘, 東 美智代, 谷本 昭英, 杉浦 剛, 大塚 隆生 .  【膵癌基礎研究の最前線RELOADED】膵管内乳頭粘液性腫瘍の腫瘍内細菌叢の病的意義 .  胆と膵45 ( 2 ) 189 - 196   2024.2Reviewed

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Language：Japanese   Publisher：医学図書出版(株)  

膵臓は元来,腸内細菌叢(マイクロバイオータ)とは無縁と考えられていたが,近年の研究で腸内細菌や真菌が膵内に移行すること,膵癌の腫瘍内には活発な細菌が豊富に存在すること,腫瘍内細菌叢が局所の免疫機能を抑制することで癌の増殖と進展を促進していることが明らかとなった。われわれは膵癌の危険因子の一つである膵管内乳頭粘液性腫瘍(intraductal papillary mucinous neoplasm:IPMN)の発生や進展にも腫瘍内細菌叢が関与しているという仮説を立てて,IPMNの腫瘍内細菌叢を調査し,腫瘍内細菌叢が腫瘍と宿主に及ぼす影響について検証した。その結果を踏まえてIPMNにおける腫瘍内細菌叢の病的意義について概説する。(著者抄録)

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有馬 直佑, 藤崎 真由, 中別府 聖一郎, 島 晃大, 林田 真衣子, 鎌田 勇平, 中村 大輔, 吉満 誠, 橋口 照人, 東 美智代, 谷本 昭英, 大島 孝一, 石塚 賢治 .  抗レトロウイルス療法による免疫再構築により消失したHIV関連EBV陽性粘膜皮膚潰瘍 .  臨床血液65 ( 1 ) 13 - 17   2024.1Reviewed

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

症例は24歳男性。倦怠感や体重減少の精査のため実施した下部消化管内視鏡検査で回盲部潰瘍を認め,生検でびまん性大細胞型B細胞リンパ腫と診断された。その後の精査中にニューモシスチス肺炎を併発し,後天性免疫不全症候群(AIDS)の合併が判明した。回盲部潰瘍以外に明確な病変はなく,生検組織のin situ hybridization法により腫瘍細胞はEpstein-Barr encoding region(EBER)がびまん性に強陽性であったため,EBV陽性粘膜皮膚潰瘍(EBVMCU)と診断した。免疫再構築により病変が改善することを期待し,抗レトロウイルス療法(ART)を開始した。ART開始79日後には回盲部潰瘍の完全消失を確認し,その後3年以上にわたって寛解を維持している。EBVMUCは種々の免疫抑制状態を背景に発症することが知られておりAIDSもその一つであるが,ARTによる免疫再構築によってEBVMCUが寛解に至った初めての報告である。(著者抄録)

ARIMA Naosuke, FUJISAKI Mayu, NAKABEPPU Seiichiro, SHIMA Kodai, HAYASHIDA Maiko, KAMADA Yuhei, NAKAMURA Daisuke, YOSHIMITSU Makoto, HASHIGUCHI Teruto, HIGASHI Michiyo, TANIMOTO Akihide, OHSHIMA Kouichi, ISHITSUKA Kenji .  Spontaneous regression of HIV-associated EBV-positive mucocutaneous ulcer due to immune reconstruction with antiretroviral therapy .  Rinsho Ketsueki65 ( 1 ) 13 - 17   2024Reviewed

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Hematology  

<p>A 24-year-old man was found to have an ileocecal ulcer by colonoscopy. A pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) with diffuse positive reaction of Epstein-Barr encoding region (EBER) by <i>in situ</i> hybridization was made based on analysis of the specimen. Acquired immunodeficiency syndrome (AIDS) complicated by pneumocystis jirovecii pneumonia was also diagnosed. As no other significant lymphomatous lesions were identified by further examination, a clinical diagnosis of EBV-positive mucocutaneous ulcer (EBVMCU) was made. Rather than performing systemic chemotherapy, the lesion was closely monitored and antiretroviral therapy (ART) for AIDS was started with the hope of treating the lesion through immune reconstitution. The lesion had completely disappeared by day 79 after starting ART, and has not recurred for over 3 years. EBVMCU is known to develop secondary to various immunosuppressive states including AIDS. Here we report a rare case of EBVMCU detected at diagnosis of AIDS that entered complete remission after immune reconstitution by ART.</p>

DOI： 10.11406/rinketsu.65.13

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Tomonobu Yamada, Hiroaki Kawaguchi, Aki Matsuoka, Kohei Akioka, Naoki Miura, Hiroyuki Izumi, Akihide Tanimoto .  Development of a Microminipig Model of Atherosclerosis for the Evaluation of a HMGCR Inhibitor. .  In vivo (Athens, Greece)38 ( 1 ) 98 - 106   2024Reviewed International journal

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BACKGROUND/AIM: Atherosclerosis is known as a major risk factor for cardiovascular disease, and development of an animal model of atherosclerosis is required to investigate its clinical pathogenesis. We studied the optimal amount of cholesterol in the diet and the optimal experimental period for development of a Microminipig model of atherosclerosis for the evaluation of a hydroxymethylglutaryl-CoA reductase (HMGCR) inhibitor (atorvastatin). MATERIALS AND METHODS: Eighteen male animals (3-4 months old) were divided into 3 groups. Group 1 consisted of control animals receiving a normal chow diet, Group 2 animals received a high fat (12% w/w) and low cholesterol (0.1% w/w) diet (HFLCD), and Group 3 animals received HFLCD+statin for 12 weeks. Animals received statin at 3 mg/kg body weight per day. HFLCD did not down-regulate the hepatic expression of HMGCR mRNA. RESULTS: HFLCD increased body, omentum, and mesenteric adipose tissue weight, and induced hypercholesterolemia and atherosclerotic lesions in the abdominal aorta. HFLCD+statin inhibited hypercholesterolemia and atherosclerotic lesions, but not obesity. CONCLUSION: A microminipig atherosclerosis model induced by HFLCD can be used in the evaluation of HMGCR inhibitors for the treatment of hypercholesterolemia and atherosclerosis.

DOI： 10.21873/invivo.13415

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Ikumi Kitazono, Toshiaki Akahane, Seiya Yokoyama, Emi Kubota, Yukari Nishida-Kirita, Hirotsugu Noguchi, Miki Murakami, Shintaro Yanazume, Hiroaki Kobayashi, Akihide Tanimoto .  Cervical Cytology Preserves Histologically Detected Surface Epithelial Slackening, Unique to the POLE Mutation-subtype in Endometrial Cancer. .  In vivo (Athens, Greece)38 ( 1 ) 321 - 333   2024Reviewed International journal

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BACKGROUND/AIM: Among the four genomic subtypes of endometrial cancer, distinguishing between the DNA polymerase epsilon mutation (POLEmut) and no specific molecular profile (NSMP) subtypes requires genomic profiling owing to the lack of surrogate immunohistochemical markers. We have previously found that, histologically, the POLEmut-subtype exhibits surface epithelial slackening (SES). Therefore, to improve subtype identification, we aimed to extract cytological features corresponding to SES in POLEmut-subtype cervical cytology specimens. MATERIALS AND METHODS: We analyzed 104 endometrial cancer cervical cytology specimens, with integrative diagnosis confirmation via histology, immunohistochemistry, and genomic profiling. Cytological features were evaluated for the presence of atypical glandular cells, atypical cell appearance in single cells and clusters, and cytological SES and the presence of tumor-infiltrating inflammatory cells in clusters. RESULTS: Based on cervical cytology, the POLEmut- and p53mut-subtypes exhibited more frequent atypical cells in smaller clusters, giant tumor cells, and cytological SES patterns than the NSMP-subtype. Tumor-infiltrating lymphocytes were frequent in the POLEmut- and mismatch repair-deficient subtypes. CONCLUSION: Histologically-detected SES as well as other endometrial cancer features may be preserved in the atypical cell clusters observed in cervical cytology specimens. Cytological detection of SES and of smaller clusters of atypical cells and inflammatory cells with moderate atypia are suggestive of POLEmut-subtype. Integrative diagnosis including genomic profiling remains critical for diagnostic confirmation.

DOI： 10.21873/invivo.13442

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Shintaro Yanazume, Yukari Kirita, Yusuke Kobayashi, Ikumi Kitazono, Toshiaki Akahane, Mika Mizuno, Shinichi Togami, Akihide Tanimoto, Hiroaki Kobayashi .  Can Endometrial Cytology Identify Patients Who Would Benefit from Immunotherapy? .  Acta cytologica68 ( 2 ) 128 - 136   2024Reviewed International journal

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INTRODUCTION: Patients with polymerase epsilon (POLE) mutation (POLEmut) subtype, MMR-deficient (MMR-d) subtype as classified by The Cancer Genome Atlas (TCGA), and a high tumor mutation burden (TMB-high) potentially benefit from immunotherapy. However, characteristics of the cytological morphology within these populations remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded tissues was subjected to next-generation sequencing analysis. Genomic mutations related to gynecological cancers, TMB, and microsatellite instability were analyzed and were placed in four TCGA classification types. The following morphological cytological investigations were conducted on endometrial cancer using a liquid-based preparation method, prior to the commencement of initial treatment: (i) cytological backgrounds; (ii) differences between each count of neutrophils and lymphocytes as described below. RESULTS: Insignificant differences in the cytological background patterns of TCGA groups and TMB status were found. Although there was no significant difference in neutrophil count (p = 0.955) in the TCGA groups, POLEmut and MMR-d had significantly higher lymphocyte counts than no specific molecular profile (NSMP) (p = 0.019 and 0.037, respectively); furthermore, p53mut also tended to be significant (p = 0.064). Lymphocyte counts in TMB-high were also significantly greater than TMB-low (p = 0.002). POLEmut showed a positive correlation between TMB levels and lymphocyte counts. For predicting patients with POLEmut plus MMR-d, lymphocyte counts demonstrated a superior diagnostic accuracy of area under the curve (AUC) (0.70, 95% CI: 0.57-0.84), with a cutoff value of 26 high-power field. CONCLUSION: Lymphocyte count using liquid-based cytology for patients with endometrial cancer may predict POLEmut plus MMR-d of TCGA groups and TMB-high in those who can benefit from immunotherapy.

DOI： 10.1159/000538288

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野口 紘嗣, Baldwin William, 谷本 昭英 .  Role of C1q in Resolving Ischemia Reperfusion in Kidney Transplants .  移植59 ( Supplement ) s372_1 - s372_1   2024Reviewed

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>[Introduction]Complement has been implicated as a pro-inflammatory mediator in ischemia reperfusion injury (IRI). However, C1q, a subcomponent of C1, functions as a pattern recognition receptor (PRR) that removes injured cells. [Method]We examined the effects of C1q in kidney allografts. A/J kidneys were transplanted to wild type C57BL6 or C1q-knockout (KO) recipients. Treated mice were euthanized from 1 day to 28 day after transplantation to see the C1q function in early to chronic phase inflammation by these tests.[Result]All kidney allografts survived more than 14 days in wild type recipients. In contrast, allografts subjected to cold or warm ischemia failed acutely in C1q-KO recipients with unresolved IRI. C1q transcripts increased in allografts from 1 day to 7 days after transplantation. nanoString analysis on flow sorted infiltrating versus resident myeloid cells isolated from transplants indicated higher C1q transcripts from resident macrophages than infiltrating macrophages.[Conclusion]These data indicate that C1q functions as a PRR to resolve IRI incurred at the time of transplantation.</p>

DOI： 10.11386/jst.59.supplement_s372_1

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YAMANAKA Sae, TOKIMURA Hiroshi, HIGA Nayuta, IWAMOTO Hirofumi, NISHIMUTA Yosuke, SUEYOSHI Kazunobu, YONEZAWA Hajime, TAJITSU Kenichiro, AKAHANE Toshiaki, TANIMOTO Akihide, HANAYA Ryosuke .  Pilocytic Astrocytoma Presenting with Spontaneous Cerebellar Hemorrhage: A Case Report .  NMC Case Report Journal10 ( 0 ) 303 - 308   2023.12Reviewed

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Language：English   Publisher：The Japan Neurosurgical Society  

<p>Hemorrhagic pilocytic astrocytomas (PAs) are rare, accounting for 1.1%-8.0% of all PA cases. They are reported to occur more frequently in older populations, with a male predominance. In this study, we report a case of a 14-year-old boy who presented with a headache, vertigo, and diplopia. As per his brain computed tomography scan, a small hematoma was observed in the left inferior cerebellar peduncle. Follow-up magnetic resonance imaging (MRI) revealed repeated minor bleeding from the lesion and mild expansion, with no neurological deficits. Four years later, the patient developed nausea, vomiting, and left abducens palsy. MRI revealed a mulberry-shaped mass surrounded by a hypointense rim, suggesting a cavernous angioma. The lesion was surgically resected via midline occipital craniotomy with the opening of the cerebellomedullary fissure. Histopathological examination of the lesion revealed PA. Next-generation sequencing analyses revealed that PAs harbored mutations in the <i>ARID1A</i>, <i>ATM</i>, and <i>POLE</i> genes but not in the <i>BRAF</i> gene. To the best of our knowledge, there are yet no reported studies on these mutations in PAs to date. Thus, PA should be considered in the differential diagnosis of cerebellar hemorrhage, especially in young adults and children. </p>

DOI： 10.2176/jns-nmc.2023-0152

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Yamanaka Sae, Tokimura Hiroshi, Higa Nayuta, Iwamoto Hirofumi, Nishimuta Yosuke, Sueyoshi Kazunobu, Yonezawa Hajime, Tajitsu Kenichiro, Akahane Toshiaki, Tanimoto Akihide, Hanaya Ryosuke .  自然小脳出血を呈した毛様細胞性星細胞腫　症例報告(Pilocytic Astrocytoma Presenting with Spontaneous Cerebellar Hemorrhage: A Case Report) .  NMC Case Report Journal10 ( 1 ) 303 - 308   2023.12Reviewed

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Language：English   Publisher：(一社)日本脳神経外科学会  

症例は14歳男児。バスケットボール中に頭部を負傷した後、頭痛、めまい、複視を呈した。CTで左下小脳小帯に小さな血腫を認めた。MRIによる経過観察では、血腫からの軽度の出血と軽度の拡張を繰り返されたが、神経学的障害は認められなかった。しかし、4年後に悪心、嘔吐、左外転麻痺を発症した。MRIにより腫瘤が認められ、mulberry-shaped腫瘍が示唆された。病変は外科的切除された。病変の病理組織学的検査の結果、毛様細胞性星細胞腫が認められた。次世代シーケンス解析の結果、毛様細胞性星細胞腫はARIDIA遺伝子、ATM遺伝子、POLE遺伝子変異を有していたが、BRAJ遺伝子には変異は認められなかった。

窪田 恵美, 北薗 育美, 岩切 かおり, 切田 ゆかり, 田崎 貴嗣, 東 美智代, 簗詰 伸太郎, 小林 裕明, 谷本 昭英 .  液状化検体細胞診で診断した子宮頸部明細胞癌の1例 .  日本臨床細胞学会雑誌62 ( 6 ) 287 - 292   2023.11Reviewed

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

背景:子宮頸部原発明細胞癌はまれであり,液状化検体細胞診(liquid-based cytology:LBC)の細胞像の報告はほとんどない.われわれは,LBC標本で診断しえた子宮頸部明細胞癌の1例を経験したので,塗抹標本所見との異同および他の腺癌との鑑別点について検討し報告する.症例:70歳代,女性.約1年前より持続する性器出血があり,子宮頸部のポリープ状腫瘍を指摘された.擦過細胞診および組織診で明細胞癌と診断された.LBC標本では,異型細胞が重積性のある集塊状や孤立性に認められ,腺腔構造や乳頭状構造およびhobnail状の核の突出も認めた.異型細胞の核は軽度の腫大を示す類円形を呈しており,大型で明瞭な核小体を認め,細胞質は豊富で,淡く微細顆粒状を呈していた.結論:LBC標木においても,塗抹標本と同様に明細胞癌の特徴とされる,大型で明瞭な核小体および豊富な細胞質を有する異型細胞を認め,LBC標本で明細胞癌の診断を行う際にも重要な細胞所見である.(著者抄録)

Yumisashi Riho, Saito Ryosuke, Togami Shinichi, Kobayashi Yusuke, Kitazono Ikumi, Tanimoto Akihide, Kobayashi Hiroaki .  分子生物学的解析により組織学的グレードが異なるsynchronous endometrial and ovarian cancerの症例が子宮内膜癌からの転移性卵巣癌であることが明らかになった　症例報告と文献レビュー(Molecular biological analysis revealed a case of synchronous endometrial and ovarian cancer with different histological grade as metastatic ovarian cancer from endometrial cancer: Case report and review of literature) .  The Journal of Obstetrics and Gynaecology Research49 ( 11 ) 2766 - 2770   2023.11Reviewed

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症例は38歳の女性で、下腹部痛により来院した。超音波とMRIにて右卵巣と付属器に腫瘍を認め、腹腔鏡下にて切除した。子宮内膜及び卵巣において病理学的にグレード3の類内膜癌が認められた。進行度の検査にて子宮内膜と播種結節に腫瘍を認め、直腸への浸潤も含め切除し、卵管卵巣摘除術を行った。子宮内膜癌はグレード1、子宮漿膜内の播種結節はグレード3の類内膜腺癌と診断された。synchronous endometrial and ovarian cancer(SEOC)を疑い、DNA解析を行った。その結果、SEOCではなく子宮内膜癌の卵巣転移と診断された。パクリタキセルとカルボプラチンによるアジュバント化学療法を受け、再発は認められていない。

窪田 恵美, 北薗 育美, 岩切 かおり, 切田 ゆかり, 田崎 貴嗣, 東 美智代, 簗詰 伸太郎, 小林 裕明, 谷本 昭英 .  液状化検体細胞診で診断した子宮頸部明細胞癌の1例 .  日本臨床細胞学会雑誌62 ( 6 ) 287 - 292   2023.11Reviewed

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

背景:子宮頸部原発明細胞癌はまれであり,液状化検体細胞診(liquid-based cytology:LBC)の細胞像の報告はほとんどない.われわれは,LBC標本で診断しえた子宮頸部明細胞癌の1例を経験したので,塗抹標本所見との異同および他の腺癌との鑑別点について検討し報告する.症例:70歳代,女性.約1年前より持続する性器出血があり,子宮頸部のポリープ状腫瘍を指摘された.擦過細胞診および組織診で明細胞癌と診断された.LBC標本では,異型細胞が重積性のある集塊状や孤立性に認められ,腺腔構造や乳頭状構造およびhobnail状の核の突出も認めた.異型細胞の核は軽度の腫大を示す類円形を呈しており,大型で明瞭な核小体を認め,細胞質は豊富で,淡く微細顆粒状を呈していた.結論:LBC標木においても,塗抹標本と同様に明細胞癌の特徴とされる,大型で明瞭な核小体および豊富な細胞質を有する異型細胞を認め,LBC標本で明細胞癌の診断を行う際にも重要な細胞所見である.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01209&link_issn=&doc_id=20231208230002&doc_link_id=%2Few5saibo%2F2023%2F006206%2F003%2F0287-0292%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Few5saibo%2F2023%2F006206%2F003%2F0287-0292%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Riho Yumisashi, Ryosuke Saito, Shinichi Togami, Yusuke Kobayashi, Ikumi Kitazono, Akihide Tanimoto, Hiroaki Kobayashi .  Molecular biological analysis revealed a case of synchronous endometrial and ovarian cancer with different histological grade as metastatic ovarian cancer from endometrial cancer: Case report and review of literature. .  The journal of obstetrics and gynaecology research49 ( 11 ) 2766 - 2770   2023.8Reviewed International journal

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The diagnosis of synchronous endometrial and ovarian cancer or metastatic cancer of the same histological type is difficult. In this study, molecular biology analysis was performed to determine ovarian metastasis from endometrial cancer. A 38-year-old woman had pathological evidence of endometrial cancer (endometrioid carcinoma, grade 1) and ovarian cancer (endometrioid carcinoma, grade 3); a disseminated nodule in the serosa uteri was also diagnosed as endometrioid carcinoma (grade 3). Customized panel sequencing revealed a common mutation pattern in ovarian cancer and disseminated nodules. Furthermore, endometrial cancer showed the same mutation patterns for FGFR3 and PTEN as ovarian cancer and disseminated nodules. All tumors were microsatellite instability high. Clinicopathological and molecular biology analyses suggested that the patient had ovarian metastasis from endometrial cancer. The patient underwent adjuvant chemotherapy with paclitaxel and carboplatin, with no recurrence. Molecular biology techniques may enable appropriate treatment based on clinically accurate diagnosis.

DOI： 10.1111/jog.15773

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Mari Kirishima, Toshiaki Akahane, Tomoko Takajo, Nayuta Higa, Hajime Yonezawa, Hiroyuki Uchida, Kiyohisa Kamimura, Ryosuke Hanaya, Koji Yoshimoto, Michiyo Higashi, Takashi Yoshiura, Akihide Tanimoto .  A case of glioblastoma harboring non-amplified epidermal growth factor receptor variant III: Critical molecular detection using RNA-based panel analysis. .  Pathology, research and practice248   154712 - 154712   2023.7Reviewed International journal

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Amplification of the epidermal growth factor receptor gene (EGFR) and its variants are the most commonly detected pathogenic gene alterations in glioblastoma. Herein, we report a case of molecularly defined glioblastoma harboring an EGFR variant III (EGFRvIII) without EGFR amplification. The initial histological diagnosis was isocitrate dehydrogenase (IDH)-wildtype low-grade glioma, due to an absence of anaplasia, necrosis, and microvascular proliferation, and a low Ki-67 labeling index. DNA-based next-generation sequencing (NGS) panel analysis revealed a TERTp promoter mutation but no EGFR mutation or amplification, supporting the diagnosis of "molecular glioblastoma." However, RNA-based NGS panel analysis revealed mRNA expression of EGFRvIII. Therefore, the final integrative diagnosis was glioblastoma with non-amplified EGFRvIII. Our report suggests that non-amplified EGFRvIII might be an early molecular event in glioblastoma tumorigenesis. In addition to the usual DNA-based analysis, RNA-based analysis is required to identify exon-skipping EGFR variants without EGFR amplification.

DOI： 10.1016/j.prp.2023.154712

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Tatsuhiko Furukawa, Kentaro Mimami, Toshiyuki Nagata, Masatasu Yamamoto, Masami Sato, Akihide Tanimoto .  Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development. .  International journal of molecular sciences24 ( 14 )   2023.7Reviewed International journal

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The circadian rhythm-related genes BHLHE40/DEC1 and BHLHE41/DEC2 have various functions under different cell and tissue conditions. BHLHE41/DEC2 has been reported to be both a cancer-suppressive and an oncogenic gene during cancer development. The effects of BHLHE41/DEC2 on differentiation have been examined using Bhlhe41/Dec2 knockout mice and/or in vitro differentiation models, and research has been conducted using genetic analysis of tumor cells, in vitro analysis of cancer cell lines, and immunohistochemical studies of the clinical samples. We summarize some of these studies, detail several problems, and consider possible reasons for contradictory results and the needs for further research.

DOI： 10.3390/ijms241411731

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古家 淳行, 亀澤 雅, 窪田 恵美, 岩切 かおり, 霧島 茉莉, 田崎 貴嗣, 北薗 育美, 東 美智代, 谷本 昭英 .  右臀部に発生した類上皮肉腫の一例 .  日本臨床細胞学会九州連合会雑誌54   83 - 86   2023.7Reviewed

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 類上皮肉腫は形態および免疫組織学的に上皮様を呈する腫瘍細胞が胞巣形成性に増殖する稀な悪性軟部腫瘍で,しばしばラブドイド細胞が出現する.今回,右臀部に発生した類上皮肉腫を経験したので報告する.症例 30代,女性.右臀部の筋肉内腫瘤および右鼠径部腫瘤を認めた.穿刺吸引細胞診では血性背景に上皮様結合を有した異型細胞が集塊状に出現していた.異型細胞の結合性は緩く,豊富な細胞質を有し,核は偏在傾向を示し,核縁は菲薄で平滑で,クロマチンは細顆粒状で均等に分布していた.癌の転移や肉腫が疑われたが,組織型の推定は困難であった.摘出された腫瘍は,組織学的に好酸性胞体の上皮様腫瘍細胞が線維性間質内に索状やシートに増殖し,腫瘍中心に壊死を伴っていた.免疫組織化学的に腫瘍細胞は,cytokeratin(AE1/AE3,CAM5.2),Vimentin,CD34陽性を示し,INI-1の欠失を認めた.細胞所見,免疫組織化学を含む組織所見より類上皮肉腫と診断した.結語 類上皮肉腫の細胞像では,豊富な細胞質を有する上皮様結合を示す異型細胞を認めるが,結合性は緩いこと,肉腫を示唆する菲薄で平滑な核縁であることに着目することが重要であると考えられた.(著者抄録)

Ikumi Kitazono, Toshiaki Akahane, Seiya Yokoyama, Yusuke Kobayashi, Shinichi Togami, Shintaro Yanazume, Takashi Tasaki, Hirotsugu Noguchi, Kazuhiro Tabata, Hiroaki Kobayashi, Akihide Tanimoto .  "Surface epithelial slackening" pattern in endometrioid carcinoma: A morphological feature for differentiating the POLE mutation-subtype from the no specific molecular profile subtype. .  Pathology, research and practice247   154563 - 154563   2023.5Reviewed International journal

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Endometrial cancers are classified into mismatch repair (MMR) deficient- (MMRd), p53 mutation- (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP) subtypes according to The Cancer Genome Atlas (TCGA). The distinction between POLEmut and NSMP subtypes is made on the basis of molecular analysis because the specific histological and immunohistochemical features of these two subtypes are still unknown. In this study, we analyzed histological features by scoring the presence of a mucinous pool, giant cells, clear cells, keratinization, neutrophilic abscess, and surface proliferating pattern in 82 cases of endometrial cancers in which an integrative diagnosis was confirmed by immunohistochemistry and genomic profiles showing POLE mutations, tumor mutation burden, and microsatellite instability. In contrast to the hierarchical branching of micropapillary proliferation observed in serous carcinoma, POLEmut-subtype endometrioid carcinomas often showed a surface epithelial slackening (SES) pattern in the tumor cells facing the uterine surface. The POLEmut subtype exhibited higher scores for clear cells and SES patterns than the other three subtypes. The scores for giant cells, clear cells, and the SES pattern were significantly higher in the POLEmut subtype than in the NSMP subtype, suggesting that these morphometric parameters are useful for differentiating POLEmut- and NSMP-subtype endometrioid carcinomas, although genomic profiling is still necessary for a definite molecular diagnosis.

DOI： 10.1016/j.prp.2023.154563

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Akahane T, Isochi-Yamaguchi T, Hashiba-Ohnuki N, Bandoh N, Aimono E, Kato Y, Nishihara H, Kamada H, Tanimoto A .  Cancer gene analysis of liquid-based cytology specimens using next-generation sequencing: A technical report of bimodal DNA- and RNA-based panel application. .  Diagnostic cytopathology   2023.5Reviewed

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DOI： 10.1002/dc.25149

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Hamada T, Higashi M, Yokoyama S, Akahane T, Hisaoka M, Noguchi H, Furukawa T, Tanimoto A .  MALAT1 functions as a transcriptional promoter of MALAT1::GLI1 fusion for truncated GLI1 protein expression in cancer. .  BMC cancer23 ( 1 ) 424   2023.5Reviewed

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DOI： 10.1186/s12885-023-10867-6

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Shintaro Yanazume, Kaori Iwakiri, Yusuke Kobayashi, Ikumi Kitazono, Toshiaki Akahane, Mika Mizuno, Shinichi Togami, Akihide Tanimoto, Hiroaki Kobayashi .  Cytopathological features associated with POLE mutation in endometrial cancer. .  Cytopathology : official journal of the British Society for Clinical Cytology34 ( 3 ) 211 - 218   2023.5Reviewed International journal

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OBJECTIVE: For patients with endometrial cancer, the POLE (polymerase epsilon) mutation (POLEmut)-subtype, one of four molecular-analysis-based categories in the Cancer Genome Atlas (TCGA), has the best prognosis. The following histological characteristics are typically observed in endometroid carcinoma cases with the POLEmut-subtype: (1) the presence of tumour giant cells, (2) numerous tumour-infiltrating lymphocytes (TILs) and/or peri-tumoral lymphocytes, and (3) a high grade. However, in the context of cytology, the morphological characteristics of this subtype remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues was subjected to next-generation sequencing analysis and categorised according to the TCGA classifications. Genomic mutation, tumour mutation burden (TMB), and microsatellite instability were also assessed. Cytological specimens of resected uteri obtained using the Papanicolaou method were histologically separated into three types. RESULTS: Seven out of 112 patients (6%) with endometrial cancer were diagnosed with the POLEmut-subtype between January 2019 and August 2021. Tumour giant cells were observed in three cases (43%) on histology and cytology. TIL and/or peritumoral lymphocytes with inflammatory cells were detected in five cases (71%) on histology and three cases (43%) on cytology. Cases in which these three characteristics were observed on both cytology and histology may have belonged to the POLEmut-subtype. There were no cases in which these characteristics were absent on histology but present on cytology. TMB tended to be higher in cases when the three characteristics were observed in both cytological and histological findings. CONCLUSIONS: Preoperative endometrial cytology highlighted the characteristics of the POLEmut-subtype in the histological analysis of resected uterine specimens and has the potential to play an important role in treatment decisions.

DOI： 10.1111/cyt.13215

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赤羽 俊章, 坂本 一平, 比嘉 那優大, 霧島 茉莉, 牧野 隆太郎, 米澤 大, 内田 裕之, 吉本 幸司, 花谷 亮典, 谷本 昭英 .  がんゲノム診断とバイオインフォマティクス 神経膠腫の統合分子病理診断のための自動レポーティングシステムの構築とバイオインフォマティクスの重要性 .  Brain Tumor Pathology40 ( Suppl. ) 067 - 067   2023.5Reviewed

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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比嘉 那優大, 赤羽 俊章, 横山 勢也, 米澤 大, 内田 裕之, 霧島 茉莉, 山本 淳考, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  IDH wildtype-TERTp wildtype glioblastomaにおけるPTENの予後への影響 .  Brain Tumor Pathology40 ( Suppl. ) 098 - 098   2023.5Reviewed

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牧野 隆太郎, 比嘉 那優大, 赤羽 俊章, 米澤 大, 内田 裕之, 霧島 茉莉, 山本 淳考, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  がんゲノム診断 日本人膠芽腫患者におけるチロシンキナーゼ受容体変異と臨床像 .  Brain Tumor Pathology40 ( Suppl. ) 061 - 061   2023.5Reviewed

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Hirofumi Yoshino, Seiya Yokoyama, Motoki Tamai, Shunsuke Okamura, Sayaka Iizasa, Takashi Sakaguchi, Yoichi Osako, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Masayuki Nakagawa, Shuichi Tatarano, Akihide Tanimoto, Hideki Enokida .  Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor. .  FEBS open bio13 ( 6 ) 1056 - 1066   2023.4Reviewed International journal

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Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found report that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

DOI： 10.1002/2211-5463.13616

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Hiromichi Iwaya, Akihide Tanimoto, Koshiro Toyodome, Issei Kojima, Makoto Hinokuchi, Shiroh Tanoue, Shinichi Hashimoto, Machiko Kawahira, Shiho Arima, Shuji Kanmura, Toshiaki Akahane, Michiyo Higashi, Shinsuke Suzuki, Shinichi Ueno, Takao Ohtsuka, Akio Ido .  Next-Generation Sequencing Analysis of Pancreatic Cancer Using Residual Liquid Cytology Specimens from Endoscopic Ultrasound-Guided Fine-Needle Biopsy: A Prospective Comparative Study with Tissue Specimens. .  Diagnostics (Basel, Switzerland)13 ( 6 )   2023.3Reviewed International journal

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This study evaluated the feasibility and clinical utility of liquid-based cytology (LBC) specimens via endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) for next-generation sequencing (NGS) of pancreatic cancer (PC). We prospectively evaluated the performance of DNA extraction and NGS using EUS-FNB samples obtained from PC. Thirty-three consecutive patients with PC who underwent EUS-FNB at our hospital were enrolled. DNA samples were obtained from 96.8% of the patients. When stratified with a variant allele frequency (VAF) > 10% tumor burden, the NGS success rate was 76.7% (n = 23) in formalin-fixed paraffin-embedded (FFPE), 83.3% (n = 25) in LBC, and 76.7% (n = 23) in frozen samples. The overall NGS success rate was 86.7% (n = 26) using FFPE, LBC, or frozen samples. The detection rates for the main mutated genes were as follows: 86.7% for KRAS, 73.3% for TP53, 66.7% for CDKN2A, 36.7% for SMAD4, and 16.7% for ARID1A. LBC had the highest median value of VAF (23.5%) for KRAS and TP53. PC mutation analysis using NGS was successfully performed using LBC compared with FFPE and frozen samples. This approach provides an alternative and affordable source of molecular testing materials.

DOI： 10.3390/diagnostics13061078

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Shinichi Togami, Akihide Tanimoto, Shintaro Yanazume, Hideki Tokunaga, Tomoyuki Nagai, Mika Watanabe, Hideaki Yahata, Kazuo Asanoma, Hidetaka Yamamoto, Tomohito Tanaka, Masahide Ohmichi, Takashi Yamada, Yukiharu Todo, Ryutaro Yamada, Hidenori Kato, Wataru Yamagami, Kenta Masuda, Miho Kawaida, Hitoshi Niikura, Takuya Moriya, Hiroaki Kobayashi .  Evaluation of the one-step nucleic acid amplification assay for detecting lymph node metastasis in patients with cervical and endometrial cancer: A multicenter prospective study. .  Gynecologic oncology170   70 - 76   2023.3Reviewed International journal

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OBJECTIVE: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. METHODS: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-μm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. RESULTS: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961-0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819-0.973) and 0.989 (95% CI: 0.973-0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. CONCLUSIONS: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

DOI： 10.1016/j.ygyno.2022.12.016

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Yuto Hozaka, Hideyuki Oi, Souichi Satake, Yoshinori Uchino, Yuichi Goto, Tetsuya Idichi, Kiyonori Tanoue, Yoichi Yamasaki, Yota Kawasaki, Yuko Mataki, Hiroshi Kurahara, Akihiro Nakajo, Michiyo Higashi, Akihide Tanimoto, Tsuyoshi Sugiura, Takao Ohtsuka .  Are intratumoral microbiota involved in the progression of intraductal papillary mucinous neoplasms of the pancreas? .  Surgery173 ( 2 ) 503 - 510   2023.2Reviewed International journal

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BACKGROUND: Microbiota have been reported to influence the development of various gastrointestinal neoplasms through the mechanism of sustained inflammation; however, few data are available regarding their influence on intraductal papillary mucinous neoplasms. The aim of this study was to assess the association between specific microbiota and the clinicopathologic characteristics of intraductal papillary mucinous neoplasms of the pancreas. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples of 30 patients who underwent pancreatectomy for intraductal papillary mucinous neoplasm, and polymerase chain reaction was used to create sequence libraries using the primer set for the V3 and V4 region of 16S recombinant DNA. Filtered sequence reads were then processed into operational taxonomic units with a 97% identity threshold and the relative abundance of bacteria compared between the 2 groups using operational taxonomic units. RESULTS: There was a trend toward fewer Firmicutes and more Proteobacteria and Fusobacteria in the relative abundance of main duct operational taxonomic units than in branch duct operational taxonomic units. The relative abundances of Bacteroidetes (P < .01) and Fusobacteria (P = .04) were significantly higher in invasive intraductal papillary mucinous neoplasms than in noninvasive intraductal papillary mucinous neoplasms. The relative abundance of the intestinal type was significantly lower in Firmicutes than the relative abundance of the nonintestinal type (P = .04). Notably, main duct operational taxonomic units with the intestinal subtype were affected by increased proportions of Proteobacteria and Fusobacteria, and Fusobacteria were abundant in the intestinal type of invasive main duct operational taxonomic units. CONCLUSION: Intratumoral microbiota may be involved in the progression of operational taxonomic units.

DOI： 10.1016/j.surg.2022.10.003

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Takumi Koji, Nagano Hiroaki, Myogasako Tsuyoshi, Nakano Tsubasa, Fukukura Yoshihiko, Ueda Kazuhiro, Tabata Kazuhiro, Tanimoto Akihide, Yoshiura Takashi .  Feasibility of iodine concentration and extracellular volume fraction measurement derived from the equilibrium phase dual-energy CT for differentiating thymic epithelial tumors(タイトル和訳中) .  Japanese Journal of Radiology41 ( 1 ) 45 - 53   2023.1Reviewed

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2017年1月～2020年12月にかけ、当院で治療前に平衡相デュアルエネルギーCT(DECT)を受けた胸腺上皮性腫瘍(TET)の治療継続患者33例(男性11例、女性22例、年齢34～89歳)を対象に、ヨウ素濃度(IC)と細胞外容積(ECV)分画測定がTET診断に実現可能か後向きに調査した。なお、TET病理診断の内訳は低リスク胸腺腫が11例(Aが0例、ABが4例、B1が7例)、高リスク胸腺腫が11例(B2が6例、B3が5例)、胸腺癌が11例であった。平衡相でICを測定し、胸腺病変と大動脈ICからECV分画を求めTETサブタイプ間でICとECV分画を比較した。次に、ROC曲線解析によりICとECV分画の胸腺癌に対する診断能を評価した結果、平衡相のICとECV分画ではTET群間で異なったが、胸腺癌に対する平衡相ICとECV分画では胸腺腫に比べ有意に高く、胸腺癌を診断するための平衡相ICとECV分画の最適なカットオフ値が、各々1.5mg/mLおよび26.8%であることが確認された。以上の結果から、DECTを用いたICとECV分画測定がTET診断に有用で、平衡相高ICと高ECV分画から胸腺癌が推察されることが明らかにされた。

田崎 貴嗣, 霧島 茉莉, 北薗 育美, 田畑 和宏, 東 美智代, 安村 拓人, 豊川 建二, 谷本 昭英 .  胸部大動脈瘤を呈した巨細胞性動脈炎の1例 .  診断病理40 ( 1 ) 91 - 95   2023.1Reviewed

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症例は80代女性。リウマチ性多発筋痛症の治療中に胸部大動脈瘤を指摘され,人工血管置換術が行われた。大動脈では内膜に軽度の粥状硬化を認めた。中膜ではリンパ球や形質細胞,少数の多核巨細胞の浸潤,内膜側優位の弾性線維の配列の乱れと消失を認めたが,外膜の線維化や炎症細胞浸潤は軽度であり,巨細胞性動脈炎と診断した。大動脈瘤において巨細胞性動脈炎と病理診断される症例では,側頭動脈炎の既往がなく臨床症状に乏しいことがあり,大動脈瘤を注意深く検索することで,巨細胞性動脈炎の可能性を見落とさないことが重要である。(著者抄録)

Koji Takumi, Hiroaki Nagano, Tsuyoshi Myogasako, Tsubasa Nakano, Yoshihiko Fukukura, Kazuhiro Ueda, Kazuhiro Tabata, Akihide Tanimoto, Takashi Yoshiura .  Feasibility of iodine concentration and extracellular volume fraction measurement derived from the equilibrium phase dual-energy CT for differentiating thymic epithelial tumors. .  Japanese journal of radiology41 ( 1 ) 45 - 53   2023.1Reviewed

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PURPOSE: To assess the diagnostic feasibility of iodine concentration (IC) and extracellular volume (ECV) fraction measurement using the equilibrium phase dual-energy CT (DECT) for the evaluation of thymic epithelial tumors (TETs). MATERIALS AND METHODS: This study included 33 TETs (11 low-risk thymomas, 11 high-risk thymomas, and 11 thymic carcinomas) that were assessed by pretreatment DECT. IC was measured during the equilibrium phases and ECV fraction was calculated using IC of the thymic lesion and the aorta. IC and ECV fraction were compared among TET subtypes using the Kruskal-Wallis H test and Mann-Whitney U test. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate the ability of IC and ECV fraction to diagnose thymic carcinoma. RESULTS: IC during the equilibrium phase and ECV fraction differed among the three TET groups (both p < 0.001). IC during the equilibrium phase and ECV fraction was significantly higher in thymic carcinomas than in thymomas (1.9 mg/mL vs. 1.2 mg/mL, p < 0.001; 38.2% vs. 25.9%, p < 0.001; respectively). The optimal cutoff values of IC during the equilibrium phase and of ECV fraction to diagnose thymic carcinoma were 1.5 mg/mL (AUC, 0.955; sensitivity, 100%; specificity, 90.9%) and 26.8% (AUC, 0.888; sensitivity, 100%; specificity, 72.7%), respectively. CONCLUSION: IC and ECV fraction measurement using DECT are helpful in diagnosing TETs. High IC during the equilibrium phase and high ECV fraction are suggestive of thymic carcinoma.

DOI： 10.1007/s11604-022-01331-9

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KUBOTA Emi, KITAZONO Ikumi, IWAKIRI Kaori, KIRITA Yukari, TASAKI Takashi, HIGASHI Michiyo, YANAZUME Shintaro, KOBAYASHI Hiroaki, TANIMOTO Akihide .  A case of clear cell cancer of the cervix diagnosed by liquid-based cytology .  The Journal of the Japanese Society of Clinical Cytology62 ( 6 ) 287 - 292   2023

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<p><i><b>Background</b></i> : Few studies have investigated the usefulness of liquid-based cytology (LBC) specimens in patients with primary clear cell carcinoma of the cervix, a rare neoplasm. Herein, we report the case of a patient who was diagnosed as having primary clear cell carcinoma of the cervix based on LBC, and discuss the differences between LBC and smear cytology, and useful findings for differentiation from other adenocarcinomas.</p><p><i><b>Case</b></i> : The patient was a 70-year-old woman. LBC examination revealed both isolated tumor cells and tumor cells in clusters ; glandular, papillary, and hobnail-like formations were also observed. On LBC, tumor cells with abundant and fine granular cytoplasm, enlarged round nuclei, and large and prominent nucleoli were observed.</p><p><i><b>Conclusion</b></i> : These findings could be helpful in the diagnosis of cervical cell carcinoma using LBC.</p>

DOI： 10.5795/jjscc.62.287

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Jun Kaminosono, Yuki Kambe, Akihide Tanimoto, Tomoyuki Kuwaki, Akira Yamashita .  The physiological response during optogenetic-based cardiac pacing in awake freely moving mice. .  Frontiers in physiology14   1130956 - 1130956   2023Reviewed International journal

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There are several methods to control a heart rate, such as electrical stimulation and drug administration. However, these methods may be invasive or affect other organs. Recently, an optogenetic-based cardiac pacing method has enabled us to stimulate the cardiac muscle in non-contact. In many previous studies, the pacing was applied ex vivo or in anesthetized animals. Therefore, the physiologic response of animals during optogenetic pacing remains unclear. Here, we established a method of optogenetic-based cardiac pacing in awake, freely moving mice and simultaneously measured electrocardiogram, blood pressure, and respiration. As a result, light-induced myocardial contraction produces blood flow and indirectly affects the respiration rhythm. Additionally, light illumination enabled heart rate recovery in bradycardic mice. These findings may be employed for further research that relates a heartbeat state to animal behavior. Together, this method may drive the development of less invasive pacemakers without pacing leads.

DOI： 10.3389/fphys.2023.1130956

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Ryutaro Makino, Nayuta Higa, Toshiaki Akahane, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Shingo Fujio, Mari Kirishima, Taiji Hamada, Hitoshi Yamahata, Kiyohisa Kamimura, Takashi Yoshiura, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya .  Alterations in EGFR and PDGFRA are associated with the localization of contrast-enhancing lesions in glioblastoma. .  Neuro-oncology advances5 ( 1 ) vdad110   2023Reviewed International journal

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BACKGROUND: Glioblastoma (GBM) is a malignant brain tumor, with radiological and genetic heterogeneity. We examined the association between radiological characteristics and driver gene alterations. METHODS: We analyzed the driver genes of 124 patients with IDH wild-type GBM with contrast enhancement using magnetic resonance imaging. We used a next-generation sequencing panel to identify mutations in driver genes and matched them with radiological information. Contrast-enhancing lesion localization of GBMs was classified into 4 groups based on their relationship with the subventricular zone (SVZ) and cortex (Ctx). RESULTS: The cohort included 69 men (55.6%) and 55 women (44.4%) with a mean age of 66.4 ± 13.3 years. EGFR and PDGFRA alterations were detected in 28.2% and 22.6% of the patients, respectively. Contrast-enhancing lesion touching both the SVZ and Ctx was excluded because it was difficult to determine whether it originated from the SVZ or Ctx. Contrast-enhancing lesions touching the SVZ but not the Ctx had significantly worse overall survival than non-SVZ lesions (441 days vs. 897 days, P = .002). GBM touching only the Ctx had a better prognosis (901 days vs. 473 days, P < .001) than non-Ctx lesions and was associated with EGFR alteration (39.4% vs. 13.2%, P = .015). Multiple contrast lesions were predominant in PDGFRA alteration and RB1-wild type (P = .036 and P = .031, respectively). CONCLUSIONS: EGFR alteration was associated with cortical lesions. And PDGFRA alteration correlated with multiple lesions. Our results suggest that clarifying the association between driver genes and tumor localization may be useful in clinical practice, including prognosis prediction.

DOI： 10.1093/noajnl/vdad110

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Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Ryutaro Makino, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Taiji Hamada, Naoki Noguchi, Ryosuke Otsuji, Daisuke Kuga, Shohei Nagasaka, Hitoshi Yamahata, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya .  Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma. .  Neuro-oncology advances5 ( 1 ) vdad078   2023Reviewed International journal

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BACKGROUND: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas. METHODS: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH. RESULTS: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients. CONCLUSIONS: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.

DOI： 10.1093/noajnl/vdad078

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Kazuyasu Fujii, Mari Kirishima, Makoto Yoshimitsu, Takaki Hashiguchi, Akihide Tanimoto, Takuro Kanekura .  Adult T-cell leukemia/lymphoma presenting with ulceration of the digits. .  The Journal of dermatology50 ( 5 ) e168 - e170   2022.12Reviewed International journal

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DOI： 10.1111/1346-8138.16698

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Taiji Hamada, Seiya Yokoyama, Toshiaki Akahane, Kei Matsuo, Akihide Tanimoto .  Genome Editing Using Cas9 Ribonucleoprotein Is Effective for Introducing PDGFRA Variant in Cultured Human Glioblastoma Cell Lines. .  International journal of molecular sciences24 ( 1 )   2022.12Reviewed International journal

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Many variants of uncertain significance (VUS) have been detected in clinical cancer cases using next-generation sequencing-based cancer gene panel analysis. One strategy for the elucidation of VUS is the functional analysis of cultured cancer cell lines that harbor targeted gene variants using genome editing. Genome editing is a powerful tool for creating desired gene alterations in cultured cancer cell lines. However, the efficiency of genome editing varies substantially among cell lines of interest. We performed comparative studies to determine the optimal editing conditions for the introduction of platelet-derived growth factor receptor alpha (PDGFRA) variants in human glioblastoma multiforme (GBM) cell lines. After monitoring the copy numbers of PDGFRA and the expression level of the PDGFRα protein, four GBM cell lines (U-251 MG, KNS-42, SF126, and YKG-1 cells) were selected for the study. To compare the editing efficiency in these GBM cell lines, the modes of clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) delivery (plasmid vs. ribonucleoprotein (RNP)), methods of transfection (lipofection vs. electroporation), and usefulness of cell sorting were then evaluated. Herein, we demonstrated that electroporation-mediated transfer of Cas9 with single-guide RNA (Cas9 RNP complex) could sufficiently edit a target nucleotide substitution, irrespective of cell sorting. As the Cas9 RNP complex method showed a higher editing efficiency than the Cas9 plasmid lipofection method, it was the optimal method for single-nucleotide editing in human GBM cell lines under our experimental conditions.

DOI： 10.3390/ijms24010500

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Tatsuhiko Furukawa, Sho Tabata, Kentaro Minami, Masatatsu Yamamoto, Kohichi Kawahara, Akihide Tanimoto .  Metabolic reprograming of cancer as a therapeutic target. .  Biochimica et biophysica acta. General subjects1867 ( 3 ) 130301 - 130301   2022.12Reviewed International journal

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Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.

DOI： 10.1016/j.bbagen.2022.130301

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Jun Nagahama, Takuro Nishikawa, Takashi Tasaki, Yuki Yasudome, Tatsuro Nakamura, Takanari Abematsu, Shunsuke Nakagawa, Yuichi Kodama, Akihide Tanimoto, Yasuhiro Okamoto .  Systemic Epstein-Barr virus-positive T-cell lymphoma of childhood treated with the ICE regimen and allogeneic hematopoietic stem-cell transplantation. .  Pediatric blood & cancer70 ( 3 ) e30041   2022.10Reviewed International journal

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DOI： 10.1002/pbc.30041

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Mari Kirishima, Toshiaki Akahane, Nayuta Higa, Shinsuke Suzuki, Shinichi Ueno, Hajime Yonezawa, Hiroyuki Uchida, Ryosuke Hanaya, Koji Yoshimoto, Shohei Shimajiri, Ikumi Kitazono, Akihide Tanimoto .  IDH-mutant astrocytoma with an evolutional progression to CDKN2A/B homozygous deletion and NTRK fusion during recurrence: A case report. .  Pathology, research and practice239   154163 - 154163   2022.10Reviewed International journal

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We reported a case of molecularly defined isocitrate dehydrogenase (IDH)-mutant astrocytoma that recurred twice with aggressive behavior and increased anaplastic morphology. Primary and recurrent tumors were analyzed using custom-made DNA-based cancer gene and RNA-based fusion panels for next-generation sequencing (NGS). NGS analyses revealed that recurrent astrocytoma, in addition to IDH1 and tumor protein 53 mutations detected in the primary lesion, harbored cyclin-dependent kinase inhibitor (CDKN) 2 A/B homozygous deletion and neurotrophic tropomyosin receptor kinase 2 (NTRK2) fusion genes that consisted of golgin A1- and cyclin-dependent kinase 5 regulatory subunit associated protein 2-NTRK2 fusions. Anaplasia and necrosis were observed in the recurrent tumors, but not in the primary lesion. Therefore, the integrative diagnosis was primary IDH-mutant astrocytoma grade 2 and recurrent IDH-mutant astrocytoma grade 4 with NTRK2 fusions. This is a worthwhile report describing a case of IDH-mutant astrocytoma that showed genomic evolution during tumor recurrence. Our report suggests that NTRK fusion and CDKN2A/B homozygous deletion promote high-grade transformation and indicate an unfavorable prognosis of IDH-mutant astrocytoma.

DOI： 10.1016/j.prp.2022.154163

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北薗 育美, 霧島 茉莉, 田崎 貴嗣, 田畑 和宏, 東 美智代, 野口 紘嗣, 簗詰 伸太郎, 神宮司 メグミ, 谷本 昭英 .  FDG-PET高集積を示した遺残副腎由来のOncocytomaの1例 .  診断病理39 ( 4 ) 319 - 325   2022.10Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

遺残副腎は異所性に認められる副腎皮質組織であり,腫瘍化は非常に稀である。80代女性の骨盤腔内にFDGの高集積を呈する腫瘍を認めた。腫瘍は右子宮広間膜内に卵巣とは離れて存在し,好酸性顆粒状の豊富な細胞質を有する腫瘍細胞のびまん性増殖からなり,腫瘍辺縁には非腫瘍性の副腎皮質組織を伴っていた。免疫染色でSF-1,mitochondria陽性であった。Lin-Weiss-Bisceglia criteriaを満たす所見はなく,遺残副腎由来のoncocytomaと診断した。(著者抄録)

Higa Nayuta, Akahane Toshiaki, Yokoyama Seiya, Yonezawa Hajime, Uchida Hiroyuki, Fujio Shingo, Kirishima Mari, Takigawa Kosuke, Hata Nobuhiro, Toh Keita, Yamamoto Junkoh, Hanaya Ryosuke, Tanimoto Akihide, Yoshimoto Koji .  Molecular Genetic Profile of 300 Japanese Patients with Diffuse Gliomas Using a Glioma-tailored Gene Panel(タイトル和訳中) .  Neurologia medico-chirurgica62 ( 9 ) 391 - 399   2022.9Reviewed

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Language：English   Publisher：(一社)日本脳神経外科学会  

日本人患者のびまん性神経膠腫にみられる、分子遺伝学的プロファイルについて調査した。著者等の大学で収集した、びまん性神経膠腫患者303例の腫瘍組織試料を用いて、神経膠腫に特化した遺伝子パネルから、分子遺伝学的プロファイルを解析した。その結果、膠芽腫(GBM)患者185例に最も変異が多く認められた遺伝子は、TERTp遺伝子、TP53遺伝子、PTEN遺伝子、NF1遺伝子とPDGFRA遺伝子であった。また、欠失が最も多く認められた遺伝子は、PTEN遺伝子およびCDKN2A/B及びRB1遺伝子で、増加/増幅が最も多く認められた遺伝子は、EGFR遺伝子とPDGFRA遺伝子およびCDK4遺伝子であった。さらに、グレードIII乏突起膠腫22例のうち3例には、CDKN2A/B遺伝子のホモ接合性欠失が、4例にはARID1A遺伝子変異が検出され、ARID1A遺伝子変異が無増悪生存転帰不良と関連することが示唆された。なお、WHO脳腫瘍分類2021により、グレードII/IIIでIDH野生型星状細胞腫の62.5%が、IDH野生型のGBMに再分類された。本報により、神経膠腫に特化した遺伝子パネルが、WHO脳腫瘍分類2021に準じた分子診断に適用可能であることが確認された。

Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Shingo Fujio, Mari Kirishima, Kosuke Takigawa, Nobuhiro Hata, Keita Toh, Junkoh Yamamoto, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto .  Molecular Genetic Profile of 300 Japanese Patients with Diffuse Gliomas Using a Glioma-tailored Gene Panel. .  Neurologia medico-chirurgica62 ( 9 ) 391 - 399   2022.8Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Neurosurgical Society  

Rapid technological advances in molecular biology, including next-generation sequencing, have identified key genetic alterations in central nervous system (CNS) tumors. Accordingly, the fifth edition of the World Health Organization (WHO) CNS tumor classification was published in 2021. We analyzed 303 patients with diffuse glioma using an amplicon-based glioma-tailored gene panel for detecting 1p/19q codeletion and driver gene mutations such as IDH1/2, TERTp, EGFR, and CDKN2A/B on a single platform. Within glioblastomas (GBMs), the most commonly mutated genes were TERTp, TP53, PTEN, NF1, and PDGFRA, which was the most frequently mutated tyrosine kinase receptor in GBM, followed by EGFR. The genes that most commonly showed evidence of loss were PTEN, CDKN2A/B, and RB1, whereas the genes that most commonly showed evidence of gain/amplification were EGFR, PDGFRA, and CDK4. In 22 grade III oligodendroglial tumors, 3 (14%) patients had CDKN2A/B homozygous deletion, and 4 (18%) patients had ARID1A mutation. In grade III oligodendroglial tumors, an ARID1A mutation was associated with worse progression-free survival. Reclassification based on the WHO 2021 classification resulted in 62.5% of grade II/III isocitrate dehydrogenase (IDH) -wildtype astrocytomas being classified as IDH-wildtype GBM and 37.5% as not elsewhere classified. In summary, our glioma-tailored gene panel was applicable for molecular diagnosis in the WHO 2021 classification. In addition, we successfully reclassified the 303 diffuse glioma cases based on the WHO 2021 classification and clarified the genetic profile of diffuse gliomas in the Japanese population.

DOI： 10.2176/jns-nmc.2022-0103

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Sieya Yokoyama, Hiromichi Iwaya, Toshiaki Akahane, Taiji Hamada, Michiyo Higashi, Shinichi Hashimoto, Shiroh Tanoue, Takao Ohtsuka, Akio Ido, Akihide Tanimoto .  Sequential evaluation of <scp>MUC</scp> promoter methylation using next‐generation sequencing‐based custom‐made panels in liquid‐based cytology specimens of pancreatic cancer .  Diagnostic Cytopathology50 ( 11 ) 499 - 507   2022.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND: As liquid-based cytology (LBC) specimens preserve high-quality DNA, clinical sequencing of LBC specimens using next-generation sequencing (NGS) is becoming a common strategy. This study aimed to evaluate the feasibility of NGS-based custom-made panels for evaluating MUC promoter methylation in LBC specimens. METHODS: Thirty-one patients with pancreatic cancer were enrolled in the study. Cancer tissue samples were obtained using endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB). LBC, formalin-fixed paraffin-embedded (FFPE), and fresh frozen specimens were prepared for DNA extraction after pathological diagnosis. These specimens were then subjected to NGS analysis using custom-made cancer gene screening and methylation panels comprising 28 cancer-related genes and 13 gene promoter regions, including MUC1, MUC2, and MUC4. RESULTS: The success rate of NGS using the cancer gene panel was comparable among the LBC, FFPE, and frozen specimens, and the presence of cancer cell-derived somatic mutations in each specimen was confirmed. The specimens were then tested using a methylation panel that revealed the sequential methylation status of CpG islands located in the promoter regions of MUC genes. The methylation status results obtained from LBC specimens were almost comparable with those from FFPE and frozen specimens. CONCLUSIONS: MUC and other gene methylation analyses using an NGS-based panel were successfully performed in residual LBC specimens obtained by EUS-FNA/FNB. Therefore, this approach provides an alternative source of molecular tests for gene mutations and methylation, especially in the pancreatic cancers, which are often unresectable and unsuitable for obtaining FFPE specimens.

DOI： 10.1002/dc.25022

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窪田 恵美, 宿里 亜李沙, 岩切 かおり, 切田 ゆかり, 霧島 茉莉, 田崎 貴嗣, 北薗 育美, 田畑 和宏, 東 美智代, 谷本 昭英 .  乳腺転移を来した膵solid-pseudopapillary neoplasmの1例 .  日本臨床細胞学会九州連合会雑誌53   79 - 82   2022.7Reviewed

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 膵solid-pseudopapillary neoplasm(以下、SPN)は、膵外分泌腫瘍の1～3%を占める稀な腫瘍である。今回、乳腺細胞診において原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の1例を経験したので報告する。症例 50代女性。7年前に手術された膵SPN術後の定期検診にて左乳腺外側に1cm大の結節を指摘された。原発性乳癌が疑われ、針生検及び穿刺針洗浄細胞診が施行された。穿刺針洗浄細胞診で、血性背景に乳頭状、管状あるいは孤立散在性の異型細胞を多数認め、血管性間質を軸とした重積性を示す集塊も存在していた。核偏在傾向や核溝も見られ、浸潤性乳管癌充実型や粘液癌Type Bを疑った。摘出生検では、シート状構造を示す腫瘍細胞と淡好塩基性を示す疎な線維性間質を認め、偽乳頭状構造も認めた。免疫染色では、β-cateninが腫瘍細胞の核・細胞質に陽性であった。以上の所見から膵SPNの乳腺転移と判断した。結論 原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の一例を経験した。膵SPNの肝や腹腔以外への転移は稀ではあるが、臨床情報に留意し検鏡することで診断し得ると考えられた。(著者抄録)

Iwaizako Hiroki, Nishikawa Takuro, Kitazono Ikumi, Tanimoto Akihide, Okamoto Yasuhiro .  急性白血病によく似た所見を呈する原発不明悪性小円形細胞腫瘍(Unknown primary malignant small round cell tumor masquerading as acute leukemia) .  Pediatrics International64 ( 1 ) 1 of 3 - 3 of 3   2022.6Reviewed

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は16歳女性で、4ヵ月前から断続的な左腰背部痛および下肢痛を呈し総合病院を受診した。急性リンパ性白血病と診断され、直ちにプレドニゾロン投与が開始されたが、治療反応は不良であった。その後、小児固形腫瘍の骨髄浸潤が疑われたため当科に転科となった。病理診断の結果、悪性小円形細胞腫瘍であり、小細胞神経内分泌癌の可能性が高かった。PET-CTにて複数の骨、骨髄、腹腔内に異常集積を認めたが、原発巣は特定できなかった。シスプラチン・エトポシド療法後、骨髄検査にて異常細胞の消失が認められ、NSE値の低下も認められた。しかし、2回目の化学療法後、左腸骨病変が拡大し、骨髄に異常細胞が再び出現し、NSEは再び上昇した。がんゲノムプロファイリング検査を実施したが、有効な治療候補は見つからなかった。その後、ビンクリスチン/イリノテカン、左腸骨病変放射線療法、イホスファミド/エトポシド、アムルビシン、エベロリムスなどの治療が行われた。しかし、病状進行に伴い、肝不全、腎不全が再発し、144日目に死亡した。

野元 翔平, 上笹貫 太郎, 田畑 和宏, 谷本 昭英, 坂本 泰二 .  上眼瞼Merkel細胞癌の1例 .  臨床眼科76 ( 5 ) 597 - 602   2022.5Reviewed

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞目的:上眼瞼Merkel細胞癌の症例について報告する。症例:83歳,男性。所見:左上眼瞼の腫瘤を主訴に来院した。細隙灯顕微鏡検査では,左上眼瞼に8×9mm大の赤色調の球状腫瘤を認めた。急速に増大したためMerkel細胞癌を疑い,初診から6日後に左上眼瞼悪性腫瘍拡大切除術を施行した。腫瘍辺縁から5mmのsafety marginをとって拡大切除を行い,術中迅速病理診断で断端の腫瘍細胞が陰性であることを確認した。その後,switch flap法を用いて欠損した眼瞼を再建した。免疫組織学的検査の結果はMerkel細胞癌であった。術翌日に抗凝固薬を再開したところ,創部より多量の出血を認めたため,術後5日目および6日目に止血術を行った。2ヵ月後に同部位に再び腫瘤を認めたが,切除したところ化膿性肉芽腫の診断で再発ではなかった。結論:上眼瞼のMerkel細胞癌を経験した。術後に再度腫瘤を認めたが,再発ではなかった。ただし,再発しやすい腫瘍であるため,今後も慎重な経過観察が必要である。

Fukuda Kosuke, Arigami Takaaki, Tokuda Koki, Yanagita Shigehiro, Matsushita Daisuke, Kawasaki Yota, Iino Satoshi, Sasaki Ken, Nakajo Akihiro, Kirishima Mari, Tanimoto Akihide, Tsubouchi Hitoshi, Kurahara Hiroshi, Ohtsuka Takao .  肝転移を伴うステージIV胃癌に対するラムシルマブ+パクリタキセルのセカンドライン化学療法後のコンバージョン手術　1症例報告(Successful conversion surgery for stage IV gastric cancer with liver metastases after second-line chemotherapy with ramucirumab and paclitaxel: a case report) .  Surgical Case Reports8   1 of 7 - 7 of 7   2022.4Reviewed

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Language：English   Publisher：Springer Berlin Heidelberg  

症例は77歳男性で、体重減少をきたして受診した。血清CEA 371.5ng/mLを示し、食道胃十二指腸鏡検査で胃上部から中部1/3にかけて半周性の2型腫瘍を認め、生検後の病理診断では高分化型腺癌であった。造影CTにて腫瘍部における胃壁肥厚、小彎に沿ったリンパ節腫大、肝S3転移を認め、ステージIV HER2陽性胃癌の診断のもと、カペシタビン、シスプラチン、トラスツズマブ投与を予定した。しかし、トラスツズマブの初回投与後に重度の注入部反応を示したため、S-1+シスプラチン(SP療法)に切り替えた。3コース施行後にリンパ節と肝転移巣のサイズ縮小が得られたが、6コース終了後に血清CEAの上昇をきたして腫瘍コントロール不良と判断し、セカンドライン化学療法としてラムシルマブ+パクリタキセルを開始した。6コース終了後、原発巣と肝転移巣の著明な縮小がみられPRと判定、コンバージョン手術を行う方針とした。胃全摘術、D2リンパ節郭清、S3およびS4に対する肝部分切除を施行し、病理所見では原発腫瘍は固有筋層に浸潤しており組織学的グレード1aと考えられた。合併症の発症なく術後10日目に退院となり、42ヵ月後も再発徴候は認めていない。

児島 一成, 佐々木 文郷, 樺山 雅之, 藤野 悠介, 軸屋 賢一, 田中 啓仁, 霧島 茉莉, 東 美智代, 谷本 昭英, 井戸 章雄 .  腸管重複症と腔内憩室の鑑別が困難だった腺腫を伴う十二指腸隆起病変の1例 .  Gastroenterological Endoscopy64 ( 4 ) 1011 - 1017   2022.4Reviewed

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

症例は63歳の男性.十二指腸下行部に15mm大の側面に陥凹を伴う粘膜下腫瘍様病変で,陥凹面に大小不同の絨毛様構造を認め,管状腺腫もしくは高分化型腺癌が疑われた.超音波内視鏡検査では,腫瘍内部に無エコー域を認めた.早期十二指腸癌も否定できず,EMRを施行した.病理組織検査では,側面の陥凹面は管状腺腫と診断した.また,十二指腸内腔側と嚢胞内腔側は粘膜筋板を共有しており,腺腫を合併した十二指腸重複症が疑われたが,十二指腸腔内憩室(Intraluminal duodenal diverticulum:IDD)との鑑別が困難であった.両疾患は,稀ではあるものの十二指腸腫瘍性病変の鑑別の一つとして考慮すべき疾患と考えられた.(著者抄録)

KOJIMA Issei, SASAKI Fumisato, KABAYAMA Masayuki, FUJINO Yusuke, JIKUYA Kenichi, TANAKA Akihito, KIRISHIMA Mari, HIGASHI Michiyo, TANIMOTO Akihide, IDO Akio .  A CASE OF A DUODENAL ELEVATED LESION WITH ADENOMA THAT WERE DIFFICULT TO DISTINGUISH BETWEEN INTESTINAL DUPLICATION AND INTRALUMINAL DIVERTICULUM .  GASTROENTEROLOGICAL ENDOSCOPY64 ( 4 ) 1011 - 1017   2022Reviewed

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

<p>A 63-year-old man showed a duodenal elevated lesion on esophagogastroduodenoscopy, which was suspected to be an adenocarcinoma or adenoma on the basis of endoscopic findings. He was subsequently referred to our hospital for further examination and treatment. Endoscopic ultrasonography showed a hypoechoic area inside the tumor. The tumor was located on the second part of the duodenum and had a depression on its lateral side. On the basis of these findings, the patient underwent endoscopic mucosal resection. Histological examination of the resected specimen revealed that the depressed area was a tubular adenoma, and the luminal side of the duodenum and cystic area shared muscularis mucosae. The lesion was eventually diagnosed as duodenal duplication or intraluminal duodenal diverticulum with tubular adenoma. Although extremely rare, these diseases should be considered in the differential diagnosis of duodenal elevated lesions.</p>

DOI： 10.11280/gee.64.1011

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古江 惠理, 上笹貫 太郎, 平木 翼, 小牧 祐雅, 東 裕子, 谷本 昭英, 井戸 章雄, 坂本 泰二 .  眼窩内に寄生したマンソン孤虫症の1例 .  臨床眼科75 ( 8 ) 1031 - 1036   2021.8Reviewed

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞緒言:マンソン孤虫症は,マンソン裂頭条虫の幼虫であるプレロセルコイドがヒトに寄生する比較的稀な疾患である。皮下への感染報告がほとんどであり,眼窩内への寄生は,わが国での報告はわずかである。今回,眼窩内のマンソン孤虫症を経験したので報告する。症例:33歳,男性。2017年7月に右眼瞼腫脹が出現し,近医で右眼の結膜炎の診断を受けた。点眼加療で改善しなかったため精査目的で2018年10月に鹿児島大学病院眼科を初診した。右上眼瞼に移動性の腫脹を認め,さらに2年後の造影MRIでは右上直筋付近に占拠性病変が出現した。特発性眼窩炎症の疑いでステロイド内服加療を開始したが,その後の皮膚生検の結果からIgG4関連疾患の診断となった。ステロイド内服を継続したが,改善・増悪を繰り返し寛解には至らなかった。2020年6月に右眼結膜に白色病変を認めたため,摘出術を施行した。摘出後,右眼瞼腫脹は改善した。摘出された白色病変は,病理組織学的検査および寄生虫抗体検査でマンソン孤虫症であると考えられた。結論:眼窩内の寄生虫感染症は稀であり,特発性眼窩炎症やIgG4関連疾患と症状が類似しているため誤診されやすい。ステロイド抵抗性の繰り返す眼瞼腫脹や外眼筋炎の診断には寄生虫感染症も念頭に置くべきである。

Yoshii Daiki, Nakagawa Takenobu, Komohara Yoshihiro, Kawaguchi Hiroaki, Yamada Sohsuke, Tanimoto Akihide .  非アルコール性脂肪性肝疾患マイクロミニブタモデルにおけるマクロファージ活性化の表現型の変化(Phenotypic Changes in Macrophage Activation in a Model of Nonalcoholic Fatty Liver Disease using Microminipigs) .  Journal of Atherosclerosis and Thrombosis28 ( 8 ) 844 - 851   2021.8Reviewed

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Language：English   Publisher：(一社)日本動脈硬化学会  

非アルコール性脂肪性肝疾患(NAFLD)マイクロミニブタモデルを用いて、NAFLDの病態進展に伴うマクロファージ表現型の変化について検討した。マイクロミニブタ25頭を普通食群、コレステロール添加高脂肪食(HcD)(0.2%、0.5%、1.5%コレステロール)群、HcD(1.5%コレステロール)+コール酸群の5群に各5頭ずつ分けて、1日1回8週間給餌した。肝臓標本を用いた免疫組織化学染色(マクロファージ、リンパ球、星細胞)を実施した。その結果、Iba-1陽性マクロファージ数は、食餌中コレステロール含量の増加に伴い増加していた。また、CD163陽性マクロファージ数およびCD204陽性マクロファージ数も食餌中コレステロール含量の増加に伴い増加したが、Iba-1陽性マクロファージ中のCD204陽性マクロファージの割合は、コール酸の補給により有意に減少していた。以上から、ブタの肝臓では脂質蓄積によりマクロファージ動員が誘導され、NAFLD初期にはM2様マクロファージが増加し、NAFLD後期にはM1様マクロファージが増加し、非アルコール性脂肪肝炎様状態の肝臓になることが示唆された。

Noguchi M, Miura N, Ando T, Kubota C, Hobo S, Kawaguchi H, Tanimoto A .  Profiles of reproductive hormone in the microminipig during the normal estrous cycle. .  In vivo (Athens, Greece)29 ( 1 ) 17 - 22   2015.1Reviewed

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PubMed

Miyoshi N, Horiuchi M, Inokuchi Y, Miyamoto Y, Miura N, Tokunaga S, Fujiki M, Izumi Y, Miyajima H, Nagata R, Misumi K, Takeuchi T, Tanimoto A, Yasuda N, Yoshida H, Kawaguchi H .  Novel microminipig model of atherosclerosis by high fat and high cholesterol diet, established in Japan. .  In vivo (Athens, Greece)24 ( 5 ) 671 - 80   2010.9Reviewed

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PubMed

Miki Murakami, Hirotsugu Noguchi, Ryosuke Matsushita, Shuichi Tatarano, Mari Kirishima, Takashi Tasaki, Ikumi Kitazono, Michiyo Higashi, Hideki Enokida, Akihide Tanimoto .  Urothelial carcinoma arising in orthotopic ileal neobladder reconstruction: A case report. .  World journal of clinical cases13 ( 26 ) 104876 - 104876   2025.9Reviewed International journal

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BACKGROUND: An ileal neobladder is a standardized form of urinary diversion that provides acceptable outcomes in terms of long-term quality of life. Urothelial carcinomas (UCs) arising in the ileal neobladder are extremely rare, and few reports on this have been published in the English language. CASE SUMMARY: We report a case of UC that developed in the ileal neobladder of a 63-year-old man. The patient was diagnosed with UC in situ and underwent radical cystoprostatectomy and ileal neobladder creation. Ten years after the surgery and neoadjuvant chemotherapy, an UC developed in the ileal neobladder. CONCLUSION: Ileal neobladder urothelial carcinoma can originate from the implanted urothelium and the intestinal mucosa can migrate intraluminally.

DOI： 10.12998/wjcc.v13.i26.104876

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Shintaro Yanazume, Ikumi Kitazono, Shinichi Togami, Akihide Tanimoto, Hiroaki Kobayashi .  Potential biomarkers for predicting the efficacy of a pembrolizumab-containing regimen in advanced cervical cancer: A real-world analysis. .  Turkish journal of obstetrics and gynecology22 ( 3 ) 246 - 256   2025.9Reviewed International journal

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OBJECTIVE: Prognostic biomarkers in patients with advanced cervical cancer treated with immune checkpoint inhibitors remain unclear. An evaluation of combined positive score (CPS) and tumor proportion score (TPS), and a comparison of their usefulness with inflammatory biomarkers in real-world data could be informative. MATERIALS AND METHODS: We analyzed 28 patients who were treated with the KEYNOTE-826 regimen between November 2022 and June 2024. The complete cohort (group 1), patients with no prior chemotherapy (group 2), and treatment-naïve (group 3) were evaluated as follows: 1) CPS, TPS, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hemoglobin, albumin, lymphocyte, and platelets (HALP score) in peripheral blood samples were obtained prior to initial treatment and KEYNOTE-826 regimen, and receiver operating curve analysis was used to compare them. The optimal cut-off values that showed the highest level of discrimination for progression-free survival were identified. RESULTS: The areas under the curve (AUC) for progression-free survival in group 2 were measured for CPS, TPS, NLR, PLR, and HALP scores before the KEYNOTE-826 regimen. The AUC values for these scores were 0.644, 0.662, 0.852, 0.667, and 0.700, respectively. The lower NLR (≤5.52) group had a significantly longer median survival than the higher NLR (>5.52) group (p˂0.001), with median survivals of 14.0 vs. 7.6 months, respectively. In group 3, CPS and TPS were highest at 0.700 for predicting progression-free survival, compared to NLR, PLR, and HALP score. CPS and TPS appear positively correlated with progression-free survival. CONCLUSION: CPS and TPS showed a modest correlation with progression-free survival and NLR prior to immunotherapy demonstrated the best treatment efficacy for advanced cervical cancer.

DOI： 10.4274/tjod.galenos.2025.93607

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Takahiro Matsuyama, Kentaro Tanaka, Ikumi Kitazono, Kiyotaka Kondo, Midori Satomura, Hiromi Matsuyama, Hiromi Sasaki, Akihide Tanimoto, Noboru Taniguchi, Hiromasa Inoue .  Pulmonary metastasis of chondrosarcoma diagnosed by transbronchial lung biopsy after differentiation from organizing pneumonia: A case report. .  Respiratory investigation63 ( 5 ) 998 - 1001   2025.9Reviewed International journal

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A 49-year-old woman presented with abdominal distention and right leg numbness. Bone biopsy from a huge tumor in her pelvis revealed chondrosarcoma, and proton beam therapy was performed. Although there were no abnormalities at 6 months, dry cough, dyspnea and fever with elevated inflammation appeared at 9 months. Computed tomography showed multiple consolidations in both lungs, different from typical images of nodular shadows with calcification in pulmonary metastases of chondrosarcoma. We first suspected infection or organizing pneumonia, but biopsy revealed chondrosarcoma metastases with severely infiltrated inflammatory cells. Imaging patterns we experienced may reflect inflammatory pathogenesis due to rapid cancer progression.

DOI： 10.1016/j.resinv.2025.07.017

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Toshiaki Akahane, Ikumi Kitazono, Seiya Yokoyama, Yuriko Higashi, Hiroaki Kobayashi, Akihide Tanimoto .  Endometrial Liquid-Based Cytology Specimens Preserve High Genome Quality for Molecular Classification After Long-Term Storage. .  Diagnostic cytopathology   2025.8Reviewed International journal

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BACKGROUND: Molecular classification of endometrial cancer is useful for predicting prognosis. Genomic examinations are performed using formalin-fixed paraffin-embedded (FFPE) tissues; however, we previously reported that liquid-based cytology (LBC) specimens can be used for next-generation sequencing (NGS). In this study, we evaluated long-term storage effects of LBC specimens on NGS-based genomic profiling, including gene mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). METHODS: Four LBC fixatives (CellPrep, ThinPrep, CytoRich Red, and SurePath) were used to prepare NGS samples from cultured endometrioid carcinoma HEK-251 cells. Twelve endometrial LBC specimens from patients with endometrioid carcinoma were fixed with CytoRich Red. The TMB, MSI, and gene mutations were analyzed after 1 week, 6 months, and 12 months of storage in cultured HEK-251 cells. Paired LBC and FFPE specimens of endometrioid carcinoma stored for 15-45 months were subjected to NGS-based analysis, and their molecular profiles were compared to those at the initial diagnosis. RESULTS: The TMB and MSI did not differ during the storage periods for any of the LBC fixatives in the cultured cells; in addition to gene mutations, they were comparable between the initial and second analyses of the clinical FFPE and LBC specimens. There were no changes in the integrative diagnosis of the endometrioid carcinoma subtype classification. CONCLUSION: LBC specimens, which preserved high-quality genomes for molecular classification after long-term storage, may be an alternative source of genomic examination for the integrative diagnosis of endometrial cancer.

DOI： 10.1002/dc.70008

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Kosuke Fukuda, Yuto Hozaka, Hideyuki Oi, Miyo Tomita, Tetsuya Idichi, Yoichi Yamasaki, Yota Kawasaki, Yodai Hayashi, Yuichi Goto, Tsuyoshi Sugiura, Toshiaki Akahane, Michiyo Higashi, Akihide Tanimoto, Takao Ohtsuka .  Association between intra-tumoral microbiome and genetic alterations in intraductal papillary mucinous neoplasms of the pancreas. .  Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]   2025.8Reviewed International journal

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BACKGROUND/OBJECTIVES: We previously demonstrated that intra-tumoral microbiome infection may affects the clinicopathological characteristics of pancreatic intraductal papillary mucinous neoplasms (IPMNs) and showed that these characteristics are also influenced by gene mutations. The aim of this study was to investigate whether specific microbiome infections lead to alterations in the expression of specific genes in IPMNs. METHODS: DNA was extracted from 26 resected IPMN samples and subjected to genetic mutation assessment and microbiome analysis. The relationship between intra-tumoral microbiome and genetic alterations was investigated. RESULTS: There was an increasing trend in the percentage of Firmicutes in KRAS- and GNAS-mutated IPMNs, whereas Proteobacteria tended to decrease in KRAS-mutated IPMNs. KLF4-mutated IPMNs, particularly within the KRAS-mutated group, had significantly low α-diversity (p < 0.05). The relative abundance of Firmicutes and Proteobacteria was significantly higher in KLF4-mutated IPMNs, especially in KLF4-mutated IPMNs among the KRAS-mutated groups. An increased relative abundance of Firmicutes and Proteobacteria, along with the associated reduction in microbial diversity, was associated with a higher frequency of gene mutations, including KLF4. CONCLUSIONS: This study suggest that the intratumoral microbiome may be linked to the genetic characteristics of IPMNs and potentially contribute to their malignant progression.

DOI： 10.1016/j.pan.2025.08.001

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Keisuke Masuda, Nayuta Higa, Toshiaki Akahane, Shingo Baba, Kazutaka Yatsushiro, Hajime Yonezawa, Hiroyuki Uchida, Ryutaro Makino, Tomoko Takajo, Mari Kirishima, Takuro Isoda, Daisuke Kuga, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya .  Potential of Preoperative 11C-Methionine Positron Emission Tomography in Predicting EGFR Alterations and CDKN2A/B Homozygous Deletion in Diffuse Astrocytic Gliomas. .  Cureus17 ( 7 ) e87747   2025.7Reviewed International journal

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Objective L-methyl-11C-methionine (MET)- and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) are used to detect gliomas. However, the efficacy of MET-PET and FDG-PET in detecting gene alterations in gliomas remains unclear. Therefore, in this study, we evaluated the relationship between genetic alterations and PET tracer uptake in diffuse astrocytic glioma. Methods Thirty-two patients who had been newly diagnosed with astrocytic gliomas at Kagoshima University and Kyushu University and had undergone MET-PET and FDG-PET were enrolled. They underwent analysis of glioma-related gene expression using a customized 48-gene panel. Results The tumors identified in this study were classified as follows: glioblastomas, isocitrate dehydrogenase (IDH) wildtype (n = 15); astrocytic glioma, IDH-mutant, World Health Organization (WHO) grade 4 (n = 2); astrocytic glioma, IDH-mutant, WHO grade 3 (n = 4); astrocytic glioma, IDH-mutant, WHO grade 2 (n = 7); and diffuse astrocytic glioma, not elsewhere classified (n = 4). Astrocytic tumors with IDH mutations, ATRX mutations, and/or loss of function (mut/loss) had a significantly lower tumor-to-normal tissue (T/N) ratio on the MET-PET and FDG-PET images compared with those without these alterations. Astrocytic tumors with CDKN2A/B homozygous deletions (HD), EGFR mutation and/or amplification (mut/amp), or PTEN mut/loss had a significantly higher T/N ratio on the MET-PET images compared with those without these alterations. Astrocytic tumors with NF1 mut/loss had a significantly higher T/N ratio on their FDG-PET images compared with those without these alterations. The cut-off T/N ratio for the MET-PET images for the identification of EGFR mut/amp was 4.50 (sensitivity: 95%; specificity: 56%, AUC: 0.77), and that for detecting CDKN2A/B HDwas 2.32 (sensitivity: 72%; specificity: 86%; AUC: 0.85). Conclusion These findings from our small, retrospective cohort study suggest that MET-PET and FDG-PET are potentially valuable approaches for preoperatively predicting the molecular status of gliomas, particularly for assessing tumors with EGFR mut/amp and CDKN2A/B HD. Preoperative genetic alteration prediction in astrocytic gliomas based on PET tracer uptake may provide accurate information for patients and inform clinical decision-making. Multicenter prospective trials are essential.

DOI： 10.7759/cureus.87747

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Yuriko Higashi, Mika Mizuno, Ikumi Kitazono, Toshiaki Akahane, Takashi Tasaki, Hirotsugu Noguchi, Masanori Hisaoka, Hiroaki Kobayashi, Akihide Tanimoto .  Heterochronic pelvic high-grade myxoinflammatory fibroblastic sarcoma and uterine endometroid carcinoma harboring common gene mutations: a rare case report with genomic analysis. .  Diagnostic pathology20 ( 1 ) 71 - 71   2025.6Reviewed International journal

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OBJECTIVE: This report presents a rare case involving an extreme epithelial-to-mesenchymal transition, in which a specific type of sarcoma developed heterochronically as a recurrence of endometrioid carcinoma. CASE PRESENTATION: A female in her 50's presented with abnormal genital bleeding, and an endometrial biopsy revealed endometrioid carcinoma. Following the diagnosis of stage IA endometrioid carcinoma according to the 2008 classification system of the International Federation of Gynecology and Obstetrics, a robot-assisted simple hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node navigation surgery were performed. Six months postoperatively, a tumor mass developed in the pelvis. A transrectal needle biopsy revealed spindle cell proliferation, and pelvic tumor resection was conducted for diagnostic therapy. The patient received no adjuvant chemotherapy or radiotherapy after the second surgery and remained free of tumor recurrence for 8 months. The resected yellowish solid tumor mass, measuring 16 × 12 × 9 cm, exhibited hemorrhage, necrosis, and cystic degeneration and was composed of fascicular proliferation of spindle tumor cells showing nuclear pleomorphism and frequent mitotic figures within a myxoid and inflammatory stroma. No epithelial component or organoid patterns were observed. Immunohistochemically, the tumor cells were positive for factor XIIIa, CD10, and cyclin D1, but negative for keratins (AE1/AE3 and CAM5.2) and other specific markers, supporting a diagnosis of high-grade myxoinflammatory fibroblastic sarcoma (MIFS). CONCLUSION: Genomic analysis revealed identical mutations in PTEN, PIK3R1, CDKN2 A, and TP53 in both the primary uterine endometrioid carcinoma and heterochronic pelvic MIFS. An integrative approach involving histology, immunohistochemistry, and genomic analysis is critical for elucidating the pathogenesis of rare pelvic and uterine tumors.

DOI： 10.1186/s13000-025-01669-4

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Masako Noumi, Michiyo Higashi, Ikumi Kitazono, Seiya Yokoyama, Takashi Tasaki, Hirotsugu Noguchi, Mari Kirishima, Miki Nurakami, Akihide Tanimoto .  Expression of mucins MUC1 and MUC4 in curative resected gallbladder adenocarcinoma. .  Histology and histopathology   18928 - 18928   2025.4Reviewed International journal

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BACKGROUND AND AIMS: Gallbladder adenocarcinoma (GBAC) is associated with high mortality because of the difficulty in its early detection and treatment. Therefore, identifying prognostic factors is crucial for managing patients with GBAC. We aimed to elucidate the relationship between immunohistochemical profiles of mucin expression, clinicopathological behavior, and prognosis for curatively resected gallbladder adenocarcinoma (GBAC) and to prove that mucin expression is a prognostic factor for GBAC. METHODS: We examined the expression of mucins (MUC1, MUC2, and MUC4) using immunohistochemical analyses and compared the prevalence of each mucin with clinicopathological features in patients with early-stage (stage 0 to IIB) GBAC. RESULTS: MUC1 expression was significantly expressed in patients with GBAC with lymphatic invasion, vascular invasion, perineural invasion, and recurrence. MUC2 was significantly expressed in patients with GBAC with perineural invasion and recurrence but not with prognosis. Patients with MUC1-high expression exhibited worse prognoses than those with MUC1-low expression. In contrast, patients with positive MUC4 expression had significantly better prognoses than those without MUC4 expression. CONCLUSION: The expression of MUC1 and MUC4 in GBAC is an independent prognostic factor for survival and a useful marker for predicting the outcomes of patients with GBAC.

DOI： 10.14670/HH-18-928

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Ryutaro Makino, Madan Bajagain, Nayuta Higa, Toshiaki Akahane, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Seiya Yokoyama, Ryosuke Otsuji, Yutaka Fujioka, Daisuke Kuga, Hitoshi Yamahata, Masamichi Kurosaki, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya .  Analysis of clinical, histological, and genomic information of molecular glioblastoma in a Japanese glioma cohort. .  Brain tumor pathology   2025.4Reviewed

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In the 2021 WHO Central Nervous System tumor classification, the "Glioblastoma, IDH-wildtype" diagnosis changed markedly. In a Japanese cohort, we compared the clinical backgrounds and prognoses of molecular glioblastoma (mGBM) and conventional glioblastoma (histological glioblastoma, hGBM). We included 270 patients with glioblastoma treated at five institutions during 2011-2023. Driver gene analysis was performed using a brain tumor-specific custom gene panel to verify the association between molecular and clinical information. Patients with mGBM had better preoperative KPS, lower Ki-67, and lower removal rates than did those with hGBM. Overall survival was longer in patients with mGBM than in those with hGBM (1207 vs 599 days, p = 0.037). TP53 mutation (hazard ratio: 5.33, 95% confidence interval: 0.26-108.7, p = 0.012) and histological grade 3 (p = 0.051) were poor prognostic factors for mGBM. Patients with mGBM had better preoperative KPS, worse removal rates, lower Ki-67 labeling index, and better overall survival than did those with hGBM. In addition, the histological grade of mGBM is potentially useful for estimating prognosis. In the WHO CNS5 2021, glioblastoma patients remain a heterogeneous population, and prognostic stratification based on the patient's clinical background and molecular information is desirable.

DOI： 10.1007/s10014-025-00500-8

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Saeki Saito, Hirofumi Yoshino, Seiya Yokoyama, Mitsuhiko Tominaga, Gang Li, Junya Arima, Ichiro Kawahara, Ikumi Fukuda, Akihiko Mitsuke, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Shuichi Tatarano, Akihide Tanimoto, Hideki Enokida .  Targeting Heat Shock Transcription Factor 4 Enhances the Efficacy of Cabozantinib and Immune Checkpoint Inhibitors in Renal Cell Carcinoma. .  International journal of molecular sciences26 ( 4 )   2025.2Reviewed International journal

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Recently, immune checkpoint inhibitors (ICIs) and cabozantinib, a tyrosine kinase inhibitor (TKI), have been used to treat renal cell carcinoma (RCC); the combination of these agents has become a standard treatment for RCC. TKIs generally target vascular endothelial growth factor. However, cabozantinib is characterized by its targeting of MET. Therefore, cabozantinib can be used as a late-line therapy for TKI-resistant RCC. According to data from The Cancer Genome Atlas (TCGA), heat shock transcription factor 4 (HSF4) expression is higher in RCC tissues than in normal renal tissues. HSF4 binds to the MET promoter in colorectal carcinoma to enhance MET expression and promote tumor progression. However, the functional role of HSF4 in RCC is unclear. We performed loss-of-function assays of HSF4, and our results showed that HSF4 knockdown in RCC cells significantly decreased cell functions. Moreover, MET expression was decreased in HSF4-knockdown cells but elevated in sunitinib-resistant RCC cells. The combination of cabozantinib and HSF4 knockdown reduced cell proliferation in sunitinib-resistant cells more than each monotherapy alone. Furthermore, HSF4 knockdown combined with an ICI showed synergistic suppression of tumor growth in vivo. Overall, our strategy involving HSF4 knockdown may enhance the efficacy of existing therapies, such as cabozantinib and ICIs.

DOI： 10.3390/ijms26041776

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Taiji Hamada, Seiya Yokoyama, Toshiaki Akahane, Kei Matsuo, Ikumi Kitazono, Tatsuhiko Furukawa, Akihide Tanimoto .  Electroporation Induces Unexpected Alterations in Gene Expression: A Tip for Selection of Optimal Transfection Method. .  Current issues in molecular biology47 ( 2 )   2025.1Reviewed International journal

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Electroporation is an efficient method for nucleotide and protein transfer, and is used for clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-mediated genome editing. In this study, we investigated the effects of electroporation on platelet-derived growth factor receptor alpha (PDGFRA) and receptor tyrosine kinase (RTK) expression in U-251 and U-87 MG cells. PDGFRA mRNA and protein expression decreased 2 days after electroporation in both cell lines, with recovery observed after 13 days in U-87 MG cells. However, in U-251 MG cells, PDGFRα expression remained suppressed, despite mRNA recovery after 13 days. Similar expression profiles were observed for lipofection in the U-251 MG cells. Comprehensive RNA sequencing confirmed electroporation-induced up- and down-regulation of RTK mRNA in U-251 MG cells 2 days post-electroporation. In contrast, recombinant adeno-associated virus (rAAV) transfected with mNeonGreen fluorescent protein or Cas9 did not affect PDGFRA, RTKs, or inflammatory cytokine expression, suggesting fewer adverse effects of rAAV on U-251 MG cells. These findings emphasize the need for adequate recovery periods following electroporation or the adoption of alternative methods, such as rAAV transfection, to ensure the accurate assessment of CRISPR-mediated gene editing outcomes.

DOI： 10.3390/cimb47020091

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Ikumi Kitazono, Miki Murakami, Aya Takeda, Hirotsugu Noguchi, Takashi Tasaki, Mari Kirishima, Michiyo Higashi, Kazuhiro Ueda, Akihide Tanimoto .  Pulmonary pleomorphic carcinoma: A rare case showing arterial carcinomatosis mimicking pulmonary artery intimal sarcoma. .  Pathology international   2025.1Reviewed International journal

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A male in his seventies presented with lung cancer in the right lower lobe. The surgically resected specimen revealed a pleomorphic carcinoma featuring an adenocarcinoma component with lepidic, acinar, and papillary patterns, alongside a spindle cell component spreading along the pulmonary artery wall, resembling intimal sarcoma. The spindle tumor cells were positive for keratins, TTF-1, napsin A, and vimentin, but negative for p40, CK14, desmin, alpha-smooth muscle actin, CDK4, and MDM2. This profile indicates that the spindle cells originated from the adenocarcinoma cells via epithelial-mesenchymal transition. The vascular spread of pleomorphic carcinoma, mimicking pulmonary artery intimal sarcoma, represents an extremely rare mode of tumor invasion, which could be termed "arterial carcinomatosis". Immunohistochemical analysis is crucial for distinguishing pleomorphic carcinoma from coexisting intimal sarcoma, as the latter's prognosis is markedly poor.

DOI： 10.1111/pin.13508

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Kazuyuki Matsushita, Takayuki Ishige, Kousuke Watanabe, Toshiaki Akahane, Akihide Tanimoto, Michiko Yoshimoto, Munekazu Yamakuchi, Teruto Hashiguchi, Yoshinaga Okugawa, Makoto Ikejiri, Toshikazu Yamaguchi, Tadashi Yamasaki, Mayu Takeda, Masaaki Hibi, Naoki Akiyama, Kaho Shimizu, Naonori Hashimoto, Hiroko Sato, Yoshinori Tanaka, Fumie Amari .  Importance of EQA/PT for the detection of genetic variants in comprehensive cancer genome testing. .  Scientific reports15 ( 1 ) 1036 - 1036   2025.1Reviewed International journal

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Comprehensive genomic profiling (CGP) is increasingly used as a clinical laboratory test and being applied to cancer treatment; however, standardization and external quality assessments (EQA) have not been fully developed. This study performed cost-effective EQA and proficiency tests (PT) for CGP testing among multiple institutions those belong to the EQA working group of Japan Association for Clinical Laboratory Science (JACLS). This study revealed that preanalytical processes, such as derived nucleic acids (NA) extraction from formalin fixed paraffine embedded (FFPE) samples, are critical. First, EQA with extracted DNA from cell lines showed a detection rate of 100% (9 out of 9) in KRAS (c.38G > A; p.G13D), PIK3CA (p.H1047R), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) (c.1799 T > A; p.V600E) in cases of > 10% variant allele frequency (VAF). However, BRAF (c.1799 T > A; p.V600E) detection decreased to 67% (6 out of 9) for a VAF of 4.9%. Second, when DNA was extracted from FFPE samples, pathogenic variants and variants with companion diagnostic indications were detected in all 10 participating laboratories. Each variant had < 20% VAFs on average (8.1-19.1%) and wide variability among laboratories was observed (relative standard deviation, 13-60%). Nonetheless, BRAF (c.1798_1799delinsAA; p.V600K) of 8.1% VAF, EGFR (c.2235_2249del; p.E746_A750del) of 9.7% VAF, and EGFR (c.2254_2277del; p.S752_I759del) of 9.8% VAF were detected with 70% (7/10), 70% (7/10), and 60% (6/10) frequency, respectively. Therefore, 10% VAF in pre-analytic processing for DNA extraction from FFPE was critical for variant detection in CGP analysis. Further, incorrect results were reported in case independent variant calling of BRAF; c.1798_1799delinsAA (p.V600K) was mistakenly interpreted as c.1798G > A, and c.1799 T > A was on the other strand. In conclusion, the EQA/PT among 10 institutes with common samples revealed the importance of VAF in pre-analysis and helped us understand the significance of the pipeline and common pitfalls usually ignored by the internal quality control in a single institute.

DOI： 10.1038/s41598-024-84714-4

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Shintaro Yanazume, Yusuke Kobayashi, Yukari Kirita, Ikumi Kitazono, Chikako Nagata, Ayumi Kozai, Akihide Tanimoto, Hiroaki Kobayashi .  A potential inflammatory biomarker for advanced endometrial cancer treated with lenvatinib plus pembrolizumab. .  The journal of obstetrics and gynaecology research51 ( 1 ) e16182   2025.1Reviewed International journal

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INTRODUCTION: To identify prognostic biomarkers that could predict how well patients will respond to lenvatinib/pembrolizumab (LEN/PEM). The utility of certain inflammatory biomarkers in endometrial liquid-based cytology (LBC) or peripheral blood samples, such as neutrophil counts, lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) were explored. METHODS: The study included 25 patients with advanced or recurrent endometrial cancer who had received LEN/PEM between August 2018 and March 2024. Predictors for overall response (OR), disease control, and progression-free survival, based on neutrophil/lymphocyte counts, NLR scores of the endometrial LBC prior to initial treatment, and peripheral blood prior to initial treatment and prior to LEM/PEM treatment were compared using a receiver operating characteristic curve. Significant predictors were evaluated using the log-rank test, and multivariate analysis. RESULTS: Although neutrophil counts and NLR score in endometrial LBC prior to initial treatment were better effective predictors for OR, the most accurate predictor of a progression-free status was NLR score in peripheral blood prior to LEM/PEM (0.722, 95% CI: 0.45-0.99, sensitivity: 57.1%, specificity: 94.4%). In peripheral blood prior to LEN/PEM, the lower NLR (NLR <5.39) group had a significantly longer PFS than the higher NLR (5.39 ≤ NLR) group (p = 0.023, median survival: 13.5 vs. 3.0 months), and tended to be independently correlated with PFS (hazard ratio = 2.571; 95% CI = 0.857-7.719; p = 0.092). CONCLUSION: Inflammatory biomarkers in endometrial LBC failed to predict the efficacy of LEN/PEM, while peripheral blood NLR score sampled prior to LEN/PEM potentially could be a significant predictor.

DOI： 10.1111/jog.16182

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Madan Bajagain, Akihisa Sakamoto, Tomoko Takajo, Ryutaro Makino, Hiroyuki Uchida, Keisuke Masuda, Nayuta Higa, Hajime Yonezawa, Kazutaka Yatsushiro, Akihide Tanimoto, Ryosuke Hanaya .  Higher Uptake of Preoperative 11C-Methionine Positron Emission Tomography Related to Preoperative Seizure in Patients With Oligodendroglioma. .  Cureus17 ( 1 ) e76991   2025.1Reviewed International journal

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OBJECTIVE: Epileptic seizures are common in patients with low-grade gliomas (LGGs). 11C-methionine (MET) is a radiolabeled amino acid tracer commonly used in positron emission tomography (PET), and MET-PET is a valuable tool for the clinical characterization of gliomas. This study aimed to evaluate the factors associated with MET uptake in patients with suspected LGG and, specifically, to characterize MET uptake in the presence or absence of epilepsy. METHODS: MET uptake on preoperative MET-PET images was retrospectively reviewed in 40 patients with a presurgical diagnosis of LGG based on the absence of gadolinium enhancement on MRI. All patients underwent surgery and had their pathological diagnosis confirmed. The correlation between MET uptake and the occurrence of seizures in patients with LGGs was investigated during their clinical course. The ratio of the lesion to the contralateral normal region (L/N ratio) was calculated by dividing the maximum standardized uptake value of the tumor by the value of the contralateral region. Clinical parameters and MET uptake data were extracted from the medical records. RESULTS: The mean age of the patients was 48 years (range: 21-90 years), consisting of 26 males and 14 females. Preoperative seizures and 1p/19q codeletion were correlated with higher MET uptake (p < 0.01). Grade 2 oligodendrogliomas had significantly higher MET uptake than grade 2 astrocytomas and glioblastomas (p < 0.01). In particular, grade 2 oligodendrogliomas with preoperative seizures showed approximately twofold higher MET uptake than those without preoperative seizures (L/N ratio 2.01 vs. 1.20, p = 0.042). The optimal cutoff value of the lesion-to-contralateral-normal ratio of MET uptake for predicting preoperative seizures was 2.13, as calculated using a receiver operating characteristic curve and an area under the curve. Conversely, grade 2 astrocytoma and glioblastoma with or without seizures (L/N ratio 1.44 vs. 1.09, 1.40 vs. 1.34), as well as oligodendroglioma without seizures (L/N ratio 1.33), showed similar MET uptake. CONCLUSIONS: An epileptogenic formation mechanism may be involved in the increased uptake of MET in oligodendrogliomas. In patients with suspected LGGs, if there is a significant increase in MET uptake, the possibility of an oligodendroglioma should be considered and attention should be paid to the risk of epileptic seizures.

DOI： 10.7759/cureus.76991

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Kiyohisa Kamimura, Tomohiro Tokuda, Junki Kamizono, Tsubasa Nakano, Tomohito Hasegawa, Masanori Nakajo, Fumitaka Ejima, Fumiko Kanzaki, Koji Takumi, Masatoyo Nakajo, Shingo Fujio, Ryosuke Hanaya, Akihide Tanimoto, Takashi Iwanaga, Hiroshi Imai, Thorsten Feiweier, Takashi Yoshiura .  Time-dependent MR diffusion analysis of functioning and nonfunctioning pituitary adenomas/pituitary neuroendocrine tumors. .  Journal of neuroimaging : official journal of the American Society of Neuroimaging35 ( 1 ) e13254   2025Reviewed International journal

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BACKGROUND AND PURPOSE: Differentiation between functioning and nonfunctioning pituitary adenomas/pituitary neuroendocrine tumors (PAs) is clinically relevant. The goal of this study was to determine the feasibility of using time-dependent diffusion MRI (dMRI) for microstructural characterization of PAs. METHODS: The study included 54 participants, 24 with functioning PA and 30 with nonfunctioning PA. Time-dependent dMRI of the pituitary gland was performed using an inner field-of-view echo-planar imaging based on 2-dimensional-selective radiofrequency excitations with oscillating gradient and pulsed gradient preparation (effective diffusion time: 7.1 and 36.3 ms) at b-values of 0 and 1000 seconds/mm2. Each tumor had its apparent diffusion coefficients (ADCs) measured at two diffusion times (ADC7.1 ms and ADC36.3 ms), its ADC change (cADC), and relative ADC change. The mean values of diffusion parameters were compared between functioning and nonfunctioning PAs. We compared the diffusion parameters of nonfunctioning PAs with those of each type of hormone-producing PAs. The diagnostic performances of the diffusion parameters were assessed. RESULTS: The cADC was significantly higher in functioning PAs than nonfunctioning PAs (p = .0124). The receiver operating characteristic (ROC) curve analysis revealed that cADC (area under the ROC curve [AUC] = .677, p = .017) is effective in distinguishing between functioning and nonfunctioning PAs. The cADC was significantly higher in growth hormone (GH)-producing PAs compared to nonfunctioning PAs (p = .006). The ROC curve analysis indicated that cADC (AUC = .771, p < .001) effectively distinguishes between GH-producing and nonfunctioning PAs. CONCLUSIONS: The cADC derived from time-dependent dMRI could distinguish between functioning and nonfunctioning PAs, particularly those producing GH.

DOI： 10.1111/jon.13254

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Yuko Onishi, Naoki Miura, Akihide Tanimoto, Hiroaki Kawaguchi .  Methotrexate Enhances Atherosclerosis Progression via Impairment of Folate Pathway in a Microminipig Model. .  In vivo (Athens, Greece)39 ( 3 ) 1262 - 1274   2025Reviewed International journal

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BACKGROUND/AIM: As the pathophysiology of Microminipigs (μMPs) is similar to that of human, μMPs are useful in atherosclerosis research. To clarify the effect of methotrexate (MTX) on atherosclerosis, we investigated the pathology of MTX-induced atherosclerosis lesion exacerbation in μMPs fed a high-fat and high-cholesterol diet (HFHCD). MATERIALS AND METHODS: The μMPs were divided into four groups: HFHCD, HFHCD+MTX, HFHCD+MTX+leucovorin (LV), and HFHCD+MTX+folic acid (FA), and fed for two weeks. Laboratory tests including blood lipid, FA, and homocysteine (Hcy) levels, and pathological evaluation of the atherosclerosis lesion area and thickness were performed. Hepatic and jejunal gene expressions related to lipid and folate metabolism pathways including 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) were monitored using RT-PCR. RESULTS: The HFHCD+MTX group showed increased blood Hcy (p<0.01) and decreased FA levels (p<0.05) in accordance with increased hepatic MTR mRNA expression (p<0.1) and exacerbation of atherosclerosis (p=0.051 for lesion area and p=0.045 for lesion thickness) compared to the HFHCD group. Administration of LV or FA attenuated the MTX-induced increase in the Hcy level (p<0.01), atherosclerosis lesion thickness (p<0.1), and MTR mRNA expression (p<0.1 in HFHCD+MTX vs. HFHCD+MTX+LV groups). CONCLUSION: MTX exacerbated HFHCD-induced atherosclerosis mediated through reduced blood FA and the subsequent increase of Hcy in μMPs, indicating that the μMP model may advance cardio-oncology research by providing useful experimental approaches. As MTX is administered for rheumatoid arthritis and malignant tumors in humans, atherosclerosis exacerbation should be acknowledged as a possible adverse effect of MTX treatment.

DOI： 10.21873/invivo.13930

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Shinsuke Suzuki, Toshiaki Akahane, Akihide Tanimoto, Michiyo Higashi, Ikumi Kitazono, Mari Kirishima, Masakazu Nishigaki, Toshiro Ikeda, Shuichi Kanemitsu, Junichi Nakazawa, Erina Akahane, Hiroshi Nishihara, Kimiharu Uozumi, Makoto Yoshimitsu, Kenji Ishitsuka, Shin-Ichi Ueno .  Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration. .  PloS one20 ( 1 ) e0305025   2025Reviewed International journal

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Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

DOI： 10.1371/journal.pone.0305025

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Yusuke Sakiyama, Jun-Hui Yuan, Akiko Yoshimura, Mika Takeuchi, Yoshimitsu Maki, Takuma Mori, Jun Takei, Masahiro Ando, Yu Hiramatsu, Satoshi Nozuma, Yujiro Higuchi, Hajime Yonezawa, Mari Kirishima, Masayuki Suzuki, Takahiro Kano, Monami Tarisawa, Shunta Hashiguchi, Misako Kunii, Shoki Sato, Ikuko Takahashi-Iwata, Akihiro Hashiguchi, Eiji Matsuura, Shuji Izumo, Akihide Tanimoto, Hiroshi Takashima .  Brain biopsy and metagenomic sequencing enhance aetiological diagnosis of encephalitis. .  Brain communications7 ( 3 ) fcaf165   2025Reviewed International journal

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Identifying the aetiology of CNS diseases, regardless of their infectious or non-infectious nature, is often intricate. Next-generation sequencing (NGS) has emerged as a powerful tool for sensitive and unbiased screening of tissue or body fluid specimens. This study aimed to investigate the underlying aetiology of patients with suspected infectious CNS diseases. Between April 2013 and October 2021, we collected brain tissue samples from 33 patients diagnosed with encephalitis or encephalitis-like CNS diseases, obtained via biopsy or autopsy, and underwent metagenomic NGS (mNGS) in conjunction with pathological evaluations. Moreover, we employed PCR-based assays and pathogen-specific immunostaining to corroborate the presence of pathogens within the tissue samples. Among the 33 patients, mNGS elucidated pathogen-specific genomic sequences in 7 cases (21.2%), including halobacteria (archaea), Balamuthia mandrillaris, Epstein-Barr virus, Toxoplasma gondii and herpes simplex virus. Additionally, brain tissue mNGS ruled out known pathogens, identifying 14 cases (42.4%) of non-infectious CNS diseases, which included neoplastic, autoimmune/inflammatory and amyloid angiopathy conditions. The adjustment of therapeutic strategies based on these findings led to improvements in clinical symptoms, imaging outcomes and patient prognosis. Brain biopsy serves as both a direct pathological research target and a valuable source of samples for unbiased high-throughput sequencing. Our study illustrates the reliability of mNGS on brain tissue, which significantly improves the diagnostic rate for suspected encephalitis or encephalitis-like diseases of unknown aetiology. These findings underscore the importance of mNGS in guiding more precise and effective therapeutic interventions for patients in clinical practice.

DOI： 10.1093/braincomms/fcaf165

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Takuya Okada, Manabu Natsumeda, Hidemoto Fujiwara, Nayuta Higa, Toshiaki Akahane, Yuki Watabe, Kaoru Tomikawa, Kyoka Nishita, Yoshihiro Tsukamoto, Shinsuke Ohshima, Arata Horii, Akihide Tanimoto, Ryosuke Hanaya, Hiroshi Shimizu, Akiyoshi Kakita, Makoto Oishi .  Case Report: Improved hearing in a rare, adult IDH2-mutant brainstem astrocytoma successfully treated with radiation and temozolomide. .  Frontiers in oncology15   1555986 - 1555986   2025Reviewed International journal

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INTRODUCTION: Brain stem gliomas harboring IDH mutations can be sensitive to temozolomide (TMZ) treatment, unlike their H3K27-altered counterparts, so distinguishing the two is essential. CASE PRESENTATION: Here, we report an adult brainstem glioma patient whose hearing loss normalized after treatment. He presented with gradual left hearing loss from two years before, and magnetic resonance (MR) images showed a diffuse mass lesion involving the pons to left middle cerebral peduncle, including the vestibular and cochlear nuclei. On MR spectroscopy (MRS), 2-hydroxyglutarate (2HG) was elevated to 3.602 mM, suggesting an IDH-mutant glioma. Subsequently, an open biopsy was performed via the lateral suboccipital approach, and the pathological diagnosis was astrocytoma, IDH-mutant, CNS WHO grade 3. Molecular analysis revealed a non-canonical IDH2 R172S mutation. Left hearing improved from 87.5 dB to 8.3dB by 6-frequency pure tone audiogram (PTA) and 90% speech discrimination at 35 dB after concomitant TMZ and radiation treatment, followed by 12 cycles of adjuvant TMZ treatment. 2HG also decreased to 0.186 mM on MRS after treatment determining treatment strategy. DISCUSSION: Studies have shown that as high as 31% of adult brainstem gliomas are IDH mutant, with most of these mutations being non-canonical IDH1/2 mutations. Approximately 70% of IDH-mutant astrocytomas are known to harbor a methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter and respond to TMZ treatment, whereas almost all H3K27M-mutant diffuse midline gliomas have unmethylated MGMT promoters and generally are not sensitive to TMZ treatment. Detection of 2HG by MRS and molecular analysis, including non-canonical IDH1/2 mutations, were helpful in determining treatment response in this adult brainstem glioma case. Notably, hearing loss normalized after TMZ treatment. CONCLUSION: The diagnosis of IDH-mutant brainstem gliomas by MRS and integrated analysis of surgically obtained specimens is essential to determine the proper treatment of these rare cases.

DOI： 10.3389/fonc.2025.1555986

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Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto .  Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma. .  Cancer & metabolism12 ( 1 ) 35 - 35   2024.11Reviewed International journal

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BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive. METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells. RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth. CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.

DOI： 10.1186/s40170-024-00364-0

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Mari Kirishima, Seiya Yokoyama, Toshiaki Akahane, Nayuta Higa, Hiroyuki Uchida, Hajime Yonezawa, Kei Matsuo, Junkoh Yamamoto, Koji Yoshimoto, Ryosuke Hanaya, Akihide Tanimoto .  Prognosis prediction via histological evaluation of cellular heterogeneity in glioblastoma. .  Scientific reports14 ( 1 ) 24955 - 24955   2024.10Reviewed International journal

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Glioblastomas (GBMs) are the most aggressive types of central nervous system tumors. Although certain genomic alterations have been identified as prognostic biomarkers of GBMs, the histomorphological features that predict their prognosis remain elusive. In this study, following an integrative diagnosis of 227 GBMs based on the 2021 World Health Organization classification system, the cases were histologically fractionated by cellular variations and abundance to evaluate the relationship between cellular heterogeneity and prognosis in combination with O-6-methylguanine-DNA methyltransferase gene promoter methylation (mMGMTp) status. GBMs comprised four major cell types: astrocytic, pleomorphic, gemistocytic, and rhabdoid cells. t-distributed stochastic neighbor embedding analysis using the histological abundance of heterogeneous cell types identified two distinct groups with significantly different prognoses. In individual cell component analysis, the abundance of gemistocytes showed a significantly favorable prognosis but confounding to mMGMTp status. Conversely, the abundance of epithelioid cells was correlated with the unfavorable prognosis. Linear model analysis showed the favorable prognostic utility of quantifying gemistocytic and epithelioid cells, independent of mMGMTp. The evaluation of GBM cell histomorphological heterogeneity is more effective for prognosis prediction in combination with mMGMTp analysis, indicating that histomorphological analysis is a practical and useful prognostication tool in an integrative diagnosis of GBMs.

DOI： 10.1038/s41598-024-76826-8

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大西 俊平, 山崎 文之, Jeet Amatya Vishwa, 米澤 潮, 比嘉 那優大, 赤羽 俊章, 谷本 昭英, 武島 幸男, 花谷 亮典, 堀江 信貴 .  Astrocytoma,IDH-mutant with primitive neuronal componentの一例 .  Brain Tumor Pathology41 ( Suppl. ) 146 - 146   2024.5Reviewed

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比嘉 那優大, 赤羽 俊章, 米澤 大, 横山 勢也, 牧野 隆太郎, 内田 裕之, 霧島 茉莉, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  脳腫瘍1 小児脳腫瘍におけるカスタムDNA/RNAパネルを用いたクリニカルシーケンス .  小児の脳神経49 ( 2 ) 168 - 168   2024.4Reviewed

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霧島 茉莉, 赤羽 俊章, 横山 勢也, 比嘉 那優大, 米澤 大, 内田 裕之, 花谷 亮典, 吉本 幸司, 谷本 昭英 .  膠芽腫の細胞形態とゲノム変化による予後推定の試み .  日本病理学会会誌113 ( 1 ) 435 - 436   2024.2Reviewed

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Kiyohisa Kamimura, Tsubasa Nakano, Tomohito Hasegawa, Masanori Nakajo, Chihiro Yamada, Yoshiki Kamimura, Kentaro Akune, Fumitaka Ejima, Takuro Ayukawa, Hiroaki Nagano, Koji Takumi, Masatoyo Nakajo, Nayuta Higa, Hajime Yonezawa, Ryosuke Hanaya, Mari Kirishima, Akihide Tanimoto, Takashi Iwanaga, Hiroshi Imai, Thorsten Feiweier, Takashi Yoshiura .  Differentiating primary central nervous system lymphoma from glioblastoma by time-dependent diffusion using oscillating gradient. .  Cancer imaging : the official publication of the International Cancer Imaging Society23 ( 1 ) 114 - 114   2023.11Reviewed International journal

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BACKGROUND: This study aimed to elucidate the impact of effective diffusion time setting on apparent diffusion coefficient (ADC)-based differentiation between primary central nervous system lymphomas (PCNSLs) and glioblastomas (GBMs) and to investigate the usage of time-dependent diffusion magnetic resonance imaging (MRI) parameters. METHODS: A retrospective study was conducted involving 21 patients with PCNSLs and 66 patients with GBMs using diffusion weighted imaging (DWI) sequences with oscillating gradient spin-echo (Δeff = 7.1 ms) and conventional pulsed gradient (Δeff = 44.5 ms). In addition to ADC maps at the two diffusion times (ADC7.1 ms and ADC44.5 ms), we generated maps of the ADC changes (cADC) and the relative ADC changes (rcADC) between the two diffusion times. Regions of interest were placed on enhancing regions and non-enhancing peritumoral regions. The mean and the fifth and 95th percentile values of each parameter were compared between PCNSLs and GBMs. The area under the receiver operating characteristic curve (AUC) values were used to compare the discriminating performances among the indices. RESULTS: In enhancing regions, the mean and fifth and 95th percentile values of ADC44.5 ms and ADC7.1 ms in PCNSLs were significantly lower than those in GBMs (p = 0.02 for 95th percentile of ADC44.5 ms, p = 0.04 for ADC7.1 ms, and p < 0.01 for others). Furthermore, the mean and fifth and 95th percentile values of cADC and rcADC were significantly higher in PCNSLs than in GBMs (each p < 0.01). The AUC of the best-performing index for ADC7.1 ms was significantly lower than that for ADC44.5 ms (p < 0.001). The mean rcADC showed the highest discriminating performance (AUC = 0.920) among all indices. In peritumoral regions, no significant difference in any of the three indices of ADC44.5 ms, ADC7.1 ms, cADC, and rcADC was observed between PCNSLs and GBMs. CONCLUSIONS: Effective diffusion time setting can have a crucial impact on the performance of ADC in differentiating between PCNSLs and GBMs. The time-dependent diffusion MRI parameters may be useful in the differentiation of these lesions.

DOI： 10.1186/s40644-023-00639-7

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Yoshiaki Shinden, Kayo Kamimura, Naoki Hayashi, Yuki Nomoto, Ayako Nagata, Yuka Eguchi, Hanako Yano, Hazuki Saho, Akihiro Nakajo, Koji Minami, Tadahiro Hirashima, Ken Sasaki, Heiji Yoshinaka, Tetsuhiro Owaki, Akihide Tanimoto, Masayuki Nakamura, Takao Otsuka .  Relationship between Delayed Breast Cancer Diagnosis and Behavioral Economic Factors and Personality Characteristics. .  Asian Pacific journal of cancer prevention : APJCP24 ( 10 ) 3437 - 3440   2023.10Reviewed International journal

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BACKGROUND: Delays in breast cancer diagnosis can allow the disease to progress to an incurable stage. However, factors that cause patients to delay seeking treatment are unclear. In this study, we aimed to identify behavioral economic factors and personality characteristics of patients with breast cancer who had a delayed diagnosis. METHODS: We analyzed questionnaires completed by 41 patients with breast cancer. A delayed diagnosis was defined if the time between the first symptom and the medical visit was more than 6 months. RESULTS: We found 11 patients who had a delayed diagnosis. The significant characteristics associated with patients with breast cancer who had delayed diagnosis were: (i) less experience with breast cancer screening; (ii) progressive disease stage; and (iii) low time and future time preference. We found no significant behavioral economic factors other than time preference, and personality that differed between patients with breast cancer who did and did not have a delayed diagnosis. CONCLUSION: Low time preference rate is a characteristic of patients with breast cancer who had a delayed diagnosis.

DOI： 10.31557/APJCP.2023.24.10.3437

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霧島 茉莉, 赤羽 俊章, 横山 勢也, 比嘉 那優大, 米澤 大, 内田 裕之, 花谷 亮典, 吉本 幸司, 谷本 昭英 .  膠芽腫の形態とゲノム変化の相関 .  日本病理学会会誌112 ( 2 ) 137 - 137   2023.10Reviewed

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谷本 昭英, 赤羽 俊彰, 比嘉 那優大, 花谷 亮典, 吉本 幸司 .  ゲノムと病理のコラボが推進する、真のプレシジョンメディシン 脳腫瘍におけるゲノム病理診断の有用性 .  日本癌治療学会学術集会抄録集61回   CCWS7 - 2   2023.10Reviewed

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切田 ゆかり, 北薗 育美, 亀澤 雅, 古家 淳行, 窪田 恵美, 霧島 茉莉, 村上 未樹, 田崎 貴嗣, 簗詰 伸太郎, 東 美智代, 小林 裕明, 谷本 昭英 .  子宮腟部液状化検体細胞診(LBC)に出現した卵巣原発yolk sac tumorの一例 .  日本臨床細胞学会雑誌62 ( Suppl.2 ) 508 - 508   2023.10Reviewed

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兒玉 憲人, 西中間 祐希, 甲斐 祐介, 濱之上 仁美, 堂園 美香, 野口 悠, 武井 潤, 永田 龍世, 樋口 雄二郎, 菅田 淳, 比嘉 那優大, 米澤 大, 霧島 茉莉, 谷本 昭英, 高嶋 博 .  当院で経験した脳アミロイドアンギオパチー関連炎症の3例の検討 .  Dementia Japan37 ( 4 ) 692 - 692   2023.10Reviewed

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Language：Japanese   Publisher：(一社)日本認知症学会  

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古家 淳行, 亀澤 雅, 窪田 恵美, 岩切 かおり, 霧島 茉莉, 田崎 貴嗣, 北薗 育美, 東 美智代, 谷本 昭英 .  右臀部に発生した類上皮肉腫の一例 .  日本臨床細胞学会九州連合会雑誌54   83 - 86   2023.7Reviewed

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背景 類上皮肉腫は形態および免疫組織学的に上皮様を呈する腫瘍細胞が胞巣形成性に増殖する稀な悪性軟部腫瘍で,しばしばラブドイド細胞が出現する.今回,右臀部に発生した類上皮肉腫を経験したので報告する.症例 30代,女性.右臀部の筋肉内腫瘤および右鼠径部腫瘤を認めた.穿刺吸引細胞診では血性背景に上皮様結合を有した異型細胞が集塊状に出現していた.異型細胞の結合性は緩く,豊富な細胞質を有し,核は偏在傾向を示し,核縁は菲薄で平滑で,クロマチンは細顆粒状で均等に分布していた.癌の転移や肉腫が疑われたが,組織型の推定は困難であった.摘出された腫瘍は,組織学的に好酸性胞体の上皮様腫瘍細胞が線維性間質内に索状やシートに増殖し,腫瘍中心に壊死を伴っていた.免疫組織化学的に腫瘍細胞は,cytokeratin(AE1/AE3,CAM5.2),Vimentin,CD34陽性を示し,INI-1の欠失を認めた.細胞所見,免疫組織化学を含む組織所見より類上皮肉腫と診断した.結語 類上皮肉腫の細胞像では,豊富な細胞質を有する上皮様結合を示す異型細胞を認めるが,結合性は緩いこと,肉腫を示唆する菲薄で平滑な核縁であることに着目することが重要であると考えられた.(著者抄録)

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赤羽 俊章, 坂本 一平, 比嘉 那優大, 霧島 茉莉, 牧野 隆太郎, 米澤 大, 内田 裕之, 吉本 幸司, 花谷 亮典, 谷本 昭英 .  がんゲノム診断とバイオインフォマティクス 神経膠腫の統合分子病理診断のための自動レポーティングシステムの構築とバイオインフォマティクスの重要性 .  Brain Tumor Pathology40 ( Suppl. ) 067 - 067   2023.5Reviewed

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比嘉 那優大, 赤羽 俊章, 横山 勢也, 米澤 大, 内田 裕之, 霧島 茉莉, 山本 淳考, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  IDH wildtype-TERTp wildtype glioblastomaにおけるPTENの予後への影響 .  Brain Tumor Pathology40 ( Suppl. ) 098 - 098   2023.5Reviewed

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牧野 隆太郎, 比嘉 那優大, 赤羽 俊章, 米澤 大, 内田 裕之, 霧島 茉莉, 山本 淳考, 吉本 幸司, 谷本 昭英, 花谷 亮典 .  がんゲノム診断 日本人膠芽腫患者におけるチロシンキナーゼ受容体変異と臨床像 .  Brain Tumor Pathology40 ( Suppl. ) 061 - 061   2023.5Reviewed

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田崎 貴嗣, 霧島 茉莉, 北薗 育美, 田畑 和宏, 東 美智代, 安村 拓人, 豊川 建二, 谷本 昭英 .  胸部大動脈瘤を呈した巨細胞性動脈炎の1例 .  診断病理40 ( 1 ) 91 - 95   2023.1Reviewed

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症例は80代女性。リウマチ性多発筋痛症の治療中に胸部大動脈瘤を指摘され,人工血管置換術が行われた。大動脈では内膜に軽度の粥状硬化を認めた。中膜ではリンパ球や形質細胞,少数の多核巨細胞の浸潤,内膜側優位の弾性線維の配列の乱れと消失を認めたが,外膜の線維化や炎症細胞浸潤は軽度であり,巨細胞性動脈炎と診断した。大動脈瘤において巨細胞性動脈炎と病理診断される症例では,側頭動脈炎の既往がなく臨床症状に乏しいことがあり,大動脈瘤を注意深く検索することで,巨細胞性動脈炎の可能性を見落とさないことが重要である。(著者抄録)

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Takashi Tasaki, Eisuke Shiba, Hirotsugu Noguchi, Mari Kirishima, Ikumi Kitazono, Wataru Terabaru, Kazuhiro Tabata, Michiyo Higashi, Naohiro Shinohara, Hiromi Sasaki, Masanori Nakajo, Masatoyo Nakajo, Masanori Hisaoka, Akihide Tanimoto .  Low-grade Fibromyxoid Sarcoma With Massive Degeneration: A Case of Unusual Gross and Histological Features. .  In vivo (Athens, Greece)37 ( 6 ) 2863 - 2868   2023Reviewed International journal

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BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of sarcoma which is observed in the soft tissue of proximal extremities, typically in young and middle-aged adults. It consists of a solid proliferation of bland spindle cells within collagenous and myxoid stroma. CASE REPORT: Herein, we report a case of LGFMS with massive degeneration and hyalinization. A 30-year-old man presented with a well-circumscribed mass measuring 15 cm in diameter in his left biceps femoris muscle. Marginal tumor resection was performed under the clinical diagnosis of an ancient schwannoma or chronic expanding hematoma (CEH). The resected tissue revealed a well-demarcated tumor mass with massive degeneration and hyalinization with focal calcification. Proliferation of spindle tumor cells with abundant collagenous stroma, which resembled the fibrous capsule of CEH, was observed exclusively in a small area of the periphery of the tumor. No nuclear palisading, myxoid stroma, or collagen rosettes were identified. Immunohistochemical analysis demonstrated that the spindle tumor cells expressed mucin 4 and epithelial membrane antigen. Reverse transcriptase-polymerase chain reaction analysis detected mRNA expression of fused in sarcoma::CAMP-responsive element binding protein 3-like protein 2 (FUS::CREB3L2) fusion gene. Thus, a final diagnosis of LGFMS with massive degeneration and FUS::CREB3L2 fusion was made. CONCLUSION: The recognition of massive degeneration and hyalinization as unusual features of LGFMS might be helpful to differentiate it from CEH and other benign spindle-cell tumors.

DOI： 10.21873/invivo.13404

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Takuro Nishikawa, Takahiro Tomoda, Aki Nakamura, Jun Nagahama, Akihito Tanaka, Shuji Kanmura, Mari Kirishima, Akihide Tanimoto, Tsubasa Okano, Takahiro Kamiya, Kentaro Okamoto, Susumu Kirimura, Tomohiro Morio, Yasuhiro Okamoto, Hirokazu Kanegane .  Case Report: The leopard sign as a potential characteristic of chronic granulomatous disease-associated colitis, unrelated to colitis severity. .  Frontiers in immunology14   1208590 - 1208590   2023Reviewed International journal

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BACKGROUND: Chronic granulomatous disease (CGD) is an inborn immune disorder in which the phagocytic system cannot eradicate pathogens, and autoinflammation occurs. Approximately half of the patients have associated gastrointestinal symptoms. Although most cases with CGD-associated colitis present nonspecific histology, colonoscopy in some cases shows brownish dots over a yellowish oedematous mucosa, which is termed a "leopard sign". However, the significance of these signs remains unclear. METHODS: We collected data from patients with CGD whose colonoscopic findings showed the leopard sign. RESULTS: Three patients with CGD and leopard signs were enrolled in this study. One patient underwent colonoscopy for frequent diarrhoea and weight gain failure, and another for anal fistula. The third patient was without gastrointestinal symptoms and underwent colonoscopy as a screening test before allogeneic haematopoietic cell transplantation (HCT). Endoscopic findings showed a mild leopard sign in the first case; however, non-contiguous and diffuse aphthae were observed throughout the colon. The other two cases were unremarkable except for the leopard sign. All the patients achieved remission with oral prednisolone or HCT. One patient underwent colonoscopy after HCT; results revealed improvements in endoscopy (including the leopard sign) and histological findings. However, another patient underwent colonoscopy after prednisolone treatment; this revealed no change in the leopard sign. CONCLUSION: The leopard sign in the colon may be a characteristic endoscopic finding of CGD, even in patients who do not develop severe gastrointestinal symptoms; however, it does not reflect the severity of CGD-associated colitis.

DOI： 10.3389/fimmu.2023.1208590

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北薗 育美, 霧島 茉莉, 田崎 貴嗣, 田畑 和宏, 東 美智代, 野口 紘嗣, 簗詰 伸太郎, 神宮司 メグミ, 谷本 昭英 .  FDG-PET高集積を示した遺残副腎由来のOncocytomaの1例 .  診断病理39 ( 4 ) 319 - 325   2022.10Reviewed

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遺残副腎は異所性に認められる副腎皮質組織であり,腫瘍化は非常に稀である。80代女性の骨盤腔内にFDGの高集積を呈する腫瘍を認めた。腫瘍は右子宮広間膜内に卵巣とは離れて存在し,好酸性顆粒状の豊富な細胞質を有する腫瘍細胞のびまん性増殖からなり,腫瘍辺縁には非腫瘍性の副腎皮質組織を伴っていた。免疫染色でSF-1,mitochondria陽性であった。Lin-Weiss-Bisceglia criteriaを満たす所見はなく,遺残副腎由来のoncocytomaと診断した。(著者抄録)

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窪田 恵美, 宿里 亜李沙, 岩切 かおり, 切田 ゆかり, 霧島 茉莉, 田崎 貴嗣, 北薗 育美, 田畑 和宏, 東 美智代, 谷本 昭英 .  乳腺転移を来した膵solid-pseudopapillary neoplasmの1例 .  日本臨床細胞学会九州連合会雑誌53   79 - 82   2022.7Reviewed

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背景 膵solid-pseudopapillary neoplasm(以下、SPN)は、膵外分泌腫瘍の1～3%を占める稀な腫瘍である。今回、乳腺細胞診において原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の1例を経験したので報告する。症例 50代女性。7年前に手術された膵SPN術後の定期検診にて左乳腺外側に1cm大の結節を指摘された。原発性乳癌が疑われ、針生検及び穿刺針洗浄細胞診が施行された。穿刺針洗浄細胞診で、血性背景に乳頭状、管状あるいは孤立散在性の異型細胞を多数認め、血管性間質を軸とした重積性を示す集塊も存在していた。核偏在傾向や核溝も見られ、浸潤性乳管癌充実型や粘液癌Type Bを疑った。摘出生検では、シート状構造を示す腫瘍細胞と淡好塩基性を示す疎な線維性間質を認め、偽乳頭状構造も認めた。免疫染色では、β-cateninが腫瘍細胞の核・細胞質に陽性であった。以上の所見から膵SPNの乳腺転移と判断した。結論 原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の一例を経験した。膵SPNの肝や腹腔以外への転移は稀ではあるが、臨床情報に留意し検鏡することで診断し得ると考えられた。(著者抄録)

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Nayuta Higa, Toshiaki Akahane, Taiji Hamada, Hajime Yonezawa, Hiroyuki Uchida, Ryutaro Makino, Shoji Watanabe, Tomoko Takajo, Seiya Yokoyama, Mari Kirishima, Kei Matsuo, Shingo Fujio, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto .  Distribution and favorable prognostic implication of genomic EGFR alterations in IDH-wildtype glioblastoma. .  Cancer medicine12 ( 1 ) 49 - 60   2022.6Reviewed International journal

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BACKGROUND: We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor (EGFR) gene in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). METHODS: We sequenced EGFR, evaluated the EGFR splicing profile using a next-generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH-wildtype GBM cases. RESULTS: EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis (p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores (p = 0.014) and lower Ki-67 scores (p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR-amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6-7 (Δe 6-7) and exons 2-14 (Δe 2-14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2-14 mutation during recurrence. CONCLUSIONS: We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH-wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII.

DOI： 10.1002/cam4.4939

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Mari Kirishima, Seiya Yokoyama, Kei Matsuo, Taiji Hamada, Michiko Shimokawa, Toshiaki Akahane, Tomoyuki Sugimoto, Hirohito Tsurumaru, Matsujiro Ishibashi, Yuko Mataki, Takao Ootsuka, Mitsuharu Nomoto, Chihiro Hayashi, Akihiko Horiguchi, Michiyo Higashi, Akihide Tanimoto .  Gallbladder microbiota composition is associated with pancreaticobiliary and gallbladder cancer prognosis. .  BMC microbiology22 ( 1 ) 147 - 147   2022.5Reviewed International journal

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BACKGROUND: The microbial population of the intestinal tract and its relationship to specific diseases has been extensively studied during the past decade. However, reports characterizing the bile microbiota are rare. This study aims to investigate the microbiota composition in patients with pancreaticobiliary cancers and benign diseases by 16S rRNA gene amplicon sequencing and to evaluate its potential value as a biomarker for the cancer of the bile duct, pancreas, and gallbladder. RESULTS: We enrolled patients who were diagnosed with cancer, cystic lesions, and inflammation of the pancreaticobiliary tract. The study cohort comprised 244 patients. We extracted microbiome-derived DNA from the bile juice in surgically resected gallbladders. The microbiome composition was not significantly different according to lesion position and cancer type in terms of alpha and beta diversity. We found a significant difference in the relative abundance of Campylobacter, Citrobacter, Leptotrichia, Enterobacter, Hungatella, Mycolicibacterium, Phyllobacterium and Sphingomonas between patients without and with lymph node metastasis. CONCLUSIONS: There was a significant association between the relative abundance of certain microbes and overall survival prognosis. These microbes showed association with good prognosis in cholangiocarcinoma, but with poor prognosis in pancreatic adenocarcinoma, and vice versa. Our findings suggest that pancreaticobiliary tract cancer patients have an altered microbiome composition, which might be a biomarker for distinguishing malignancy.

DOI： 10.1186/s12866-022-02557-3

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野元 翔平, 上笹貫 太郎, 田畑 和宏, 谷本 昭英, 坂本 泰二 .  臨床報告 上眼瞼Merkel細胞癌の1例 .  臨床眼科76 ( 5 ) 597 - 602   2022.5Reviewed

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DOI： 10.11477/mf.1410214373

窪田 恵美, 岩切 かおり, 古家 淳行, 亀澤 雅, 霧島 茉莉, 田崎 貴嗣, 北薗 育美, 東 美智代, 谷本 昭英 .  診断に苦慮した耳下腺の乳腺相似分泌癌の一例 .  日本臨床細胞学会雑誌61 ( Suppl.1 ) 281 - 281   2022.5Reviewed

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Michiyo Higashi, Taiji Hamada, Ken Sasaki, Yusuke Tsuruda, Masataka Shimonosono, Ikumi Kitazono, Mari Kirishima, Takashi Tasaki, Hirotsugu Noguchi, Kazuhiro Tabata, Masanori Hisaoka, Yoshihiko Fukukura, Takao Ohtsuka, Akihide Tanimoto .  Esophageal plexiform fibromyxoma: A case report with molecular analysis for MALAT1-GLI1 fusion. .  Pathology, research and practice233   153878 - 153878   2022.5Reviewed International journal

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Plexiform fibromyxoma (PFM) is a rare gastrointestinal tract tumor that develops in the stomach in most cases. Here, we report an extremely rare case of esophageal PFM. A female in her mid-30 s presented with difficulty in swallowing and breathing. Endoscopic examination revealed a submucosal tumor measuring approximately 45 × 50 mm in the upper thoracic esophagus. The biopsied specimen did not show definite histological evidence of gastrointestinal stromal tumors (GISTs). Since imatinib administration based on a clinical diagnosis of GIST did not show a therapeutic effect for tumor reduction, tumor resection was performed. The resected tumor exhibited proliferation of spindle tumor cells with abundant myxoid and vascular stroma separated by a muscular layer, indicating a plexiform arrangement. Immunohistochemical analysis demonstrated that the tumor cells diffusely expressed vimentin and alpha-smooth muscle actin, but not desmin, c-kit, DOG1, and CD34. MALAT1-GLI1 fusion was detected in formalin-fixed paraffin-embedded tissue using RT-PCR and Sanger sequencing. The results suggested that a fibromyxoid tumor can develop in the esophagus, showing an identical histology and MALAT1-GLI1 fusion to gastric PFM.

DOI： 10.1016/j.prp.2022.153878

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赤羽 俊章, 比嘉 那優大, 霧島 茉莉, 内田 裕之, 米澤 大, 吉本 幸司, 谷本 昭英 .  頭頸部・脳腫瘍用カスタム融合遺伝子パネルで認められた、IDH1変異陽性神経膠腫のNTRK融合遺伝子 .  Brain Tumor Pathology39 ( Suppl. ) 086 - 086   2022.5Reviewed

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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比嘉 那優大, 赤羽 俊章, 横山 勢也, 米澤 大, 内田 裕之, 浜田 大治, 霧島 茉莉, 谷本 昭英, 花谷 亮典, 吉本 幸司 .  IDH wild-type GBMにおけるPDGFRA amplificationおよびMGMTpの予後への影響 .  Brain Tumor Pathology39 ( Suppl. ) 086 - 086   2022.5Reviewed

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Kosuke Fukuda, Takaaki Arigami, Koki Tokuda, Shigehiro Yanagita, Daisuke Matsushita, Yota Kawasaki, Satoshi Iino, Ken Sasaki, Akihiro Nakajo, Mari Kirishima, Akihide Tanimoto, Hitoshi Tsubouchi, Hiroshi Kurahara, Takao Ohtsuka .  Successful conversion surgery for stage IV gastric cancer with liver metastases after second-line chemotherapy with ramucirumab and paclitaxel: a case report. .  Surgical case reports8 ( 1 ) 58 - 58   2022.4Reviewed International journal

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BACKGROUND: In recent years, conversion surgery after chemotherapy has been considered a promising strategy for improving the prognosis of patients with stage IV gastric cancer. However, there are few reports on conversion gastrectomy after second-line chemotherapy. Here, we report a case of long-term survival of a patient with liver metastases from gastric cancer who underwent conversion surgery after second-line chemotherapy with ramucirumab and paclitaxel. CASE PRESENTATION: A 77-year-old man complaining of weight loss was diagnosed with human epidermal growth factor receptor 2-positive gastric cancer with multiple liver metastases. Although the patient initially received trastuzumab-based chemotherapy, it was discontinued, because he experienced trastuzumab-induced infusion reactions. Thereafter, he was treated with six courses of S-1 plus cisplatin and six courses of ramucirumab plus paclitaxel as the first- and second-line regimens, respectively. The primary tumor and liver metastases remarkably shrank, and the reduction rate of the measurable metastatic liver lesions was 81.1%. According to the Response Evaluation Criteria in Solid Tumors, the patient responded partially. Therefore, he underwent total gastrectomy with D2 lymphadenectomy and partial hepatectomy of segments 3 and 4. Pathological examination revealed tumor invasion into the muscularis propria, a grade 1a histological response, and no lymph node metastases. No viable cancer cells were identified in the specimens resected from liver segments 3 and 4. Accordingly, the patient was pathologically diagnosed with stage IB (ypT2N0M0). Postoperatively, the patient received adjuvant chemotherapy with S-1 for 6 months, and he survived without recurrence for 42 months after conversion surgery. CONCLUSIONS: Conversion surgery might be clinically useful for improving survival in certain patients with gastric cancer, including those who previously received second-line chemotherapy.

DOI： 10.1186/s40792-022-01412-x

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大庭 優士, 安田 俊介, 鶴薗 健太郎, 冨岡 勇也, 松山 崇弘, 三山 英夫, 末次 隆行, 水野 圭子, 井上 博雅, 田畑 和宏, 谷本 昭英 .  イピリムマブ+ニボルマブ+カルボプラチン+ペメトレキセド併用療法で視力の改善が得られた脈絡膜転移を有する肺腺癌の1例 .  肺癌62 ( 2 ) 141 - 141   2022.4Reviewed

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Ikumi Kitazono, Toshiaki Akahane, Yusuke Kobayashi, Shintaro Yanazume, Kazuhiro Tabata, Takashi Tasaki, Hirotsugu Noguchi, Mari Kirishima, Michiyo Higashi, Hiroaki Kobayashi, Akihide Tanimoto .  Pelvic Carcinosarcoma Showing a Diverse Histology and Hierarchical Gene Mutation with a Common POLE Mutation to Endometrial Endometroid Carcinoma: A Case Report. .  International journal of surgical pathology30 ( 8 ) 10668969221088880 - 10668969221088880   2022.3Reviewed International journal

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POLE mutation-type endometrial cancer is characterized by an extremely high tumor mutation burden. Most POLE mutation-type endometrial cancers are histologically endometrioid carcinomas, and POLE mutation-type carcinosarcomas are rare among endometrial cancers. We report a case of endometrial and pelvic cancer in a 53-year-old woman who was analyzed using next-generating sequencing. The endometrial lesion harbored a p.T457del POLE mutation with an elevated tumor mutation burden and low microsatellite instability. The pelvic lesion showed divergent histological features, consisting of high-grade endometrioid carcinoma, neuroendocrine carcinoma, and chondrosarcoma. In addition to the common POLE mutation detected in the endometrial lesion, the pelvic lesion in each element showed additional gene mutations in a hierarchical manner. Therefore, it is indicated that the p.T457del POLE mutation is a pathogenic mutation and may be related to POLE mutation-induced carcinogenesis and divergent morphogenesis in endometrial cancer.

DOI： 10.1177/10668969221088880

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Aya Takeda, Kazuhiro Ueda, Masaya Aoki, Toshiyuki Nagata, Go Kamimura, Tadashi Umehara, Takuya Tokunaga, Kazuhiro Tabata, Akihide Tanimoto, Masami Sato .  Altered lymphatic structure and function in pleural anthracosis: negative role in skip N2 metastasis. .  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery62 ( 3 )   2022.2Reviewed International journal

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OBJECTIVES: The present study investigated whether or not pleural anthracosis is associated with changes in the pleural lymphatic structures or function, which would interfere with nodal skip metastasis. METHODS: This study comprised 2 different case series. In the first series, we observed pleural lymphatic drainage using near-infrared fluorescent endoscopy by the subpleural injection of indocyanine green immediately after thoracotomy for lung cancer. We also performed a histological assessment of the pleura. In the second series, we reviewed the nodal metastatic pattern (skip or non-skip metastasis) in pathological N2 lung cancer involving the pleura. These findings were compared with the severity of pleural anthracosis, which was quantified by thoracoscopic vision and a software-based imaging analysis. RESULTS: In the first series (n = 42), pleural lymphatic drainage was not visualized in 19 (45%) patients who had relatively severe anthracosis, while it was visualized in the remaining 23 (55%) patients who had relatively minimal anthracosis. Histologically, severe anthracosis was associated with pleural thickening accompanied by a decreased incidence of straight-running lymphatic vessels and, in turn, an increased incidence of short lymphatic vessels, which was suggested to be the result of pleural remodelling. In the second series (n = 53), a skip metastatic pattern was found in 24 (45%) patients who predominantly had less-severe anthracosis, while a non-skip metastatic pattern was found in 29 (55%) patients who predominantly had severe anthracosis. CONCLUSIONS: Pleural anthracosis was associated with pathological changes in the pleural lymphatics and decreased pleural lymphatic drainage, thereby interfering with nodal skip metastasis.

DOI： 10.1093/ejcts/ezac123

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Ikumi Kitazono, Yusuke Kobayashi, Toshiaki Akahane, Tomomi Yamaguchi, Shintaro Yanazume, Sachio Nohara, Ippei Sakamoto, Kazuhiro Tabata, Takashi Tasaki, Hiroaki Kobayashi, Akihide Tanimoto .  ATM immunohistochemistry as a potential marker for the differential diagnosis of no specific molecular profile subtype and POLE-mutation subtype endometrioid carcinoma. .  Pathology, research and practice230   153743 - 153743   2022.2Reviewed International journal

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Ancillary immunohistochemical tools can facilitate an integrated diagnosis of endometrial pathology. According to The Cancer Genome Atlas classification, endometrial cancers are of four molecular subtypes: mismatch repair (MMR)-deficient (MMR-d), p53 mutation (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP). As the specific histological and immunohistochemical features of POLEmut and NSMP subtypes are unknown, these cancers are categorized based on molecular analysis. In this study, we analyzed POLEmut-subtype endometrioid carcinoma (EC) using a custom-made cancer gene panel and the Catalog of Somatic Mutations in Cancer (COSMIC) database, extracted a characteristic genome profile, and identified an immunohistochemical marker that could be used as a diagnostic tool. The results indicated that the POLEmut-subtype EC exhibited nonsense mutations in the ataxia telangiectasia mutated (ATM) gene and a subsequent loss of ATM expression, which was monitored through immunohistochemical analysis. Moreover, analyses using the COSMIC database indicated that POLEmut-subtype EC cases often harbored similar ATM nonsense mutations. These results suggest that ATM expression is a potential immunohistochemical marker for the differential diagnosis of POLEmut- and NSMP-subtype EC. DATA AVAILABILITY: The data supporting the findings of this study are available upon request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.

DOI： 10.1016/j.prp.2021.153743

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Taiji Hamada, Toshiaki Akahane, Seiya Yokoyama, Nayuta Higa, Mari Kirishima, Kei Matsuo, Michiko Shimokawa, Koji Yoshimoto, Akihide Tanimoto .  An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors. .  Scientific reports12 ( 1 ) 1275 - 1275   2022.1Reviewed International journal

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Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3'-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.

DOI： 10.1038/s41598-022-05391-9

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Mari Kirishima, Toshiaki Akahane, Nayuta Higa, Hajime Yonezawa, Hiroyuki Uchida, Ikumi Kitazono, Michiyo Higashi, Koji Yoshimoto, Akihide Tanimoto .  Integrated diagnosis of adult-type glioma according to 2021 World Health Organization classification: Analysis of 184 cases using a custom-made next-generation sequencing panel. .  Pathology international72 ( 3 ) 207 - 210   2022.1Reviewed International journal

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DOI： 10.1111/pin.13197

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Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Ryosuke Otsuji, Taiji Hamada, Kei Matsuo, Mari Kirishima, Nobuhiro Hata, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto .  Prognostic impact of <i>PDGFRA</i> gain/amplification and <i>MGMT</i> promoter methylation status in patients with <i>IDH</i> wild-type glioblastoma .  Neuro-Oncology Advances4 ( 1 ) vdac097   2022.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

Platelet-derived growth factor receptor alpha (PDGFRA) is the second most frequently mutated tyrosine kinase receptor in glioblastoma (GBM). However, the prognostic impact of PDGFRA amplification on GBM patients remains unclear. Herein, we evaluated this impact by retrospectively analyzing outcomes of patients with IDH wild-type GBM.

Methods

Using a custom-made oncopanel, we evaluated PDGFRA gain/amplification in 107 GBM samples harboring wild-type IDH, along with MGMT promoter (MGMTp) methylation status.

Results

We detected PDGFRA gain/amplification in 31 samples (29.0%). PDGFRA gain/amplification predicted poor prognosis (P = .003). Compared to unamplified PDGFRA, PDGFRA gain/amplification in GBM was associated with higher patient age (P = .031), higher Ki-67 score (P = .019), and lower extent of surgical resection (P = .033). Unmethylated MGMTp also predicted poor prognosis (P = .005). As PDGFRA gain/amplification and unmethylated MGMTp were independent factors for poor prognosis in multivariate analyses, we grouped GBM cases based on PDGFRA and MGMTp status: poor (PDGFRA gain/amplification and unmethylated MGMTp), intermediate (PDGFRA gain/amplification or unmethylated MGMTp), and good (PDGFRA intact and methylated MGMTp) prognosis. The Kaplan-Meier survival analysis indicated that these groups significantly correlated with the OS of GBM patients (P &amp;lt; .001).

Conclusions

Here we report that PDGFRA gain/amplification is a predictor of poor prognosis in IDH wild-type GBM. Combining PDGFRA gain/amplification with MGMTp methylation status improves individual prognosis prediction in patients with IDH wild-type GBM.

DOI： 10.1093/noajnl/vdac097

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Other Link： https://academic.oup.com/noa/article-pdf/4/1/vdac097/45178840/vdac097.pdf

Hiroki Iwaizako, Takuro Nishikawa, Ikumi Kitazono, Akihide Tanimoto, Yasuhiro Okamoto .  Unknown primary malignant small round cell tumor masquerading as acute leukemia. .  Pediatrics international : official journal of the Japan Pediatric Society64 ( 1 ) e15158   2022.1Reviewed International journal

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DOI： 10.1111/ped.15158

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Takuya Yoshimura, Shotaro Higashi, Sohsuke Yamada, Hirotsugu Noguchi, Mitsuharu Nomoto, Hajime Suzuki, Takayuki Ishida, Hirotaka Takayama, Yuka Hirano, Masaru Yamashita, Akihide Tanimoto, Norifumi Nakamura .  PCP4/PEP19 and HER2 Are Novel Prognostic Markers in Mucoepidermoid Carcinoma of the Salivary Gland. .  Cancers14 ( 1 )   2021.12Reviewed International journal

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Mucoepidermoid carcinoma (MEC) is one of the most common malignant salivary gland carcinomas, but no effective treatment strategy has been established other than surgical resection. Purkinje cell protein (PCP) 4/peptide (PEP) 19 is a calmodulin-binding antiapoptotic peptide that is expressed and inhibits apoptosis in human breast cancer cells. Human epidermal growth factor receptor 2 (HER2) is an epidermal growth factor that has been implicated in the pathogenesis of many carcinomas, particularly breast and gastric carcinomas. In the present study, we performed immunohistochemical analyses of samples from 73 patients who underwent surgical resection for MEC of the salivary gland using antibodies against PCP4/PEP19 and HER2. PCP4/PEP19 expression was related to better prognosis, while HER2 expression was associated with worse prognosis. Patients that were PCP4/PEP19-positive and HER2-negative showed similar outcomes to PCP4/PEP19 and HER2 alone. Therefore, PCP4/PEP19 and HER2 are predicted to play important roles in the pathogenesis and progression of MEC.

DOI： 10.3390/cancers14010054

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田代 葵子, 上笹貫 太郎, 堀之内 道子, 谷本 昭英, 坂本 泰二 .  臨床報告 インターフェロン-β結膜下注射が奏効した結膜悪性黒色腫の1例 .  臨床眼科75 ( 13 ) 1650 - 1656   2021.12Reviewed

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DOI： 10.11477/mf.1410214248

田代 葵子, 上笹貫 太郎, 堀之内 道子, 谷本 昭英, 坂本 泰二 .  インターフェロン-β結膜下注射が奏効した結膜悪性黒色腫の1例 .  臨床眼科75 ( 13 ) 1650 - 1656   2021.12Reviewed

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞目的:インターフェロン-β(IFN-β)結膜下注射の頻回投与で縮小に至った結膜悪性黒色腫の症例を報告する。症例:患者は91歳,女性。20XX年8月に増大と出血を伴う右下眼瞼結膜の隆起性腫瘤を自覚し,加療を目的として鹿児島大学病院眼科を紹介された。高血圧症,糖尿病,ネフローゼ症候群の既往があった。所見:初診時,右下眼瞼結膜に15mm大の出血を伴う隆起性腫瘤を認めた。拡大切除術を提案したが,高齢のため外科的治療を希望しなかった。下眼瞼結膜腫瘤を部分切除し,悪性黒色腫と組織診断した。全身検査では遠隔転移は検出されなかった。出血傾向の改善のため放射線治療(線量28Gy/14Fr)を行ったのち,IFN-β結膜下注射(300万単位/回)の継続で経過観察した。1回目の注射後から出血傾向は改善した。さらに週1回で注射を継続したところ,投与開始後3回目より隆起性病変は縮小を認め,8回目でほぼ消失した。副作用として視力低下を認めたため,投与間隔を延ばし,1回量を半減して投与を継続した。その後も病変の増悪や遠隔転移は認めなかったが,投与開始から8ヵ月後に既往のネフローゼ症候群の悪化を認めたため治療を中止した。結論:IFN-β結膜下注射は結膜悪性黒色腫の治療に有効であった。しかし,眼局所および全身に副作用を及ぼす可能性があり,投与量および投与間隔に注意が必要である。

林 知実, 門野 潤, 井上 真岐, 坂元 昭彦, 二渡 久智, 平木 翼, 谷本 昭英, 風呂井 彰 .  Dubin-Johnson症候群に発生した肝細胞癌の1例 .  日本臨床外科学会雑誌82 ( 12 ) 2262 - 2269   2021.12Reviewed

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肝細胞癌(HCC)を合併したDubin-Johnson症候群(DJS)の肝予備能評価と周術期経過を報告する.66歳の男性がRickettsia属による感染の際に肝障害と肝S4,S2にHCCを指摘された.T-bil 4.6(D-bil 3.4)mg/dL,Alb 4.2g/dL,PT 92%,indocyanine green 15分停滞率(ICGR15)11%,Child-Pugh B(7点),肝障害度Aであった,99mTc-galactosyl human serum albumin(GSA)シンチグラフィのLHL15は0.909で,肝予備能はほぼ正常と判断し,肝内側区域切除術+S2部分切除術を行った.術後3日目にT-bilが15.7mg/dLまで上昇したが28日目に術前値に復した.ICGR15とGSAシンチグラフィは正確に肝予備能を反映した.術後のT-bilの上昇は一過性であった.(著者抄録)

Shinichi Togami, Takashi Ushiwaka, Ikumi Kitazono, Shintaro Yanazume, Masaki Kamio, Akihide Tanimoto, Hiroaki Kobayashi .  One-step nucleic acid amplification (OSNA) assay for detecting lymph node metastasis in cervical and endometrial cancer: a preliminary study. .  Journal of gynecologic oncology33 ( 2 ) e11   2021.11Reviewed International journal

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OBJECTIVE: To evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay for the diagnosis of lymph node (LN) metastasis in uterine cancer. METHODS: A total of 116 LNs from 30 patients with cervical and endometrial cancer, enrolled in this prospective study, were used. Excised LNs were cut into 4 to 6 blocks at 2 mm intervals, and nonadjacent blocks were alternately subjected to either histological examination or the OSNA assay. RESULTS: The concordance rate between histological examination and the OSNA assay in cervical cancer and in endometrial cancer was 95.9% and 95.2%, respectively. The sensitivity, specificity, and negative predictive value of the OSNA assay were 80%, 97.7%, and 97.7% in cervical cancer, and 85.7%, 93.3%, and 98.2% in endometrial cancer, respectively. In cervical cancer, discordant results were observed in 2 out of 49 LNs (4.1%); 1 was OSNA assay-positive and histological examination-negative, and 1 was OSNA assay-negative and histological examination-positive. In endometrial cancer, discordant results were observed in 5 out of 67 LNs (7.5%); 4 were OSNA assay-positive and histological examination-negative, and 1 was OSNA assay-negative and histological examination-positive. CONCLUSION: The OSNA assay showed high concordance rate with histological examination, sensitivity, and specificity in uterine cancer, suggesting that it could enhance the accuracy of conventional pathological examination for the detection of LN metastasis by reducing false negative rate.

DOI： 10.3802/jgo.2022.33.e11

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Kaori Kato, Masato Tsutsui, Shingo Noguchi, Yukitoshi Iha, Keisuke Naito, Takaaki Ogoshi, Chinatsu Nishida, Masahiro Tahara, Hirotaka Yamashita, Ke-Yong Wang, Yumiko Toyohira, Nobuyuki Yanagihara, Hiroaki Masuzaki, Hiroaki Shimokawa, Akihide Tanimoto, Kazuhiro Yatera .  Spontaneous pulmonary emphysema in mice lacking all three nitric oxide synthase isoforms. .  Scientific reports11 ( 1 ) 22088 - 22088   2021.11Reviewed International journal

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The roles of endogenous nitric oxide (NO) derived from the entire NO synthases (NOSs) system have yet to be fully elucidated. We addressed this issue in mice in which all three NOS isoforms were deleted. Under basal conditions, the triple n/i/eNOSs-/- mice displayed significantly longer mean alveolar linear intercept length, increased alveolar destructive index, reduced lung elastic fiber content, lower lung field computed tomographic value, and greater end-expiratory lung volume as compared with wild-type (WT) mice. None of single NOS-/- or double NOSs-/- genotypes showed such features. These findings were observed in the triple n/i/eNOSs-/- mice as early as 4 weeks after birth. Cyclopaedic and quantitative comparisons of mRNA expression levels between the lungs of WT and triple n/i/eNOSs-/- mice by cap analysis of gene expression (CAGE) revealed that mRNA expression levels of three Wnt ligands and ten Wnt/β-catenin signaling components were significantly reduced in the lungs of triple n/i/eNOSs-/- mice. These results provide the first direct evidence that complete disruption of all three NOS genes results in spontaneous pulmonary emphysema in juvenile mice in vivo possibly through down-regulation of the Wnt/β-catenin signaling pathway, demonstrating a novel preventive role of the endogenous NO/NOS system in the occurrence of pulmonary emphysema.

DOI： 10.1038/s41598-021-01453-6

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Toshiyuki Nagata, Kentaro Minami, Masatatsu Yamamoto, Tsubasa Hiraki, Masashi Idogawa, Katsumi Fujimoto, Shun Kageyama, Kazuhiro Tabata, Kohichi Kawahara, Kazuhiro Ueda, Ryuji Ikeda, Yukio Kato, Masaaki Komatsu, Akihide Tanimoto, Tatsuhiko Furukawa, Masami Sato .  BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma. .  International journal of molecular sciences22 ( 21 )   2021.10Reviewed International journal

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Lung cancer constitutes a threat to human health. BHLHE41 plays important roles in circadian rhythm and cell differentiation as a negative regulatory transcription factor. This study investigates the role of BHLHE41 in lung cancer progression. We analyzed BHLHE41 function via in silico and immunohistochemical studies of 177 surgically resected non-small cell lung cancer (NSCLC) samples and 18 early lung squamous cell carcinoma (LUSC) cases. We also examined doxycycline (DOX)-inducible BHLHE41-expressing A549 and H2030 adenocarcinoma cells. BHLHE41 expression was higher in normal lung than in lung adenocarcinoma (LUAD) tissues and was associated with better prognosis for the overall survival (OS) of patients. In total, 15 of 132 LUAD tissues expressed BHLHE41 in normal lung epithelial cells. Staining was mainly observed in adenocarcinoma in situ and the lepidic growth part of invasive cancer tissue. BHLHE41 expression constituted a favorable prognostic factor for OS (p = 0.049) and cause-specific survival (p = 0.042) in patients with LUAD. During early LUSC, 7 of 18 cases expressed BHLHE41, and this expression was inversely correlated with the depth of invasion. DOX suppressed cell proliferation and increased the autophagy protein LC3, while chloroquine enhanced LC3 accumulation and suppressed cell death. In a xenograft model, DOX suppressed tumor growth. Our results indicate that BHLHE41 expression prevents early lung tumor malignant progression by inducing autophagic cell death in NSCLC.

DOI： 10.3390/ijms222111509

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Hirotsugu Noguchi, Michiyo Higashi, Ryo Desaki, Takashi Tasaki, Mari Kirishima, Ikumi Kitazono, Kazuhiro Tabata, Akihide Tanimoto .  Adult Hepatocellular Carcinoma Coexisting with Extramedullary Hematopoiesis. .  International journal of surgical pathology30 ( 3 ) 10668969211050904 - 10668969211050904   2021.10Reviewed International journal

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Extramedullary hematopoiesis (EMH) in adults usually occurs in the liver, spleen, and lymph nodes when bone marrow hematopoiesis fails. EMH has also been recognized in benign or malignant hepatic tumors, such as hepatoblastoma, hepatocellular adenoma, and vascular tumors. However, it is rarely encountered in hepatocellular carcinoma (HCC) in elderly adults, and the molecular mechanism of EMH in hepatic tumors remains unclear. We present a case of a 74-year-old man without any hematopoietic disorders and hepatitis viral infection who underwent hepatic resection for HCC. Histological examination revealed a well-differentiated HCC with trilineage hematopoiesis in the tumor and non-neoplastic liver. The coexistence of HCC and EMH in adult patients with no hematopoietic disorders is very rare and must be distinguished from poorly differentiated or dedifferentiated HCC and hepatoblastoma.

DOI： 10.1177/10668969211050904

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Tokuro Baba, Takafumi Kawano, Yusuke Saito, Shun Onishi, Koji Yamada, Waka Yamada, Ryuta Masuya, Kazuhiko Nakame, Yota Kawasaki, Satoshi Iino, Masahiko Sakoda, Mari Kirishima, Tatsuru Kaji, Akihide Tanimoto, Shoji Natsugoe, Takao Ohtsuka, Hiroshi Moritake, Satoshi Ieiri .  Malignant perivascular epithelioid cell neoplasm in the liver: report of a pediatric case. .  Surgical case reports7 ( 1 ) 212 - 212   2021.9Reviewed International journal

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BACKGROUND: Perivascular epithelioid cell neoplasm (PEComa) in a child is very rare. We herein report the first malignant case of PEComa developing in the liver of a pediatric patient. CASE PRESENTATION: A 10-year-old boy visited a private clinic with prolonged fever of unknown etiology. Abdominal ultrasonography was performed to evaluate the fever's origin, revealing a large tumor in the liver. He was thus referred to a nearby hospital to investigate the tumor further. Enhanced computed tomography (CT) showed a 6.8 × 5.9 × 10.5-cm solid lesion on S4 and S5. On magnetic resonance imaging (MRI), the tumor had a low signal intensity on T1 imaging and high signal intensity on T2 imaging, with partial diffusion restriction. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed a marked uptake in the mass lesion with no evidence of metastasis. The patient was negative for all tumor markers, including AFP, CEA and PIVKA-II. The results of a needle biopsy suggested hepatocellular carcinoma. The tumor's rapid growth suggested malignancy. Hepatic segmentectomy (S4 + S5 + S8) was performed. The tumor was resected en bloc with a margin. Microscopically, the tumor showed atypical spindle, polygonal or oval-shaped cells with a high nuclear grade, and vascular invasion. Immunohistochemistry was positive for alpha-smooth muscle antigen (α-SMA), human melanin black-45 (HMB-45) and melan A. The pathological diagnosis was malignant PEComa. In the 6 months after surgery, the patient complained of shoulder pain. MRI showed a dumbbell-shaped tumor at the 2nd thoracic vertebrae, which was confirmed to be bone metastasis of PEComa. After chemotherapy, including ifosfamide and doxorubicin, vertebrectomy was performed. Two years later, thoracoabdominal CT showed a 10-cm solid mass occupying the pelvis and a 15-mm nodule in the middle lobe of the right lung. Under a diagnosis of peritoneal and lung metastases, they were surgically removed and metastasis of PEComa was pathologically confirmed. Four months after the 2nd relapse, pelvic metastasis appeared again and mTOR (mammalian target of rapamycin) inhibitor was initiated. To our knowledge, this is the first report of malignant hepatic PEComa in a pediatric patient. CONCLUSION: Although extremely rare, malignant hepatic PEComa can develop in a child.

DOI： 10.1186/s40792-021-01300-w

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Yuto Hozaka, Hiroshi Kurahara, Hideyuki Oi, Tetsuya Idichi, Yoichi Yamasaki, Yota Kawasaki, Kiyonori Tanoue, Megumi Jinguji, Masatoyo Nakajo, Atsushi Tani, Akihiro Nakajo, Yuko Mataki, Yoshihiko Fukukura, Hirotsugu Noguchi, Michiyo Higashi, Takashi Yoshiura, Akihide Tanimoto, Takao Ohtsuka .  Clinical Utility and Limitation of Diagnostic Ability for Different Degrees of Dysplasia of Intraductal Papillary Mucinous Neoplasms of the Pancreas Using 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography. .  Cancers13 ( 18 )   2021.9Reviewed International journal

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The diagnostic value of 18F-fluorodeoxyglucose (FDG) uptake in the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas remains unclear. This study aimed to assess the role of FDG uptake in the diagnosis of different degrees of dysplasia of IPMNs. We retrospectively analyzed the following three points in 84 patients with IPMNs: (1) risk factors to predict high-grade dysplasia (HGD) and invasive carcinoma (INV); (2) the relationship between FDG uptake and glucose transporter 1 (GLUT-1) expression; and (3) the relationship between FDG uptake and the presence of mural nodules. The histopathological diagnosis was low-grade dysplasia (LGD) in 43 patients, HGD in 16, and INV in 25. The maximum standardized uptake value (SUV-max) was significantly higher in INV than in LGD/HGD (p < 0.0001, p = 0.0136). The sensitivity and specificity to discriminate INV from LGD/HGD were 80.0% and 86.2%, respectively, using the receiver operator characteristic curve, when the optimal cutoff score of SUV-max was set at 4.03. Those values were not different between HGD and LGD. More than half of HGD patients had low GLUT-1 expression. Taken together, FDG-PET/CT is useful in distinguishing between non-invasive and invasive IPMN. Our results offer critical information that may determine surgical treatment strategies.

DOI： 10.3390/cancers13184633

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Baba Tokuro, Kawano Takafumi, Saito Yusuke, Onishi Shun, Yamada Koji, Yamada Waka, Masuya Ryuta, Nakame Kazuhiko, Kawasaki Yota, Iino Satoshi, Sakoda Masahiko, Kirishima Mari, Kaji Tatsuru, Tanimoto Akihide, Natsugoe Shoji, Ohtsuka Takao, Moritake Hiroshi, Ieiri Satoshi .  肝悪性血管周囲類上皮細胞腫瘍　1小児例の報告(Malignant perivascular epithelioid cell neoplasm in the liver: report of a pediatric case) .  Surgical Case Reports7   1 of 11 - 11 of 11   2021.9Reviewed

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Language：English   Publisher：Springer Berlin Heidelberg  

症例は10歳男児で、1ヵ月前から高熱が続いており、血液検査でCRP高値を認めたため精査目的に前医を受診した。腹部超音波検査では肝に大型固形腫瘍を認め、造影CTで肝S4とS5に局在する腫瘍がみられ、MRIではT1強調像で低信号、T2強調像で高信号を呈し、18F-FDG-PETにてFDGの著明な取り込みがみられた。AFP、PIVKA-II、CEA、CA19-9はいずれも正常範囲内にあり、未分化癌疑いにて手術目的に当院紹介となった。コア針生検を施行したところ肝細胞癌が疑われ、術前の造影CTでは腫瘍サイズの著明な増大が生じていた。開腹下に腫瘍切除を行い、術中所見では大型腫瘍は肝中心部に位置しており、腹膜播種や腹腔内転移は認めなかった。胆嚢切除後に肝実質を切離し、S8背側は温存した。切除標本の肉眼所見では出血と壊死を伴った黄白色の10×9cm大の腫瘍であり、境界明瞭であったが腫瘍細胞に浸潤性増殖パターンと脈管浸潤がみられ、血管周囲の多角形ないし楕円形細胞を呈し、束状配列の紡錘細胞、淡明な細胞質を有する円形類上皮細胞が認められた。また、免疫組織化学染色では細胞の一部はα-SMAとメランAに陽性を示しており、血管周囲類上皮細胞腫瘍(PEComa)と診断した。術後6ヵ月、肩関節痛を訴え、生検にてPEComaの骨転移と診断、化学療法後に脊椎切除術を施行した。その2年後に骨盤転移と肺転移をきたして転移巣に対する手術を行い、さらに骨盤転移を認めたためmTOR阻害剤にて治療中である。

松下 裕亮, 上笹 貫太郎, 平木 翼, 谷本 昭英, 坂本 泰二 .  20年前に迷入したと考えられる涙嚢内異物の1例 .  あたらしい眼科38 ( 9 ) 1123 - 1126   2021.9Reviewed

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Language：Japanese   Publisher：(株)メディカル葵出版  

外傷時に迷入したと考えられる涙嚢内異物の症例を報告する。症例は34歳、男性。約20年前に左眼下涙点付近を竹で受傷した既往がある。受傷後から慢性的に左鼻汁を自覚していた。最近になって左眼の眼脂を自覚し、近医で涙道閉塞を疑われ当科へ紹介となった。初診時に左眼内眼角部に外傷の痕跡はなかった。通水検査で左側の通水を認めなかった。単純CT検査を行ったところ左眼涙嚢内に10mm大で高信号の棒状陰影を認めた。涙道内視鏡検査では左眼涙嚢内の異物が疑われた。涙道内視鏡による摘出は困難と考え涙嚢鼻腔吻合術(DCR)鼻内法を行った。摘出した異物は、病理組織学的検査で放線菌が全周に付着した植物片と診断された。術直後より左眼の眼脂は消失し、通水は改善した。異物は涙小管や鼻涙管の通過が困難な大きさであり、また外傷の既往があることから、受傷時に涙嚢内へ迷入したものと考えられた。大型の涙嚢内異物であったがDCR鼻内法で抽出が可能であった。(著者抄録)

Rakan Kotoku, Shintaro Yanazume, Takafumi Kuroda, Yusuke Kobayashi, Ikumi Kitazono, Toshiaki Akahane, Akihide Tanimoto, Hiroaki Kobayashi .  Two Components of Variant Profiles in Primary Vaginal Carcinosarcoma via Next-Generation Sequencing and a Literature Review. .  International journal of surgical pathology30 ( 3 ) 10668969211037915 - 10668969211037915   2021.8Reviewed International journal

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Primary vaginal carcinosarcoma (VCS) is an extremely rare and aggressive tumor consisting of admixed malignant epithelial and mesenchymal elements. We report a case of VCS that was subjected to analysis by immunohistochemistry and next-generation sequencing (NGS). A 53-year-old woman with post-menopausal vaginal bleeding underwent surgical excision followed by concurrent chemoradiation. A well demarcated tumor was growing in a discontinuous fashion at a location some distance from both the cervix and vulva. Microscopically, the tumor consisted of adenocarcinoma components and sarcoma components consisting of a sheet-like growth of spindle-shaped cells, and we diagnosed this tumor as primary vaginal carcinosarcoma. NGS analysis of each component identified the following variants, TP53, PIK3CA, KRAS and FBXW7. A comparison of microsatellite instability (MSI) and tumor mutation burden (TMB) showed that within both tissues the sarcomatous components had a higher MSI and TMB than the carcinomatous components. This case supports "a monoclonal theory" with the genome profile being similar to other malignant mixed Müllerian tumors.

DOI： 10.1177/10668969211037915

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古江 惠理, 上笹貫 太郎, 平木 翼, 小牧 祐雅, 東 裕子, 谷本 昭英, 井戸 章雄, 坂本 泰二 .  臨床報告 眼窩内に寄生したマンソン孤虫症の1例 .  臨床眼科75 ( 8 ) 1031 - 1036   2021.8Reviewed

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214064

Toshiaki Akahane, Ikumi Kitazono, Yusuke Kobayashi, Yukari Nishida-Kirita, Tomomi Yamaguchi, Shintaro Yanazume, Kazuhiro Tabata, Hiroaki Kobayashi, Akihide Tanimoto .  Direct next-generation sequencing analysis using endometrial liquid-based cytology specimens for rapid cancer genomic profiling. .  Diagnostic cytopathology49 ( 9 ) 1078 - 1085   2021.7Reviewed International journal

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BACKGROUND: Genomic examination of cytology specimens is often performed on cell blocks or conventional smears rather than on liquid-based cytology (LBC) specimens. Since LBC specimens preserve high-quality DNA, cancer genome profiling using next-generation sequencing (NGS) is also attainable from residual LBC specimens. One of the advantages of using LBC specimens for NGS is that it allows direct extraction of DNA from residual specimens, avoiding a sacrifice of smear slides and minimizing genomic profiling processing time. METHODS: Endometrial LBC specimens were subjected to NGS analysis to validate the practicality of rapid cancer genomic profiling in a pathology laboratory. The extracted DNA was subjected to NGS using a customized cancer gene panel comprising 56 genes and 17 microsatellite regions. The workflow strategy was defined, and the processing time estimated for specimen sampling, cell counting, NGS run, and genome profiling. RESULTS: NGS analysis of most LBC specimens revealed somatic mutations, tumor mutation burden, and microsatellite instability, which were almost identical to those obtained from formalin-fixed paraffin-embedded tissues. The processing time for direct NGS analysis and cancer genomic profiling of the residual LBC specimens was approximately 5 days. CONCLUSION: The residual LBC specimens collected using endometrial cytology were verified to carry a high tumor fraction for NGS analysis and could serve as an alternate source for rapid molecular classification and diagnosis of endometrial cancers, as a routine process in a pathology laboratory.

DOI： 10.1002/dc.24841

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Mari Kirishima, Ikuma Kato, Masanori Hisaoka, Yukio Nakatani, Aya Harada Takeda, Keiko Mizuno, Akihide Tanimoto .  Solid endobronchial tumor with EWSR1-FLI1 fusion gene - A diagnostically challenging case of the Ewing sarcoma. .  Pathology international71 ( 7 ) 488 - 490   2021.7Reviewed International journal

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DOI： 10.1111/pin.13109

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Tasaki Takashi, Hatanaka Kazuhito, Kitazono Ikumi, Noguchi Hirotsugu, Tabata Kazuhiro, Higashi Michiyo, Maeda Kouki, Yokose Tomoyuki, Uekusa Toshimasa, Tanimoto Akihide .  サルコイドーシスの血管病変によって引き起こされた肺梗塞　症例報告(Pulmonary infarction caused by sarcoidosis vascular involvement: A case report) .  Pathology International71 ( 7 ) 480 - 484   2021.7Reviewed

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は60歳女性で、喀血を主訴とした。喀血は手術の5ヵ月前から始まり、2ヵ月間断続的に続いていた。血管炎や膠原病を示唆する皮膚病変や関節痛などの徴候はなく、関節リウマチや他の膠原病の既往歴もなかった。臨床検査では、血清アンジオテンシンI変換酵素や血清腫瘍マーカーが正常で、細菌、真菌、マイコバクテリウムも全て陰性であった。造影剤を用いた胸部CTでは、右上葉に気管支閉塞と無気肺様の腫瘤が認められ、両側の上葉には気管支や肺血管に沿って小さな結節が認められた。顕著な肺門リンパ節腫脹は認められなかった。18F-FDG PET/CTでは、右上葉の無気肺様腫瘤にFDGの取り込みが増加していた。肺癌との臨床診断の下、右上葉切除およびS6区域切除術を実施した。肉眼検査で、臓側胸膜の下に境界明瞭な暗褐色の領域が認められ、組織学的検査により、暗褐色の部分は古い梗塞であり、出血、ヘモシデローシス、線維化、軽度のリンパ球浸潤から構成されていた。弾性肺動脈では肉芽腫が副膜と中膜に浸潤し、弾性線維の崩壊と破壊を起こしていた。梗塞部位の端には肉芽腫による動脈閉塞が認められ、動脈サルコイドーシスの肉芽腫浸潤が肺梗塞の原因であると考えられた。

Masayoshi Otake, Hiroaki Kawaguchi, Satoko Enya, Akihisa Kangawa, Tadashi Koga, Kei Matsuo, Sohsuke Yamada, Md Mahfuzur Rahman, Naoki Miura, Masatoshi Shibata, Akihide Tanimoto .  High Pathological Reproducibility of Diet-induced Atherosclerosis in Microminipigs via Cloning Technology. .  In vivo (Athens, Greece)35 ( 4 ) 2025 - 2033   2021.7Reviewed International journal

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BACKGROUND/AIM: The reproducibility of athero - sclerotic lesions was evaluated after the production of cloned-microminipigs and their offspring. MATERIALS AND METHODS: Cloned-microminipig-parents were produced by microminipigsomatic cell nuclei. These parents were crossbred and delivered males (F1-offspring) were divided into two groups: normal chow diet (NcD)-fed and high-fat/high-cholesterol diet (HcD)-fed groups. One of the F1-offsprings was subjected to cloning, and delivered males (F1-clones) were fed with HcD. After 8 weeks, all animals were necropsied for patho - physiological studies compared to non-cloned-microminipigs. RESULTS: HcD-fed F1-offspring and F1-clones, but not NcD-fed F1-offspring, exhibited increased serum lipid levels and systemic atherosclerosis, which were comparable to those of HcD-fed non-cloned-microminipigs. Homogeneity of variance analysis demonstrated that standard deviation values of serum lipoprotein and aortic atherosclerosis area from HcD-fed animals decreased in F1-offspring and F1-clones. CONCLUSION: HcD-induced atherogenesis was highly reproducible in F1-offsprings and F1-clones, indicating that the atherosclerosis-prone genomic background was preserved in the cloned-microminipigs, which can be used for studies on human atherosclerosis and related diseases.

DOI： 10.21873/invivo.12471

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Yusuke Torikai, Yuji Sasaki, Keita Sasaki, Akifumi Kyuno, Shunji Haruta, Akihide Tanimoto .  Evaluation of Systemic and Mucosal Immune Responses Induced by a Nasal Powder Delivery System in Conjunction with an OVA Antigen in Cynomolgus Monkeys. .  Journal of pharmaceutical sciences110 ( 5 ) 2038 - 2046   2021.5Reviewed International journal

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An immune response for a nasal ovalbumin (OVA) powder formulation with an applied nasal delivery platform technology, consisting of a powdery nasal carrier and a device, was evaluated in monkeys with similar upper respiratory tracts and immune systems to those of humans, in order to assess the applicability to a vaccine antigen. Nasal distribution and retention studies using a 3D nasal cavity model and manganese-enhanced MRI were conducted by administering nasal dye and manganese powder formulations with the applied technology. Systemic and mucosal immune responses for the nasal OVA powder formulation were evaluated by determining serum IgG and nasal wash IgA antibody titers. The nasal dye and manganese powder formulations showed wider distribution and longer retention time than did a nasal liquid formulation. The nasal OVA powder formulation also showed comparable and higher antigen-specific IgG antibody titer to an injection and nasal liquid formulation, respectively. Furthermore, antigen-specific IgA antibody response was detected only for the nasal OVA powder formulation. The present study suggests that the technology, originally designed for drug absorption, is promising for nasal vaccines, enabling both a mucosal immunity response as the first line of defense and systemic immunity response as a second line of defense against infection.

DOI： 10.1016/j.xphs.2020.11.023

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米澤 大, 比嘉 那優大, 内田 裕之, 赤羽 俊章, 横山 勢也, 霧島 茉莉, 平木 翼, 谷本 昭英, 吉本 幸司 .  脳腫瘍に特化したがん遺伝子パネル検査の実臨床における有用性 .  Brain Tumor Pathology38 ( Suppl. ) 073 - 073   2021.5

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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赤羽 俊章, 比嘉 那優大, 霧島 茉莉, 内田 裕之, 米澤 大, 坂本 一平, 野原 祥夫, 吉本 幸司, 谷本 昭英 .  神経膠腫診断用パネル検査で見つかった新規EGFR variantを有する神経膠腫の病理組織学的特徴 .  Brain Tumor Pathology38 ( Suppl. ) 073 - 073   2021.5

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比嘉 那優大, 赤羽 俊章, 米澤 大, 内田 裕之, 藤尾 信吾, 横山 勢也, 霧島 茉莉, 濱田 大治, 谷本 昭英, 吉本 幸司 .  日本人のhigh grade glioma患者における遺伝子変異の特徴 .  Brain Tumor Pathology38 ( Suppl. ) 074 - 074   2021.5

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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内田 裕之, 赤羽 俊章, 比嘉 那優大, 米澤 大, 霧島 茉莉, 谷本 昭英, 吉本 幸司 .  Lower-grade gliomaの遺伝子プロファイル診断と予後についての検討 .  Brain Tumor Pathology38 ( Suppl. ) 077 - 077   2021.5

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Takashi Tasaki, Kazuhito Hatanaka, Ikumi Kitazono, Hirotsugu Noguchi, Kazuhiro Tabata, Michiyo Higashi, Kouki Maeda, Tomoyuki Yokose, Toshimasa Uekusa, Akihide Tanimoto .  Pulmonary infarction caused by sarcoidosis vascular involvement: A case report. .  Pathology international71 ( 7 ) 480 - 484   2021.4Reviewed International journal

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Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.

DOI： 10.1111/pin.13104

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Hirotsugu Noguchi, Michiyo Higashi, Tetsuya Idichi, Hiroshi Kurahara, Yuko Mataki, Takashi Tasaki, Ikumi Kitazono, Takao Ohtsuka, Akihide Tanimoto .  Rare histological subtype of invasive micropapillary carcinoma in the ampulla of Vater: A case report. .  World journal of clinical cases9 ( 11 ) 2671 - 2678   2021.4Reviewed International journal

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BACKGROUND: Carcinoma of the ampulla of Vater is an uncommon ampullo-pancreatobiliary neoplasm, and the most common histological type is adenocarcinoma with a tubular growth pattern. Invasive micropapillary carcinoma (IMPC) is an aggressive variant of adenocarcinoma in several organs that is associated with lymph node metastasis and poor prognosis. IMPC was first described as a histological subtype of breast cancer; however, IMPC of the ampulla of Vater is extremely rare, with only three articles reported in the English literature. CASE SUMMARY: We have reported a case of IMPC of the ampulla of Vater in an 80-year-old man. Microscopically, the surface area of the carcinoma was composed of tubulopapillary structures mimicking intra-ampullary papillary-tubular neoplasm, and the deep invasive front area exhibited a pattern of IMPC. The carcinoma showed lymphatic invasion and extensive lymph node metastasis. The immunohistochemical study revealed mixed intestinal and gastric/pan-creatobiliary phenotypes. CONCLUSION: This rare subtype tumor in the ampulla of Vater showed a histologically mixed phenotype and exhibited aggressive behavior.

DOI： 10.12998/wjcc.v9.i11.2671

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Ikumi Kitazono, Toshiaki Akahane, Mika Sakihama, Shintaro Yanazume, Michiko Matsushita, Kazuhiro Tabata, Yusuke Kobayashi, Hiroaki Kobayashi, Yoshihisa Umekita, Akihide Tanimoto .  Human Papilloma Virus 18-Positive Submucosal Small Cell Neuroendocrine Carcinoma of the Vagina: An Immunohistochemical and Genomic Study. .  International journal of surgical pathology29 ( 8 ) 10668969211007569 - 10668969211007569   2021.4Reviewed International journal

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Primary vaginal neuroendocrine carcinoma (NEC) is extremely rare among female genital tract tumors. Here, we report 2 cases of vaginal small cell NEC (SCNEC) using immunohistochemistry and next-generation sequencing (NGS) analysis. The 2 patients were in their mid-to-late 70s, presented with abnormal vaginal bleeding and had a vaginal submucosal mass. The biopsied or resected tumors showed a typical neuroendocrine morphology consisting of solid nests of atypical tumor cells, with no specific organoid patterns, and proliferating in the vaginal submucosa. Immunohistochemical analysis showed strong and diffuse expression of chromogranin A, synaptophysin, and p16, but no thyroid transcription factor 1 expression. Additionally, both cases were positive for human papillomavirus (HPV) 18. An NGS-based cancer panel analysis revealed that the tumors carried NF1 and AR mutations, but no major driver mutations were detected. The results of this study suggested that HPV18 infection is linked to vaginal SCNEC.

DOI： 10.1177/10668969211007569

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MOE IJIRI, YU-CHANG LAI, HIROAKI KAWAGUCHI, YOSHIKAZU FUJIMOTO, NAOKI MIURA, TOMOHIDE MATSUO, AKIHIDE TANIMOTO .  NR6A1 Allelic Frequencies as an Index for both Miniaturizing and Increasing Pig Body Size .  In Vivo35 ( 1 ) 163 - 167   2021.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

Background/Aim: The number of vertebrae in swine varies from 19 to 23 and is associated with body size. Nuclear receptor subfamily 6 group A member 1 (NR6A1) is considered a strong candidate for affecting the number of vertebrae in swine. Wild boars, which uniformly have 19 vertebrae, have the wild type allele while multi-vertebrae European commercial pigs have the mutated allele. Our aim was to confirm the factor of the miniaturization. Materials and Methods: We examined vertebrae number and NR6A1 polymorphism in the Microminipig and three domestic breeds that vary in body size. Results: The Microminipig had 19 or less vertebrae and a wild type NR6A1 genotype. Three domestic breeds had more than 21 vertebrae while the largest vertebrae number was observed in multi-vertebrae-fixed Large White. Heterozygous genotypes were observed in the middle-sized indigenous pig while homozygous NR6A1 mutations were observed in European commercial breeds. Conclusion: NR6A1 could be a useful index for both miniaturizing and increasing pig body size.

DOI： 10.21873/invivo.12244

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Yusuke Kobayashi, Ikumi Kitazono, Toshiaki Akahane, Shintaro Yanazume, Masaki Kamio, Shinichi Togami, Sachio Nohara, Ippei Sakamoto, Seiya Yokoyama, Kazuhiro Tabata, Hiroaki Kobayashi, Akihide Tanimoto .  Molecular Evaluation of Endometrial Dedifferentiated Carcinoma, Endometrioid Carcinoma, Carcinosarcoma, and Serous Carcinoma Using a Custom-Made Small Cancer Panel. .  Pathology oncology research : POR27   1610013 - 1610013   2021Reviewed International journal

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It is often difficult to histologically differentiate among endometrial dedifferentiated carcinoma (DC), endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma (CS) due to the presence of solid components. In this study, we aimed to categorize these carcinomas according to The Cancer Genome Atlas (TCGA) classification using a small custom-made cancer genome panel (56 genes and 17 microsatellite regions) for integrated molecular diagnosis. A total of 36 endometrial cancer cases with solid components were assessed using IHC, next-generation sequencing (NGS), and the custom-made panel. Among 19 EC cases, six were categorized as MMR-deficient (MMR-d) and eight were classified as having a nonspecific molecular profile. Three EC cases were classified as POLE mutation (POLEmut)-type, which had a very high tumor mutation burden (TMB) and low microsatellite instability (MSI). Increased TMB and MSI were observed in all three DC cases, classified as MMR-d with mutations in MLH1 and POLD1. Except for one case classified as MMR-d, all SC cases exhibited TP53 mutations and were classified as p53 mutation-type. SC cases also exhibited amplification of CCND1, CCNE1, and MYC. CS cases were classified as three TCGA types other than the POLEmut-type. The IHC results for p53 and ARID1A were almost consistent with their mutation status. NGS analysis using a small panel enables categorization of endometrial cancers with solid proliferation according to TCGA classification. As TCGA molecular classification does not consider histological findings, an integrated analytical procedure including IHC and NGS may be a practical diagnostic tool for endometrial cancers.

DOI： 10.3389/pore.2021.1610013

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HAYASHI Tomomi, KADONO Jun, INOUE Maki, SAKAMOTO Akihiko, HUTAWATARI Hisatomo, HIRAKI Tsubasa, TANIMOTO Akihide, FUROI Akira .  Evaluation of Hepatic Functional Reserve and Perioperative Course after Hepatectomy in a Case of Dubin-Johnson Syndrome .  Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association)82 ( 12 ) 2262 - 2269   2021Reviewed

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Language：Japanese   Publisher：Japan Surgical Association  

<p>A case of hepatocellular carcinoma in a patient with Dubin-Johnson syndrome (DJS) focusing on evaluation of hepatic functional reserve and the perioperative clinical course is presented.</p><p>A 66-year-old man with a medical history of DJS and diabetes mellitus was diagnosed with hepatocellular carcinoma (HCC) when he had a rickettsial infection. The preoperative liver function tests showed an increased bilirubin level (total 4.6, direct 3.4 mg/dl), and normal PT (92%) and albumin (4.2 g/dl) levels without ascites or encephalopathy. The Child-Pugh score was B (7). The ICGR₁₅ level was 11%. The LHL₁₅ value of the GSA scintigram was almost normal (0.909). S4 segmentectomy and S2 partial resection were performed uneventfully except for transient elevation of the T-Bil level that recovered to the preoperative level on the 28^th postoperative day. DJS was confirmed on histopathological examination. Both the ICG test and the GSA scintigram evaluated hepatic functional reserve accurately. Inchin-ko-to may be effective for hyperbilirubinemia after hepatectomy in DJS cases.</p>

DOI： 10.3919/jjsa.82.2262

CiNii Research

Yuto Hozaka, Yuko Mataki, Hiroshi Kurahara, Kiyonori Tanoue, Tetsuya Idichi, Yota Kawasaki, Satoshi Iino, Pramod Nepal, Takaaki Arigami, Kosei Maemura, Hirotsugu Noguchi, Hiroyuki Shinchi, Akihide Tanimoto, Shoji Natsugoe, Takao Ohtsuka .  Usefulness of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in primary cystadenocarcinoma of the mesentery: a case report. .  Surgical case reports6 ( 1 ) 306 - 306   2020.12Reviewed International journal

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BACKGROUND: Mesenteric cysts have various histological forms, including mesenteric cystadenomas and borderline cystic neoplasms. Primary cystadenocarcinoma of the mesentery is extremely rare; therefore, the clinical and radiological features of this tumor have not been fully elucidated. CASE PRESENTATION: A 50-year-old Japanese woman had a complaint of a left-sided abdominal distention. Enhanced computed tomography and magnetic resonance imaging revealed a unilocular cystic lesion measuring approximately 10 cm located in the left side of the abdomen. 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) revealed mottled mild FDG uptake in the cyst wall and intense FDG uptake in several mural nodules. The cystic mass with the descending colon was completely removed. Pathological examination of the specimens revealed various histologic patterns of adenocarcinoma, including mucin production in the mural nodules. We eventually diagnosed a primary cystadenocarcinoma arising from the mesentery of the descending colon. CONCLUSIONS: Malignancy should be suspected in mesenteric or retroperitoneal cystic tumors with high FDG uptake, and complete resection should be performed with adequate margins.

DOI： 10.1186/s40792-020-01079-2

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Ikumi Kitazono, Taiji Hamada, Takuya Yoshimura, Mari Kirishima, Seiya Yokoyama, Toshiaki Akahane, Akihide Tanimoto .  PCP4/PEP19 downregulates neurite outgrowth via transcriptional regulation of Ascl1 and NeuroD1 expression in human neuroblastoma M17 cells. .  Laboratory investigation; a journal of technical methods and pathology100 ( 12 ) 1551 - 1563   2020.12Reviewed International journal

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Purkinje cell protein 4/peptide 19 (PCP4/PEP19) is 7.6 kDa peptide originally found in Purkinje cells. PCP4/PEP19 is a differentiation maker of Purkinje cells, where it functions as an antiapoptotic factor. Cerebral neuronal cells also express PCP4/PEP19, which may be related to neuronal cell survival. However, evidence suggests that PCP4/PEP19 may also be involved in neuronal differentiation. Here, we investigated the effects of PCP4/PEP19 expression on neuronal differentiation by analyzing neurite outgrowth, and expression of neuronal differentiation markers in cultured human neuroblastoma M17 cells. When PCP4/PEP19 expression was reduced by siRNA-mediated knockdown, neurite outgrowth was significantly increased. Among many differentiation markers tested, expression of NeuroD1 was increased, while that of Ascl1 was decreased upon PCP4/PEP19 knockdown. Furthermore, luciferase reporter assays revealed that PCP4/PEP19 knockdown upregulated NeuroD1 and downregulated Ascl1 expression, at the transcriptional level. These results suggest a new function of PCP4/PEP19, which suppresses neurite outgrowth and neuronal differentiation through the regulation of NeuroD1 and Ascl1 expression in M17 cells. Furthermore, immunohistochemical studies showed that PCP4/PEP19 localizes in the nuclei of human neuroblastoma cells. Therefore, PCP4/PEP19 may also be an intranuclear negative regulator of neuronal differentiation and may thus be a potential therapeutic target to promote cellular differentiation in human neuroblastoma.

DOI： 10.1038/s41374-020-0462-z

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Hozaka Yuto, Mataki Yuko, Kurahara Hiroshi, Tanoue Kiyonori, Idichi Tetsuya, Kawasaki Yota, Iino Satoshi, Nepal Pramod, Arigami Takaaki, Maemura Kosei, Noguchi Hirotsugu, Shinchi Hiroyuki, Tanimoto Akihide, Natsugoe Shoji, Ohtsuka Takao .  腸間膜の原発性嚢胞腺癌における18F-フルオロデオキシグルコース-PET/CT検査の有用性　1症例報告(Usefulness of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in primary cystadenocarcinoma of the mesentery: a case report) .  Surgical Case Reports6   1 of 8 - 8 of 8   2020.12Reviewed

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Language：English   Publisher：Springer Berlin Heidelberg  

左腹部膨満を主訴とする50歳日本人女性症例について検討した。増強CT検査およびMRI検査では左腹部に約10cmの単房性嚢胞性病変を認めた。18F-フルオロデオキシグルコース(FDG)-PET/CT検査では、嚢胞壁に斑点状のFDG軽度取り込みを認め、いくつかの壁在性結節に強度FDG取り込みを認めた。嚢胞性腫瘤は下行結腸とともに完全に切除した。検体の病理検査では腺癌の様々な組織学的パターンを認め、その中に壁在性結節におけるムチン産生も含まれた。最終診断は下行結腸の腸間膜から生じた原発性嚢胞腺癌であった。

Tomomi Yamaguchi, Toshiaki Akahane, Ohi Harada, Yasutaka Kato, Eriko Aimono, Hidehiro Takei, Takashi Tasaki, Hirotsugu Noguchi, Hiroshi Nishihara, Hajime Kamata, Akihide Tanimoto .  Next-generation sequencing in residual liquid-based cytology specimens for cancer genome analysis. .  Diagnostic cytopathology48 ( 11 ) 965 - 971   2020.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cancer genome profiling of cytology specimens using next-generation sequencing (NGS) requires adequate and good-quality DNA. Genomic examination of cytology samples was conventionally performed on cell block (CB) or smear specimens than on residual liquid-based cytology (LBC) specimens, which are high-quality DNA sources even after long-term storage. METHODS: We estimated tumor fractions of 37 residual LBC specimens, including 30 fine needle aspiration (FNA) samples from the thyroid (12 papillary thyroid carcinomas and two malignant lymphomas), lymph node (13 metastatic carcinomas and one malignant lymphoma), and breast cancer (one phyllodes tumor and one invasive ductal carcinoma), two pancreatic carcinoma samples, and five liquid (ascites, pleural effusion, and cerebrospinal fluid) samples. The DNA was extracted from all samples and subjected to NGS using a customized cancer gene panel comprising 28 cancer-related genes. RESULTS: NGS analysis revealed somatic mutations corresponding to pathological diagnosis with adequate variant allele frequency (VAF) in 24 LBC specimens, which had significantly higher tumor fraction (72.5% ± 4.9%). Ten cases, including the five fluid samples, had very small tumor fractions (7.5% ± 2.3%) to obtain sufficient VAF. Other two samples had high tumor fractions but showed very low VAF, indicating the presence of fusion genes. The remaining one sample yielded no DNA recovery. CONCLUSION: The residual LBC specimens collected by FNA from the thyroid gland and lymph node were verified to carry high tumor fraction and could serve as an alternate source for molecular testing to screen and diagnose cancers without the use of CB or smears.

DOI： 10.1002/dc.24511

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東 美智代, 横山 勢也, 米澤 傑, 谷本 昭英 .  【IPMN大全】IPMNの歴史的変遷 IPMNにおけるMUC発現とその評価の歴史 .  胆と膵41 ( 臨増特大 ) 1159 - 1162   2020.11Reviewed

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Language：Japanese   Publisher：医学図書出版(株)  

膵管内乳頭粘液性腫瘍(intraductal papillary mucinous neoplasm:IPMN)の大きな特徴は「粘液の産生」である。ムチンは「粘液」の主成分であり、細胞の保護を行い恒常性維持に大きな役目を果たしている。ムチンの骨格であるコア蛋白が「MUC」という総称でよばれており、クローニングされた順に番号が付いている。IPMNは亜型によってMUCの発現形式が異なっていることは現在ではよく知られている。しかし、IPMNが認識されはじめた当初はMUC2(+)の症例がほとんどであった。症例数の蓄積とともにMUC2(-)の症例が認識され、臨床病理学的特徴も大きく異なることがわかり、2004年頃に亜型として確立された。MUC発現は亜型のみでなく予後などの悪性度とも関連しており、早期診断などへの臨床応用も期待される。(著者抄録)

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Daiki Yoshii, Takenobu Nakagawa, Yoshihiro Komohara, Hiroaki Kawaguchi, Sohsuke Yamada, Akihide Tanimoto .  Phenotypic Changes in Macrophage Activation in a Model of Nonalcoholic Fatty Liver Disease using Microminipigs. .  Journal of atherosclerosis and thrombosis28 ( 8 ) 844 - 851   2020.10Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

AIM: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders associated with metabolic syndrome, and its prevalence has been on the rise. The pathogenesis of NAFLD has not yet been sufficiently elucidated due to the multifactorial nature of the disease, although the activation of macrophages/Kupffer cells is considered to be involved. We previously reported an animal model of NAFLD using MicrominipigsTM (µMPs) fed high-fat diets containing cholesterol with or without cholic acid. The aim of this study was to investigate the phenotypic changes of macrophages that occur during the development of NAFLD. METHODS: Immunohistochemistry of macrophages, lymphocytes, and stellate cells was performed using liver samples, and the density of positive cells was analyzed. RESULTS: The number of Iba-1-positive macrophages increased with increasing cholesterol content in the diet. The numbers of CD163-positive macrophages and CD204-positive macrophages also increased with increasing cholesterol content in the diet; however, the proportion of CD204-positive macrophages among Iba-1-positive macrophages was significantly reduced by cholic acid supplementation. CONCLUSION: The results suggest that lipid accumulation induced macrophage recruitment in swine livers, and that the number of M2-like macrophages increased at the early stage of NAFLD, while the number of M1-like macrophages increased at the late stage of NAFLD, resulting in a liver condition like non-alcoholic steatohepatitis. We provide evidence of the phenotypic changes that occur in macrophages during the development of NAFLD that has never been reported before using µMPs.

DOI： 10.5551/jat.57703

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Toshiaki Akahane, Naoki Kanomata, Oi Harada, Tetsumasa Yamashita, Junichi Kurebayashi, Akihide Tanimoto, Takuya Moriya .  Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions. .  BMC cancer20 ( 1 ) 944 - 944   2020.10Reviewed International journal

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BACKGROUND: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions. METHODS: Triplet samples of genomic DNA were extracted from each patient's normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis. RESULTS: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions. CONCLUSIONS: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

DOI： 10.1186/s12885-020-07432-w

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Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Taiji Hamada, Kei Matsuo, Shingo Fujio, Tomoko Hanada, Hiroshi Hosoyama, Masanori Yonenaga, Akihisa Sakamoto, Tsubasa Hiraki, Akihide Tanimoto, Koji Yoshimoto .  A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas. .  Cancer science111 ( 10 ) 3902 - 3911   2020.10

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Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade Ⅳ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.

DOI： 10.1111/cas.14597

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Higa Nayuta, Akahane Toshiaki, Yokoyama Seiya, Yonezawa Hajime, Uchida Hiroyuki, Takajo Tomoko, Kirishima Mari, Hamada Taiji, Matsuo Kei, Fujio Shingo, Hanada Tomoko, Hosoyama Hiroshi, Yonenaga Masanori, Sakamoto Akihisa, Hiraki Tsubasa, Tanimoto Akihide, Yoshimoto Koji .  次世代シークエンサー用カスタム遺伝子パネルにより、野生型IDH変異およびTERTプロモーター領域に変異を有する膠芽腫の各サブタイプが同定される(A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas) .  Cancer Science111 ( 10 ) 3902 - 3911   2020.10Reviewed

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今回、神経膠腫の分子病理学的統合診断を目的として、新たに48遺伝子で構成された次世代シークエンサー(NGS)用カスタム遺伝子パネルを構築し、その実行可能性について検討した。なお、本パネルは、1p/2q共欠失とIDH1/2遺伝子、TP53遺伝子、PTEN遺伝子、PDGFRA遺伝子、NF1遺伝子、RB1遺伝子、CDKN2A/B遺伝子およびCDK4遺伝子とTERT遺伝子のプロモーター領域(TERTp)変異を検出するために、神経膠腫診断に特化した遺伝子パネルである。当院で開発した中枢神経系腫瘍組織バンクから、神経膠腫患者106例(グレードII:19例、グレードIII:23例、グレードIV:64例)を選択し、本パネルを用いて解析した結果、乏突起膠腫で1p/19q共欠失が正確に検出され、グレードIV患者64例中56例にはIDH遺伝子が野生型の膠芽腫が同定され、うち33例にTERTp変異が認められた。また、PDGFRA遺伝子の変異と増幅は、TERTp遺伝子が野生型の膠芽腫では43%に、TERTp変異を有する膠芽腫では6%に認められ、分子遺伝情報に基づいた階層分類により、IDH遺伝子が野生型の膠芽腫では、明確に3グループに分類された。さらに、PDGFRA遺伝子変異、CDK4遺伝子およびPFGFRA遺伝子の増幅、CDKN2A/B遺伝子でのホモ接合性欠失やTERTp変異の欠如により特徴付けられた主要なクラスタが、高年齢、Ki-67高スコア、予後不良および脳室周囲腫瘍と有意に関連することが明らかにされた。以上の解析結果から、本パネルにより、PDGFRA遺伝子異常が高頻度に認められ、IDH遺伝子およびTERTp遺伝子変異が野生型を示す膠芽腫患者の各サブタイプが同定された。

Hirotsugu Noguchi, Natsumi Noguchi, Tetsuya Idichi, Yota Kawasaki, Mari Kirishima, Takashi Tasaki, Ikumi Kitazono, Michiko Horinouchi, Tsubasa Hiraki, Michiyo Higashi, Akihide Tanimoto .  Case report of a lymphoepithelioma-like hepatocellular carcinoma with prominent lymphoplasmacytic infiltration .  Human Pathology: Case Reports21   2020.9Reviewed

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Lymphoepithelioma-like carcinoma (LELC) of the liver is extremely rare, and lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant form of HCC, exhibiting relatively good prognosis compared to conventional HCC. LELC is defined as a tumour composed of undifferentiated epithelial cells with densely infiltrating lymphoid stroma. LEL-HCC represents a unique immune response against tumour cells, which may contribute to the superior clinical outcomes. However, the exact aetiology remains unknown. We report a case of a 76-year-old man with a prior hepatitis B virus infection. A 20 mm tumour was detected in the liver. Microscopically, the tumour displayed characteristics of poorly differentiated HCC with a dense lymphocytic and plasma cell infiltration and was diagnosed as LEL-HCC. We describe a unique pathological finding with immunohistochemical data demonstrating T-cell dominant lymphocytic and polyclonal plasma cell infiltration, along with programmed death ligand 1 expression in the tumour cells and lymphocytes.

DOI： 10.1016/j.ehpc.2020.200402

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Yoshiaki Shinden, Hazuki Saho, Yuki Nomoto, Ayako Nagata, Koji Minami, Akihiro Nakajo, Toshiaki Akahane, Tsubasa Hiraki, Akihide Tanimoto, Tetsuhiro Owaki, Yuko Kijima, Shoji Natsugoe .  Breast cancer with an intraductal component that was proven genetically to be metastasis of contralateral breast cancer: a case report. .  Surgical case reports6 ( 1 ) 215 - 215   2020.8Reviewed International journal

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BACKGROUND: When diagnosing patients with bilateral breast cancer, it is challenging to determine the relationship between multiple breast cancer lesions at the individual patient level with certainty. CASE PRESENTATION: A 35-year-old Japanese woman was diagnosed with a left breast cancer. She was previously diagnosed with right pT3N3M0 stage IIIC breast cancer and underwent chemotherapy with targeted therapy, radiotherapy, and endocrine therapy as adjuvant treatment after mastectomy and axillary lymph node dissection. Approximately 2 years after the first surgery, her left breast cancer was preoperatively diagnosed as a contralateral primary breast cancer, and left mastectomy and axillary lymph node dissection were performed. Histopathologically, the tumor was determined to be invasive ductal carcinoma accompanied with several intraductal components. After a second surgery, mutation analysis of her bilateral breast cancer was performed in a clinical study, which revealed that her metachronous bilateral breast tumors had the same GATA3 and CSMD1 mutations. Thus, mutation analysis strongly supported her latter left breast cancer being a metastatic lesion from the former right breast cancer. Some difficulties in diagnosing bilateral breast cancer exist when determining whether they are double primary cancers or represent contralateral breast metastasis. The existence of intraductal components is a critical piece of information for suspecting primary lesions. However, this case demonstrated that metastatic contralateral breast lesions can have intraductal components. CONCLUSION: Herein we report a genetically proven contralateral breast metastasis with some intraductal components.

DOI： 10.1186/s40792-020-00966-y

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Shinden Yoshiaki, Saho Hazuki, Nomoto Yuki, Nagata Ayako, Minami Koji, Nakajo Akihiro, Akahane Toshiaki, Hiraki Tsubasa, Tanimoto Akihide, Owaki Tetsuhiro, Kijima Yuko, Natsugoe Shoji .  対側乳房への転移が遺伝学的に明らかにされた乳管内成分を有する乳癌　1症例報告(Breast cancer with an intraductal component that was proven genetically to be metastasis of contralateral breast cancer: a case report) .  Surgical Case Reports6   1 of 6 - 6 of 6   2020.8Reviewed

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症例は35歳女性で、左乳房に低エコー腫瘤を認めた。2年前に右乳癌と診断されて乳房切除術と腋窩リンパ節郭清を施行され、pT3N3M0ステージIIIC、Luminal HER2とされた。アジュバント療法として化学療法、放射線療法、内分泌療法を受け、トラスツズマブ投与終了の23ヵ月後、左乳房の上部外側に不規則な低エコー腫瘤が検出された。コア針生検にて病理学的に浸潤性乳管癌と診断し、CTと骨スキャンでは遠隔転移はみられなかった。術前診断ではT1N0M0ステージIAの対側原発性乳癌であり、左乳房切除術とセンチネルリンパ節生検を施行した。組織診の結果、浸潤性乳管癌であり、乳管内成分とリンパ浸潤がみられpT2N1M0とされた。乳管内成分を有することから左乳癌は原発性病変と考え、術後は化学療法と内分泌療法を行った。遺伝子解析を行ったところ、両側乳房に生じた異時性乳癌は同一のGATA3変異とCSMD1変異を有しており、左乳癌と右乳癌の転移であることを強く示唆する所見であった。この他に遺伝子変異は検出されず、ERBB2のコピー数は両病変とも同程度に増加していた。左乳房に対する術後12ヵ月、アジュバント療法を継続中であり、再発は認めていない。

Toshiaki Akahane, Ikumi Kitazono, Shintaro Yanazume, Masaki Kamio, Shinichi Togami, Ippei Sakamoto, Sachio Nohara, Seiya Yokoyama, Hiroaki Kobayashi, Tsubasa Hiraki, Shinsuke Suzuki, Shinichi Ueno, Akihide Tanimoto .  Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens. .  BMC medical genomics13 ( 1 ) 101 - 101   2020.7Reviewed International journal

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BACKGROUND: Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses. METHODS: Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. RESULTS: A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases. CONCLUSION: These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.

DOI： 10.1186/s12920-020-00753-6

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Shintaro Yanazume, Shinichi Togami, Masaki Kamio, Ikumi Kitazono, Tsubasa Hiraki, Akihide Tanimoto, Hiroaki Kobayashi .  Bulky cervical tumour showing mixed unique cell clusters in cervical cytology. .  Cytopathology : official journal of the British Society for Clinical Cytology31 ( 4 ) 345 - 347   2020.7Reviewed International journal

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DOI： 10.1111/cyt.12852

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Kake S, Kawaguchi H, Nagasato T, Yamada T, Ito T, Maruyama I, Miura N, Tanimoto A .  Association Between HMGB1 and Thrombogenesis in a Hyperlipaemia-induced Microminipig Model of Atherosclerosis. .  In vivo (Athens, Greece)34 ( 4 ) 1871 - 1874   2020.7

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DOI： 10.21873/invivo.11982

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Seiya Yokoyama, Taiji Hamada, Michiyo Higashi, Kei Matsuo, Kosei Maemura, Hiroshi Kurahara, Michiko Horinouchi, Tsubasa Hiraki, Tomoyuki Sugimoto, Toshiaki Akahane, Suguru Yonezawa, Marko Kornmann, Surinder K Batra, Michael A Hollingsworth, Akihide Tanimoto .  Predicted Prognosis of Patients with Pancreatic Cancer by Machine Learning. .  Clinical cancer research : an official journal of the American Association for Cancer Research26 ( 10 ) 2411 - 2421   2020.5Reviewed International journal

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PURPOSE: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. EXPERIMENTAL DESIGN: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. RESULTS: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. CONCLUSIONS: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

DOI： 10.1158/1078-0432.CCR-19-1247

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Eri Inatsu, Kazuyasu Fujii, Miho Hatanaka, Aoi Okubo, Youhei Uchida, Yuko Higashi, Tsubasa Hiraki, Akihide Tanimoto, Takuro Kanekura .  Epstein-Barr virus-positive mucocutaneous ulcer in a patient with untreated chronic lymphocytic leukemia and hypogammaglobulinemia. .  The Journal of dermatology47 ( 5 ) e204 - e206   2020.5Reviewed International journal

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DOI： 10.1111/1346-8138.15304

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Hirotsugu Noguchi, Ikumi Kitazono, Kazumasa Hamada, Takako Tanaka, Takashi Tasaki, Hiroshi Shirahama, Yoshimasa Yamamoto, Akihide Tanimoto .  Verruciform Xanthoma of the Esophagus: Two Case Reports With Review of the Literature. .  International journal of surgical pathology28 ( 3 ) 302 - 305   2020.5

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Verruciform xanthoma is a rare benign verrucopapillary lesion that develops in the oral mucosa and genital skin. Its development in the esophagus is extremely rare, with only 5 reported cases. We present 2 cases of verruciform xanthoma of the esophagus. Case 1 involved a 91-year-old woman, who had hypertension and chronic gastritis with Helicobacter pylori infection, with a 12-year history of a 10-mm white-yellow elevated lesion on the esophagus, 35 cm from the incisor teeth. Case 2 involved a 70-year-old man with fundic gland polyp, hyperlipidemia, and lung cancer, who had a 10-mm whitish granular/verrucoid lesion on the esophagus, 28 cm from the incisor teeth. Microscopically, these lesions show verrucous and papillomatous epithelial hyperplasia with neutrophilic intraepithelial exocytosis. The histological hallmark is the presence of numerous foamy histiocytes infiltrating the elongated squamous epithelial papillae. Although its etiology is unknown, irritation or trauma caused by radiotherapy has been suggested.

DOI： 10.1177/1066896919879495

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Yanazume Shintaro, Fukuda Mika, Togami Shinichi, Kamio Masaki, Kitazono Ikumi, Hiraki Tsubasa, Tanimoto Akihide, Kobayashi Hiroaki .  子宮の印環細胞癌と扁平上皮癌の衝突癌が認められた稀な1例(Rare signet-ring cell and squamous cell carcinoma collision tumor in the cervix) .  鹿児島産科婦人科学会雑誌28   39 - 44   2020.3Reviewed

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Language：English   Publisher：鹿児島産科婦人科学会  

症例は46歳の経産婦で、5年前から不正出血がみられ、38℃を超える発熱があったため来院した。白血球数、血小板数、C反応性蛋白質の上昇とヘモグロビン値の低下が認められた。子宮頸部のPapanicolaou生検で、印環細胞癌(SRCC)様腫瘍細胞と非定形扁平上皮細胞が存在することが明らかになった。子宮頸部腫瘍のパンチ生検により、粘液性SRCCとHPV18型感染が認められた。根治的子宮摘出術と両側付属器切除および腹腔リンパ節郭清を行った。各種検査の結果、最終的に子宮頸部のSRCCと扁平上皮癌の衝突癌(pT1b2N0M0)と診断した。次世代シーケンシングパネルを用いて生殖細胞変異の同定を試みたところ、両病変ともFLT3、BRCA2、R1遺伝子のChr13にヘテロ接合性消失が明らかになった。パクリタキセルとカルボプラチンによる術後化学療法を6コース行った。18ヵ月間の経過観察中、疾患の兆候は認められていない。

赤羽 俊章, 北薗 育美, 小林 裕明, 谷本 昭英 .  遺伝子パネル検査を利用した婦人科腫瘍の分子病理統合診断 .  鹿児島産科婦人科学会雑誌28   1 - 4   2020.3Reviewed

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Language：Japanese   Publisher：鹿児島産科婦人科学会  

鹿児島大学病院では、これからのゲノム医療に対応するため、産婦人科学教室と共同で婦人科腫瘍の遺伝子パネル検査の臨床研究を昨年から開始した。高品質のホルマリン固定パラフィン包埋検体を作成する取り組みや、液状処理細胞診検体を使用したパネル検査の基礎研究を行っている。当講座では独自の遺伝子パネル検査を開発し臨床研究に使用している。産婦人科学教室との臨床研究で使用したパネルは、分子標的薬関連・ミスマッチ修復関連・NCCNガイドライン関連遺伝子を含む60遺伝子と17ヶ所のマイクロサテライト領域を標的としたオリジナルの固形腫瘍専用の遺伝子パネル検査である。本稿では以下の項目で解説した。1)遺伝子パネル検査、2)類内膜腺癌で認められる遺伝子異常、3)カスタム遺伝子パネル検査。

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赤羽 俊章, 北薗 育美, 小林 裕明, 谷本 昭英 .  遺伝子パネル検査を利用した婦人科腫瘍の分子病理統合診断 .  鹿児島産科婦人科学会雑誌28   1 - 4   2020.3

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Language：Japanese   Publisher：鹿児島産科婦人科学会  

鹿児島大学病院では、これからのゲノム医療に対応するため、産婦人科学教室と共同で婦人科腫瘍の遺伝子パネル検査の臨床研究を昨年から開始した。高品質のホルマリン固定パラフィン包埋検体を作成する取り組みや、液状処理細胞診検体を使用したパネル検査の基礎研究を行っている。当講座では独自の遺伝子パネル検査を開発し臨床研究に使用している。産婦人科学教室との臨床研究で使用したパネルは、分子標的薬関連・ミスマッチ修復関連・NCCNガイドライン関連遺伝子を含む60遺伝子と17ヶ所のマイクロサテライト領域を標的としたオリジナルの固形腫瘍専用の遺伝子パネル検査である。本稿では以下の項目で解説した。1)遺伝子パネル検査、2)類内膜腺癌で認められる遺伝子異常、3)カスタム遺伝子パネル検査。

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Takuro Hirano, Yoshinari Shinsato, Kan Tanabe, Nayuta Higa, Muhammad Kamil, Kohichi Kawahara, Masatatsu Yamamoto, Kentaro Minami, Michiko Shimokawa, Takaaki Arigami, Shigehiro Yanagita, Daisuke Matushita, Yoshikazu Uenosono, Sumiya Ishigami, Yuko Kijima, Kosei Maemura, Ikumi Kitazono, Akihide Tanimoto, Tatsuhiko Furukawa, Shoji Natsugoe .  FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer. .  Oncogenesis9 ( 2 ) 13 - 13   2020.2Reviewed International journal

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Considering the poor prognosis of most advanced cancers, prevention of invasion and metastasis is essential for disease control. Ras homologous (Rho) guanine exchange factors (GEFs) and their signaling cascade could be potential therapeutic targets in advanced cancers. We conducted in silico analyses of The Cancer Genome Atlas expression data to identify candidate Rho-GEF genes showing aberrant expression in advanced gastric cancer and found FERM, Rho/ArhGEF, and pleckstrin domain protein 1 (FARP1) expression is related to poor prognosis. Analyses in 91 clinical advanced gastric cancers of the relationship of prognosis and pathological factors with immunohistochemical expression of FARP1 indicated that high expression of FARP1 is significantly associated with lymphatic invasion, lymph metastasis, and poor prognosis of the patients (P = 0.025). In gastric cancer cells, FARP1 knockdown decreased cell motility, whereas FARP1 overexpression promoted cell motility and filopodium formation via CDC42 activation. FARP1 interacted with integrin β5, and a potent integrin αvβ5 inhibitor (SB273005) prevented cell motility in only high FARP1-expressing gastric cancer cells. These results suggest that the integrin αvβ5-FARP1-CDC42 axis plays a crucial role in gastric cancer cell migration and invasion. Thus, regulatory cascade upstream of Rho can be a specific and promising target of advanced cancer treatment.

DOI： 10.1038/s41389-020-0190-7

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Tsubasa Hiraki, Miho Hatanaka, Akiko Arimura, Hisao Kawahira, Mari Kirishima, Ikumi Kitazono, Michiko Horinouchi, Michiyo Higashi, Takuro Kanekura, Akihide Tanimoto .  Granulomatous/sarcoid-like reactions in the setting of programmed cell death-1 inhibition: a potential mimic of disease recurrence. .  Journal of cutaneous pathology47 ( 2 ) 154 - 160   2020.2

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Nivolumab and pembrolizumab are humanized IgG4 monoclonal antibodies against programmed cell death 1 (PD-1). Although these agents are effective in treating advanced melanoma, non-small-cell lung carcinoma, and other types of cancers, various adverse events have been reported. Cutaneous adverse events are particularly prevalent and, while granulomatous/sarcoid-like reactions are uncommon, they are increasingly recognized as immune-related adverse events associated with immune checkpoint inhibitors. Herein, we report two cases of granulomatous/sarcoid-like reaction with foreign material, mimicking metastatic malignancy after PD-1 inhibitor treatment. Clinicians should be aware of the existence of cutaneous lesions and perform biopsy if needed to prevent misdiagnosis and unnecessary adjustments to immunotherapy.

DOI： 10.1111/cup.13569

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Takashi Kijima, Takaaki Arigami, Yoshikazu Uenosono, Tsubasa Hiraki, Shigehiro Yanagita, Daisuke Matsushita, Keishi Okubo, Masataka Shimonosono, Sumiya Ishigami, Kosei Maemura, Akihide Tanimoto, Shoji Natsugoe .  Comparison of HER2 Status Before and After Trastuzumab-based Chemotherapy in Patients With Advanced Gastric Cancer. .  Anticancer research40 ( 1 ) 75 - 80   2020.1

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BACKGROUND/AIM: The aim of the present study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. MATERIALS AND METHODS: We assessed HER2 expression using immunohistochemistry and/or fluorescence in situ hybridization in pre-treatment biopsied specimens and post-treatment resected specimens obtained from seven patients with advanced HER2-positive gastric cancer receiving trastuzumab-based chemotherapy. RESULTS: Four patients maintained the HER2-positive status and three patients had a change in HER2 expression from positive to negative. In patients showing the loss of HER2 expression after treatments, HER2-positive tumor cells with a dominant histological type disappeared, and HER2-negative tumor cells with another dominant histological type were identified. CONCLUSION: HER2 expression can change after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after treatments may be utilized to determine whether the continued use of trastuzumab is advisable.

DOI： 10.21873/anticanres.13927

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Tomoko Hanada, Ryosuke Hanaya, Fauziah Chaira Ummah, Taro Kamisasanuki, Mari Kirishima, Akihide Tanimoto, Kazunori Arita, Koji Yoshimoto .  Combined Transcranial-supraorbital and Transconjunctival Approach for Optic Nerve Coloboma with Ophthalmic Dysplasia Associated with Rheumatoid Arthritis. .  NMC case report journal7 ( 1 ) 1 - 4   2020.1Reviewed

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Language：English   Publisher：The Japan Neurosurgical Society  

We report a 59-year-old woman with optic nerve coloboma and ophthalmic dysplasia associated with rheumatoid arthritis. She experienced progressive visual dysfunction over the course of several years and presented with headache and pain in the left eye. Since infancy the visual acuity of her left eye had been compromised and her eyesight worsened gradually until she was blind in the left eye. Macroscopic observation showed a reddish lesion on the sclera thought to be due to rheumatoid arthritis (RA). Magnetic resonance imaging and computed tomography disclosed a well-defined cystic lesion at the left retro-bulbar optic nerve within the optic nerve sheath. We selected the combined transcranial-supraorbital and transconjunctival approach to remove the eyeball after detaching the optic nerve. This technique was successful and the placement of an ocular prosthetic was cosmetically acceptable.

DOI： 10.2176/nmccrj.cr.2018-0302

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Hanada Tomoko, Hanaya Ryosuke, Ummah Fauziah Chaira, Kamisasanuki Taro, Kirishima Mari, Tanimoto Akihide, Arita Kazunori, Yoshimoto Koji .  関節リウマチを伴う眼形成不全合併視神経コロボーマに対する経頭蓋眼窩上アプローチと経結膜アプローチの併用(Combined Transcranial-supraorbital and Transconjunctival Approach for Optic Nerve Coloboma with Ophthalmic Dysplasia Associated with Rheumatoid Arthritis) .  NMC Case Report Journal7 ( 1 ) 1 - 4   2020.1Reviewed

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Language：English   Publisher：(一社)日本脳神経外科学会  

症例は59歳女性で、左眼の視力障害と重度疼痛をきたして近医を受診した。関節リウマチの既往を有し、メトトレキサートとNSAIDsにてコントロールされていた。受診時、左眼の強膜炎を認め、MRIにて左眼窩に嚢胞性病変がみられたため、当院眼科紹介となった。MRIと超音波検査で左眼球と交通する嚢胞性病変を認め、強膜炎、網膜剥離および水疱性角膜症を伴うコロボーマと診断し、有痛性水疱性角膜症の治療目的に神経外科に転科となった。著明な強膜充血と浮腫のほか、肥厚化した嚢胞性視神経と左眼球の変性が認められ、眼球摘出と義眼挿入の適応と判断し、神経外科医と眼科医の協働のもと球後手術を行う方針とした。経頭蓋眼窩上アプローチと経結膜アプローチを選択し、開頭術と眼窩切開術によって視神経鞘を切離後、顕微鏡下に経結膜眼球摘出術を施行した。術後の病理所見では嚢胞性病変は視神経に付着し、嚢胞壁は線維性結合組織で構成されていた。また、網膜萎縮と視神経変性が認められ、コロボーマに一致する所見が得られた。術後MRIでは眼球とコロボーマの摘出が確認され、整容的にも満足が得られる結果となった。

Satoru Kake, Hiroaki Kawaguchi, Tomoka Nagasato, Tomonobu Yamada, Takashi Ito, Ikuro Maruyama, Naoki Miura, Akihide Tanimoto .  Association Between HMGB1 and Thrombogenesis in a Hyperlipaemia-induced Microminipig Model of Atherosclerosis. .  In vivo34 ( 4 ) 1871 - 1874   2020

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Hiroto Tokumoto, Takao Setoguchi, Yoshinobu Saitoh, Hiromi Sasaki, Satoshi Nagano, Shingo Maeda, Akihide Tanimoto, Noboru Taniguchi .  Neurotensin receptor 1 is a new therapeutic target for human undifferentiated pleomorphic sarcoma growth. .  Molecular carcinogenesis58 ( 12 ) 2230 - 2240   2019.12

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Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G-protein-coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real-time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5- to 7-fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal-regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.

DOI： 10.1002/mc.23111

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Toshinobu Imashioya, Yuichi Kodama, Tadasuke Ooka, Shunsuke Nakagawa, Takuro Nishikawa, Takayuki Tanabe, Yasuhiro Okamoto, Naoko Imuta, Mari Kirishima, Akihide Tanimoto, Toyoyasu Koriyama, Junichiro Nishi, Yoshifumi Kawano .  Liver abscess due to Sterigmatomyces halophilus in a boy with acute lymphoblastic leukemia. .  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy25 ( 12 ) 1047 - 1049   2019.12Reviewed International journal

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We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.

DOI： 10.1016/j.jiac.2019.05.021

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Takuro Kanekura, Akiko Arimura, Mari Kirishima, Akihide Tanimoto .  Eruptive squamous cell carcinoma in a patient treated with concomitant pembrolizumab and imiquimod. .  The Journal of dermatology46 ( 12 ) 1202 - 1204   2019.12

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Pembrolizumab, a humanized monoclonal antibody against programmed cell death 1, is used for various malignant neoplasms. Toll-like receptor (TLR) agonists, specifically targeting the TLR9 subfamily (TLR7-9), are treatment options for solid tumors and hematological malignancies. We experienced a case of eruptive squamous cell carcinoma (SCC) in a patient treated concomitantly with pembrolizumab and imiquimod, a TLR7 agonist. A 75-year-old woman who was given a diagnosis of bladder cancer with lung metastasis received pembrolizumab for 3 months when she was referred to our department for the evaluation of skin rashes on her hands. Her skin lesions were diagnosed as well-differentiated SCC and treated with topical imiquimod. Two months after the start of imiquimod, more than 10 reddish papules appeared on her hands. The histological diagnosis of a new plaque was the same as an earlier biopsy. We herein describe this case in detail and provide a published work review.

DOI： 10.1111/1346-8138.15101

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米盛 圭一, 日高 敬文, 吉留 伸郎, 原口 優清, 谷本 昭英, 夏越 祥次 .  子宮内膜症を伴った成人Nuck管水腫の1例 .  診断と治療107 ( 12 ) 1547 - 1549   2019.12

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26歳女。右下腹部腫瘤を主訴とした。右鼠径部に4cm大の弾性軟の腫瘤を認め、腫瘤は立位で膨隆し、仰臥位または圧迫で縮小した。自発痛や圧痛は認められなかった。腹部CTおよび腹部超音波検査にて、右鼠径部に35mm×37.4mm大の多房性嚢胞性腫瘤を認め、血液検査では異常を認めなかった。以上より、Nuck管水腫と診断し、鼠径ヘルニア根治術の前方アプローチに準じて手術を施行した。病理組織学的検査では、悪性所見を認めず、Nuck管水腫と診断した。嚢胞壁内には子宮内膜症の所見を認めた。術後は経過良好で、術後6日目には退院し、術後1年の時点で、再発は認めなかった。

Kanekura Takuro, Arimura Akiko, Kirishima Mari, Tanimoto Akihide .  ペンブロリズマブとイミキモド併用療法を行った患者における発疹性扁平上皮癌(Eruptive squamous cell carcinoma in a patient treated with concomitant pembrolizumab and imiquimod) .  The Journal of Dermatology46 ( 12 ) 1202 - 1204   2019.12Reviewed

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症例は75歳女性で、手の皮疹評価のため紹介された。15ヵ月前に肺転移を伴う膀胱癌と診断され、3ヵ月間のペンブロリズマブによる治療歴があった。身体検査では両手背部に僅かに隆起した赤色調斑と不規則な色素沈着が見られた。高分化扁平上皮癌(SCC)と診断しイミキモドによる局所治療を開始したが、治療開始2ヵ月後に赤色調丘疹数が増加し、当初よりも斑の大型化とさらなる隆起が認められた。またいくつかの斑では潰瘍化も見られた。患者希望によりイミキモドおよびペンブロリズマブの治療は中止とし、発疹性SCCに対する経口エトレチナートの治療を提案したが同意は得られなかった。2ヵ月後潰瘍は上皮化したが丘疹は持続しており、注意深い観察を行っている。

Imashioya Toshinobu, Kodama Yuichi, Ooka Tadasuke, Nakagawa Shunsuke, Nishikawa Takuro, Tanabe Takayuki, Okamoto Yasuhiro, Imuta Naoko, Kirishima Mari, Tanimoto Akihide, Koriyama Toyoyasu, Nishi Junichiro, Kawano Yoshifumi .  急性リンパ性白血病の小児におけるSterigmatomyces halophilusによる肝膿瘍(Liver abscess due to Sterigmatomyces halophilus in a boy with acute lymphoblastic leukemia) .  Journal of Infection and Chemotherapy25 ( 11-12 ) 1047 - 1049   2019.12Reviewed

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Language：English   Publisher：エルゼビア・ジャパン(株)  

6歳男児。急性リンパ性白血病にて同種骨髄移植(allo-BMT)を予定していた。導入療法にて完全寛解が得られ、大量化学療法後に発熱性好中球減少症を発症した(day 0)。抗菌薬による治療を行ったが、発熱が続き、day 28に腹部CTで肝膿瘍がみられた。真菌による肝膿瘍を疑い、アムホテリシンBリポソーム製剤を投与したが、発熱が続いた。day 37に腹腔鏡下肝生検を行い、類上皮細胞肉芽腫および酵母様真菌を認めた。真菌rRNA遺伝子のITS領域のPCR増幅により単一DNAバンドが得られ、塩基配列はSterigmatomyces halophilus CBS4609株と100%一致した。イトラコナゾールおよびフルシトシンの併用療法によりday 100頃に解熱し、day 106の腹部CTでは肝膿瘍は認められなかった。day 150にきょうだいからallo-BMTを行ったところ、急性リンパ性白血病を再発した。化学療法と父親からの造血幹細胞移植にて寛解し、肝膿瘍の再発は認めなかった。

米盛 圭一, 日高 敬文, 吉留 伸郎, 原口 優清, 谷本 昭英, 夏越 祥次 .  子宮内膜症を伴った成人Nuck管水腫の1例 .  診断と治療107 ( 12 ) 1547 - 1549   2019.12

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Language：Japanese   Publisher：(株)診断と治療社  

26歳女。右下腹部腫瘤を主訴とした。右鼠径部に4cm大の弾性軟の腫瘤を認め、腫瘤は立位で膨隆し、仰臥位または圧迫で縮小した。自発痛や圧痛は認められなかった。腹部CTおよび腹部超音波検査にて、右鼠径部に35mm×37.4mm大の多房性嚢胞性腫瘤を認め、血液検査では異常を認めなかった。以上より、Nuck管水腫と診断し、鼠径ヘルニア根治術の前方アプローチに準じて手術を施行した。病理組織学的検査では、悪性所見を認めず、Nuck管水腫と診断した。嚢胞壁内には子宮内膜症の所見を認めた。術後は経過良好で、術後6日目には退院し、術後1年の時点で、再発は認めなかった。

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Atsuko Ibusuki, Takuro Nishikawa, Tsubasa Hiraki, Tsubasa Okano, Kohsuke Imai, Hirokazu Kanegane, Hidenori Ohnishi, Zenichiro Kato, Kazuyasu Fujii, Akihide Tanimoto, Yoshifumi Kawano, Takuro Kanekura .  Prominent dermal Langerhans cells in an Omenn syndrome patient with a novel mutation in the IL2RG gene. .  The Journal of dermatology46 ( 11 ) 1019 - 1023   2019.11

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Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.

DOI： 10.1111/1346-8138.15054

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Akira I Hida, Takahiro Watanabe, Yasuaki Sagara, Masahiro Kashiwaba, Yoshiaki Sagara, Kenjiro Aogi, Yasuyo Ohi, Akihide Tanimoto .  Diffuse distribution of tumor-infiltrating lymphocytes is a marker for better prognosis and chemotherapeutic effect in triple-negative breast cancer. .  Breast cancer research and treatment178 ( 2 ) 283 - 294   2019.11

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PURPOSE: High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects. METHODS: Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed. RESULTS: A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60-8.57; overall survival [OS], HR 3.87, 95% CI 1.46-10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06-9.90; OS, HR 3.28, 95% CI 1.32-8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53-0.55; distribution pattern) to good (weighted k = 0.67-0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL. CONCLUSIONS: Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.

DOI： 10.1007/s10549-019-05390-x

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Ibusuki Atsuko, Nishikawa Takuro, Hiraki Tsubasa, Okano Tsubasa, Imai Kohsuke, Kanegane Hirokazu, Ohnishi Hidenori, Kato Zenichiro, Fujii Kazuyasu, Tanimoto Akihide, Kawano Yoshifumi, Kanekura Takuro .  IL2RG遺伝子に新規変異を有するOmenn症候群患者における、顕著な真皮Langerhans細胞(Prominent dermal Langerhans cells in an Omenn syndrome patient with a novel mutation in the IL2RG gene) .  The Journal of Dermatology46 ( 11 ) 1019 - 1023   2019.11Reviewed

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症例は生後7ヵ月の男児で、複合免疫不全を伴い、出生2週間後に出現した皮膚病変評価のため紹介された。他院にてアトピー性皮膚炎と診断され治療が行われていたが、3ヵ月時に敗血症のため入院し重症複合免疫(SCID)が疑われた。紹介後の検査では紅皮症、脱毛症、両側腋窩リンパ節腫脹、軽度肝脾腫、好酸球増加症が見られ、また血清免疫グロブリンG、A、M値は極端に低く、血清免疫グロブリンE値は非常に高かった。末梢血フローサイトメトリーではCD3陽性T細胞が全リンパ球の35%まで減少し、CD19陽性B細胞およびCD56陽性ナチュラルキラー細胞が各々37%と26%に増加していた。さらにCD4陰性/CD8陽性T細胞品は顕著に増加していた。IL2RG遺伝子の配列解析では、当該遺伝子にc.337_339delTCT、p.Ser113delのインフレーム変異が明らかとなり、最終診断はOmenn症候群となった。8ヵ月時に施行した同種移植臍帯血移植によく反応し、症状は顕著に改善し、その後3年間の臨床検査所見は正常であった。

島尾 義也, 堀之内 道子, 東 美智代, 地村 友宏, 永野 広海, 谷本 昭英 .  顎下腺に発生した扁平上皮癌の1例 .  診断病理36 ( 4 ) 320 - 323   2019.10

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唾液腺、とくに顎下腺に発生する扁平上皮癌は非常に稀である。今回、左顎下腺に発生した扁平上皮癌の1例を経験したので報告する。症例は60代女性、左顎下腺腫瘍の診断で腫瘍摘出術が施行された。腫瘍は浸潤傾向を認め内部に嚢胞様構造を認めた。組織学的には好酸性で厚い細胞質と大型核を有する癌細胞が大小の胞巣を形成し明らかな角化が認められた。CRTC1/CRTC3-MAML2癒合遺伝子は陰性で扁平上皮癌と診断した。唾液腺腫瘍では扁平上皮癌様の形態を示す腫瘍として粘表皮癌や唾液腺導管癌が挙げられ鑑別が必要である。(著者抄録)

島尾 義也, 堀之内 道子, 東 美智代, 地村 友宏, 永野 広海, 谷本 昭英 .  顎下腺に発生した扁平上皮癌の1例 .  診断病理36 ( 4 ) 320 - 323   2019.10

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唾液腺、とくに顎下腺に発生する扁平上皮癌は非常に稀である。今回、左顎下腺に発生した扁平上皮癌の1例を経験したので報告する。症例は60代女性、左顎下腺腫瘍の診断で腫瘍摘出術が施行された。腫瘍は浸潤傾向を認め内部に嚢胞様構造を認めた。組織学的には好酸性で厚い細胞質と大型核を有する癌細胞が大小の胞巣を形成し明らかな角化が認められた。CRTC1/CRTC3-MAML2癒合遺伝子は陰性で扁平上皮癌と診断した。唾液腺腫瘍では扁平上皮癌様の形態を示す腫瘍として粘表皮癌や唾液腺導管癌が挙げられ鑑別が必要である。(著者抄録)

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Hiroaki Kawaguchi, Masayuki Horie, Koki Onoue, Michiko Noguchi, Kohei Akioka, Tatsunori Masatani, Naoki Miura, Makoto Ozawa, Akihide Tanimoto .  Development of a Model of Porcine Epidemic Diarrhea in Microminipigs. .  Veterinary pathology56 ( 5 ) 711 - 714   2019.9Reviewed International journal

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Porcine epidemic diarrhea virus (PEDV) induces an often fatal gastrointestinal disease in piglets. In this study, we performed a PEDV infection experiment with the Microminipig, the smallest of experimental minipigs, as a novel small animal model. We orally inoculated a neonatal Microminipig with an intestinal homogenate of a PEDV-infected pig and housed it in a small cage originally designed for rats in an animal biosafety level 2 facility. The infected Microminipig showed the typical signs of porcine epidemic diarrhea (PED), such as watery diarrhea, loss of appetite and weight loss. We also recognized a high amount of excreted PEDV in its rectal swabs and villus atrophy of the small intestine. These results suggest that the Microminipig is a good small animal model for PED, which may contribute to a better understanding of the pathogenesis of PEDV.

DOI： 10.1177/0300985819839236

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井上 一利, 西川 拓朗, 平木 翼, 佐々木 裕美, 義岡 孝子, 中川 俊輔, 児玉 祐一, 岡本 康裕, 谷本 昭英, 河野 嘉文 .  診断に難渋した前腕原発spindle cell sarcomaの1例 .  日本小児血液・がん学会雑誌56 ( 2 ) 212 - 215   2019.9

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1歳9ヵ月の男児。左前腕部の腫脹に気付き紹介医を受診、MRI検査で6cm弱の充実性腫瘤を認め当科紹介となった。転移巣なく、生検術を行った。当初、生検材料の病理検索ではinfantile fibrosarcomaを考えたが、中央病理診断ではmyofibromaが疑われた。臨床的な判断に基づいて、vincristine、actinomycine、ifosfamideによる化学療法を開始したが、腫瘍径は変化なかった。中央病理診断の結果と治療反応から、化学療法は開始2ヵ月で中止した。中止3ヵ月後より腫瘤が増大し、中止4ヵ月後に腫瘍辺縁切除術を行った。この際の病理診断はspindle cell sarcoma、unclassifiedであった。局所照射、vincristine、ifosfamide、doxorubicinによる化学療法を3クール行い治療終了した。病理診断が臨床経過に合わない場合は、再度検体を採取し、病理検査を行うことを考慮する。(著者抄録)

井上 一利, 西川 拓朗, 平木 翼, 佐々木 裕美, 義岡 孝子, 中川 俊輔, 児玉 祐一, 岡本 康裕, 谷本 昭英, 河野 嘉文 .  診断に難渋した前腕原発spindle cell sarcomaの1例 .  日本小児血液・がん学会雑誌56 ( 2 ) 212 - 215   2019.9

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1歳9ヵ月の男児。左前腕部の腫脹に気付き紹介医を受診、MRI検査で6cm弱の充実性腫瘤を認め当科紹介となった。転移巣なく、生検術を行った。当初、生検材料の病理検索ではinfantile fibrosarcomaを考えたが、中央病理診断ではmyofibromaが疑われた。臨床的な判断に基づいて、vincristine、actinomycine、ifosfamideによる化学療法を開始したが、腫瘍径は変化なかった。中央病理診断の結果と治療反応から、化学療法は開始2ヵ月で中止した。中止3ヵ月後より腫瘤が増大し、中止4ヵ月後に腫瘍辺縁切除術を行った。この際の病理診断はspindle cell sarcoma、unclassifiedであった。局所照射、vincristine、ifosfamide、doxorubicinによる化学療法を3クール行い治療終了した。病理診断が臨床経過に合わない場合は、再度検体を採取し、病理検査を行うことを考慮する。(著者抄録)

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赤羽 俊章, 山口 朋美, 柳田 絵美衣, 西田 ゆかり, 西原 広史, 谷本 昭英 .  臨床医からの質問に答える パラフィンブロックから病理組織診断とゲノム検査の両方の検査を両立させるには? .  検査と技術47 ( 5 ) 627 - 630   2019.5

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＜文献概要＞はじめに 今回,私(赤羽)が執筆するテーマは,"パラフィンブロックから病理組織診断とゲノム検査の両方の検査を両立させるには?"です.では,いきなり答えですが,完全に両立させる方法はありません……としてしまうと終ってしまいます.ですから頑張って続きを書きます.この病理組織診断とゲノム検査は,相反します.完全にそれぞれを理想的な状態で両立させるという意味では,"ありません"ということになってしまうわけです.というわけで,それぞれの落とし所を模索しながら本稿で述べたいと思います.

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Xin Guo, Hirotsugu Noguchi, Naoki Ishii, Takujiro Homma, Taiji Hamada, Tsubasa Hiraki, Jing Zhang, Kei Matsuo, Seiya Yokoyama, Hiroaki Ishibashi, Tomoko Fukushige, Takuro Kanekura, Junichi Fujii, Hidetaka Uramoto, Akihide Tanimoto, Sohsuke Yamada .  The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma. .  Antioxidants & redox signaling30 ( 10 ) 1271 - 1284   2019.4Reviewed International journal

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AIMS: Peroxiredoxin 4 (PRDX4) is a member of the peroxiredoxin family of antioxidant enzymes. Previously, we reported that PRDX4 can restrain the initiation and progression of nonalcoholic steatohepatitis by reducing local and systemic reactive oxygen species (ROS) levels. Oxidative stress is recognized as a key factor in hepatocarcinogenesis, and a high ROS level has also been found in hepatocellular carcinoma (HCC). Here, our aim is to investigate roles of PRDX4 in the initiation and progression of HCC. RESULTS: In this study, for hepatocarcinogenesis, wild-type (WT), PRDX4 knockout (PRDX4-/y), and human PRDX4 transgenic (hPRDX4+/+) mice were given a weekly intraperitoneal injection of diethylnitrosamine for 25 weeks. The HCC incidence was higher in PRDX4-/y mice than in WT or hPRDX4+/+ mice. Intrahepatic and circulating oxidative stress and inflammatory cell infiltration in the liver were obviously decreased in hPRDX4+/+ mice, compared with WT mice. Furthermore, in our cohort study, human HCC specimens with low expression of PRDX4 had higher ROS levels and a highly malignant phenotype, which was associated with a reduced overall survival, compared with those with high PRDX4 expression. However, in human HCC cell lines, PRDX4 knockdown led to a rapidly increased intracellular ROS level and suppressed cell proliferation, inducing cell death. Innovation and Conclusion: Our results clearly indicate that PRDX4 has an inhibitory effect in the initiation of HCC, but a dual (inhibitory or promoting) role in the progression of HCC, suggesting the potential utility of PRDX4 activators or inhibitors as therapy for different stages and phenotypes of HCC.

DOI： 10.1089/ars.2017.7426

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赤羽 俊章, 谷本 昭英 .  【悪性腫瘍の病理・遺伝子診断に基づくプレシジョンメディシン】PI3K経路分子をドライバーとする悪性腫瘍の遺伝子プロファイル病理診断 .  医学のあゆみ269 ( 3 ) 207 - 213   2019.4

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ホスファチジルイノシトール3-キナーゼ(PI3K)経路に関わる遺伝子の変化は、さまざまな悪性腫瘍に認められている。そのため、治療標的や病理診断の補助マーカー、腫瘍マーカーとしても注目されるシグナル伝達経路である。本稿ではとくに、高率にPI3K経路の遺伝子に異常が認められる乳癌、子宮体部類内膜腺癌、神経膠腫について、実際の臨床例や臨床研究の結果とともに述べる。乳癌においてはPI3K経路の変異のほとんどがPIK3CAの変異であるが、AKT1変異を認めた乳癌の1例を経験したので提示したい。また子宮体部の類内膜腺癌は病理組織学的にはType 1とType 2に分類され、両者はゲノムプロファイルも異なることが知られている。当院のがん遺伝子診断外来症例のなかでERBB2増幅を認めたType 2類内膜腺癌の1例を経験したので紹介したい。神経膠腫は、先進的に分子異常と病理診断による統合診断がされてきた腫瘍である。神経膠芽腫におけるPI3K経路の異常としては、ホスファターゼテンシンホモログ(PTEN)に高頻度に機能欠失変異を認める。著者らの講座では脳腫瘍診断用の遺伝子パネル検査の臨床研究を行っており、そこから得られたPTENの知見も提示したい。(著者抄録)

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Atsunori Baba, Shigeto Matsushita, Kasumi Kitayama, Tetsuo Asakura, Hideki Sezutsu, Akihide Tanimoto, Takuro Kanekura .  Silk fibroin produced by transgenic silkworms overexpressing the Arg-Gly-Asp motif accelerates cutaneous wound healing in mice. .  Journal of biomedical materials research. Part B, Applied biomaterials107 ( 1 ) 97 - 103   2019.1Reviewed International journal

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We investigated the effect of silk fibroin (SF) on wound healing in mice. SF or an amorphous SF film (ASFF) prepared from silk produced by the wild-type silkworm Bombyx mori (WT-SF, WT-ASFF) or by transgenic worms that overexpress the Arg-Gly-Asp (RGD) sequence (TG-SF, TG-ASFF) was placed on 5-mm diameter full-thickness skin wounds made by biopsy punch on the back of 8-12 week-old BALB/c mice. Each wound was covered with WT-ASFF and urethane film (UF), TG-ASFF plus UF, or UF alone (control). Wound closure, histological thickness, the area of granulation tissue, and neovascularization were analyzed 4, 8, and 12 days later. The effect of SF on cell migration and proliferation was examined in vitro by scratch- and MTT-assay using human dermal fibroblasts. Wound closure was prompted by TG-ASFF, granulation tissue was thicker and larger in ASFF-treated wounds than the control, and neovascularization was promoted significantly by WT-ASFF. Both assays showed that SF induced the migration and proliferation of human dermal fibroblasts. The effects of TG-ASFF and TG-SF on wound closure, granulation formation, and cell proliferation were more profound than that of WT-ASFF and WT-SF. We document that SF accelerates cutaneous wound healing, and this effect is enhanced with TG-SF. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 97-103, 2019.

DOI： 10.1002/jbm.b.34098

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霧島 茉莉, 東 美智代, 後藤 優子, 北薗 育美, 平木 翼, 飛田 陽, 谷本 昭英 .  消化管出血で発見された膵十二指腸動静脈奇形の1例 .  診断病理36 ( 1 ) 39 - 45   2019.1

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45歳男性。消化管出血の精査で十二指腸動静脈奇形を疑われ、経カテーテル動脈塞栓術後に膵頭十二指腸切除術を施行された。切除標本では十二指腸に出血や潰瘍は認めず、割面では十二指腸と膵に拡張した血管を認めた。組織学的には十二指腸から膵実質にかけて静脈様の拡張血管、動脈様血管や不整な小血管の集簇と部分的な吻合がみられ、動静脈奇形(AVM)と診断した。消化管出血を契機に発見された稀な膵十二指腸AVMの1例を報告し、消化管出血との関連について、文献を交えて考察する。(著者抄録)

上笹貫 太郎, 花田 朋子, 花谷 亮典, 霧島 茉莉, 谷本 昭英, 坂本 泰二 .  角膜混濁と眼痛で発見に至ったcolobomatous cystの1例 .  日本眼科学会雑誌123 ( 1 ) 39 - 44   2019.1

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背景:Colobomatous cystは眼球発生時の視神経裂の閉鎖不全に起因して生じる神経外胚葉系の嚢腫である。典型例では小眼球を伴い、時に嚢腫による下眼瞼の膨隆を来すため、比較的幼少期に発見される。症例:59歳、女性。幼少期に左視力不良を指摘されていたが、精査は受けなかった。約1年前から左眼角膜混濁と眼痛が出現し、近医で受けた画像検査で左眼窩腫瘍を指摘され当科紹介となった。初診時の視力は右(1.2)、左光覚なしであった。右眼は軽度白内障のほかに特記すべき所見は認めなかった。左眼は角膜混濁のため前房、眼底の透見は不良であった。造影magnetic resonance imaging(MRI)で左眼球後方に硝子体腔内と連続する憩室状構造を認め、視神経は嚢腫に連続していた。画像所見からcolobomatous cystを疑った。眼痛が増悪したため、左眼球摘出術を施行した。術後に眼痛は消失した。病理組織学的検査では嚢腫は網膜様組織の内層と、強膜と連続する膠原線維の外層で構成されており、colobomatous cystと診断した。眼球には虹彩ルベオーシスや第一次硝子体過形成遺残を疑う所見を認め、角膜混濁や硝子体出血の起因となったと考えられた。眼痛の原因として続発緑内障による眼圧上昇が考えられた。結論:長期にわたって診断されず、片眼の角膜混濁と眼痛を契機に発見に至ったcolobomatous cystの症例を経験した。Colobomatous cyst例では長期経過後に角膜混濁や眼痛が出現する可能性があることが示唆された。(著者抄録)

上笹貫 太郎, 花田 朋子, 花谷 亮典, 霧島 茉莉, 谷本 昭英, 坂本 泰二 .  角膜混濁と眼痛で発見に至ったcolobomatous cystの1例 .  日本眼科学会雑誌123 ( 1 ) 39 - 44   2019.1

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Language：Japanese   Publisher：(公財)日本眼科学会  

背景:Colobomatous cystは眼球発生時の視神経裂の閉鎖不全に起因して生じる神経外胚葉系の嚢腫である。典型例では小眼球を伴い、時に嚢腫による下眼瞼の膨隆を来すため、比較的幼少期に発見される。症例:59歳、女性。幼少期に左視力不良を指摘されていたが、精査は受けなかった。約1年前から左眼角膜混濁と眼痛が出現し、近医で受けた画像検査で左眼窩腫瘍を指摘され当科紹介となった。初診時の視力は右(1.2)、左光覚なしであった。右眼は軽度白内障のほかに特記すべき所見は認めなかった。左眼は角膜混濁のため前房、眼底の透見は不良であった。造影magnetic resonance imaging(MRI)で左眼球後方に硝子体腔内と連続する憩室状構造を認め、視神経は嚢腫に連続していた。画像所見からcolobomatous cystを疑った。眼痛が増悪したため、左眼球摘出術を施行した。術後に眼痛は消失した。病理組織学的検査では嚢腫は網膜様組織の内層と、強膜と連続する膠原線維の外層で構成されており、colobomatous cystと診断した。眼球には虹彩ルベオーシスや第一次硝子体過形成遺残を疑う所見を認め、角膜混濁や硝子体出血の起因となったと考えられた。眼痛の原因として続発緑内障による眼圧上昇が考えられた。結論:長期にわたって診断されず、片眼の角膜混濁と眼痛を契機に発見に至ったcolobomatous cystの症例を経験した。Colobomatous cyst例では長期経過後に角膜混濁や眼痛が出現する可能性があることが示唆された。(著者抄録)

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霧島 茉莉, 東 美智代, 後藤 優子, 北薗 育美, 平木 翼, 飛田 陽, 谷本 昭英 .  消化管出血で発見された膵十二指腸動静脈奇形の1例 .  診断病理36 ( 1 ) 39 - 45   2019.1

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Language：Japanese   Publisher：(一社)日本病理学会  

45歳男性。消化管出血の精査で十二指腸動静脈奇形を疑われ、経カテーテル動脈塞栓術後に膵頭十二指腸切除術を施行された。切除標本では十二指腸に出血や潰瘍は認めず、割面では十二指腸と膵に拡張した血管を認めた。組織学的には十二指腸から膵実質にかけて静脈様の拡張血管、動脈様血管や不整な小血管の集簇と部分的な吻合がみられ、動静脈奇形(AVM)と診断した。消化管出血を契機に発見された稀な膵十二指腸AVMの1例を報告し、消化管出血との関連について、文献を交えて考察する。(著者抄録)

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Toshiaki Akahane, Tomomi Yamaguchi, Yasutaka Kato, Seiya Yokoyama, Taiji Hamada, Yukari Nishida, Michiyo Higashi, Hiroshi Nishihara, Shinsuke Suzuki, Shinichi Ueno, Akihide Tanimoto .  Comprehensive validation of liquid-based cytology specimens for next-generation sequencing in cancer genome analysis. .  PloS one14 ( 6 ) e0217724   2019Reviewed International journal

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In addition to conventional cytology, liquid-based cytology (LBC) is also used for immunocytochemistry and gene analysis. However, an appropriate method to obtain high quality DNA for next-generation sequencing (NGS) using LBC specimens remains controversial. We determined the optimal conditions for fixation with an alcohol-based fixative for LBC and DNA extraction using cultured cancer cell lines and clinical specimens. The extracted DNA was processed for NGS after the DNA quality was confirmed based on the DNA concentration and degree of degradation. The optimal conditions for cultured cells to obtain high quality DNA were to fix the cells at a density of 6 × 103 or 2 × 104 cells/mL and to use the magnetic bead-based DNA extraction method. Even after storing the fixed cells for 90 days, DNA extracted using the above and other extraction kits, including membrane-based methods, did not undergo degradation. Furthermore, 5-year-old residual LBC samples demonstrated high DNA quality that was suitable for NGS. Furthermore, a cancer genome panel analysis was successfully performed with DNA extracted from cultured cells fixed at 6 × 103 cells/mL for 90 days, and with DNA from residual LBC samples even after 1 year of storage. Residual LBC samples may be a useful source of DNA for clinical NGS to promote genome-based cancer medicine.

DOI： 10.1371/journal.pone.0217724

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Inoue Kazutoshi, Nishikawa Takuro, Hiraki Tsubasa, Sasaki Hiromi, Yoshioka Takako, Nakagawa Shunsuke, Kodama Yuichi, Okamoto Yasuhiro, Tanimoto Akihide, Kawano Yoshifumi .  A case report of spindle cell sarcoma of the forearm with diagnostic difficulty .  The Japanese Journal of Pediatric Hematology / Oncology56 ( 2 ) 212 - 215   2019Reviewed

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Language：English   Publisher：The Japanese Society of Pediatric Hematology / Oncology  

<p>A 1-year-and-9-month-old boy was referred to us for swelling of the left forearm. Magnetic resonance imaging revealed a solid tumor in the forearm about 6 cm in size. There was no metastatic lesion, and he underwent biopsy. Clinically, he was suspected of having infantile fibrosarcoma on the basis of the results of histopathological analysis and his clinical course. However, a central pathological review disclosed a suspicious myofibroma. Chemotherapy consisting of vincristine, actinomycin, and ifosfamide was carried out but the tumor size remained unchanged. Chemotherapy was discontinued 2 months after initiation. However, the tumor size increased 3 months after the discontinuation of chemotherapy; hence, he underwent marginal resection 4 months after the discontinuation of chemotherapy. The pathological diagnosis was unclassified spindle cell sarcoma. Local irradiation and 3 cycles of chemotherapy with vincristine, ifosfamide, and doxorubicin were carried out, and the treatment was completed. We recommend collecting another biopsy sample for histopathological examination if the pathological diagnosis is incompatible with the clinical course.</p>

DOI： 10.11412/jspho.56.212

CiNii Research

Mari Kirishima, Sohsuke Yamada, Mitsuhisa Shinya, Shun Onishi, Yuko Goto, Ikumi Kitazono, Tsubasa Hiraki, Michiyo Higashi, Akira I Hida, Akihide Tanimoto .  An autopsy case of epignathus (immature teratoma of the soft palate) with intracranial extension but without brain invasion: case report and literature review. .  Diagnostic pathology13 ( 1 ) 99 - 99   2018.12

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BACKGROUND: Epignathus is a rare congenital orofacial teratoma infrequently associated with intracranial extension. Intracranial extension of an epignathus indicates a poor prognosis; however, only a small number of such cases have been reported. While there have been some studies reporting cases of epignathus expanding directly into the cranium, others have reported no communication between an epignathus and an intracranial tumor. CASE PRESENTATION: A fetus at gestational week 27 was suspected of having an epignathus with intracranial tumor as shown by ultrasonographic and magnetic resonance imaging. The fetus was stillborn and an autopsy was performed. An epignathus measuring 12 × 6 × 6 cm and weighing 270 g protruded from the mouth, with its base on the soft palate. An intracranial tumor weighing 14 g was located at the middle intracranial fossa and connected to the epignathus through the right side of the sella turcica. The intracranial tumor was encapsulated, and there was no invasion into the brain. Histologically, both the epignathus and intracranial tumor were immature teratomas, with neural and pulmonary components that were especially immature as compared to those of the internal organs and brain tissues of the fetus. CONCLUSION: There have been several reports of epignathus and intracranial tumors that did not communicate; therefore, careful evaluation is needed when a fetus is suspected of having an epignathus extending into an intracranial lesion. Our case supports the findings that an epignathus can directly expand into the cranium. Moreover, this is a rare case of an epignathus in which the intracranial lesion was encapsulated and did not invade the brain. These rare but important findings will provide additional, potential therapeutic strategies for gynecologists, neurosurgeons, and pathologists.

DOI： 10.1186/s13000-018-0776-y

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Yoshihisa Umekita, Yasuyo Ohi, Orie Iwaya, Masakazu Souda, Yasuaki Sagara, Shugo Tamada, Daisuke Yotsumoto, Akihide Tanimoto .  Maspin mRNA expression in sentinel lymph nodes predicts non-SLN metastasis in breast cancer patients with SLN metastasis. .  Histopathology73 ( 6 ) 916 - 922   2018.12Reviewed International journal

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AIMS: Maspin is known to be a tumour suppressor protein, but its prognostic significance in breast cancer patients is controversial. There is no report focusing on maspin expression in metastatic carcinoma of sentinel lymph nodes (SLNs); we thus investigated maspin mRNA expression in SLNs using the remaining specimens after the one-step nucleic acid amplification (OSNA) assay. METHODS AND RESULTS: Ninety-three breast cancer patients with SLNs metastasis detected by the OSNA assay were enrolled. All patients experienced additional axillary lymph nodes (LNs) dissection and all dissected LNs were examined histopathologically. Maspin mRNA expression in SLNs was detected in 49.5% (46 of 93) and was correlated significantly with the presence of non-SLN metastasis (P < 0.0001) and ≥4 LN metastases (P = 0.029). In a multivariate logistic analysis, maspin mRNA expression in SLNs (P = 0.0015) had the most significant effect on predicting non-SLN metastasis, followed by pathological tumour size (P = 0.0039) and lymphovascular invasion (P = 0.009). The status of maspin mRNA expression in SLNs was correlated significantly with that of maspin protein expression in the primary carcinoma (P < 0.0001). CONCLUSIONS: This is the first study, to our knowledge, demonstrating that maspin mRNA expression in SLNs is an independent predictor of non-SLN metastasis and the presence of ≥4 LN metastases in breast cancer patients with SLN metastasis. The investigation of maspin mRNA expression in SLNs using the remaining specimens after the OSNA assay may be useful for predicting the further progression of metastatic carcinoma in breast cancer patients with SLNs metastasis.

DOI： 10.1111/his.13718

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Shun Onishi, Tatsuru Kaji, Seiro Machigashira, Waka Yamada, Ryuta Masuya, Kazuhiko Nakame, Masato Kawano, Keisuke Yano, Koji Yamada, Takafumi Kawano, Motoi Mukai, Takako Yoshioka, Akihide Tanimoto, Satoshi Ieiri .  The effect of intravenous lipid emulsions and mucosal adaptation following massive bowel resection. .  Journal of pediatric surgery53 ( 12 ) 2444 - 2448   2018.12

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AIMS AND OBJECTIVES: Fish oil (FO) lipid emulsion and a new lipid emulsion (SMOF) are important treatments for intestinal failure-associated liver disease. We evaluated the efficacy of FO and SMOF lipid emulsion on intestinal mucosal adaptation using a total parenteral nutrition (TPN)-supported rat model of short bowel syndrome. MATERIAL & METHODS: Sprague-Dawley rats underwent jugular vein catheterization and 90% small bowel resection and were divided into three groups: TPN with soy bean oil lipid emulsion (SO group), FO lipid emulsion (FO group), or SMOF (SMOF group). On day 13, the rats were euthanized, and the small intestine was harvested. The microscopic morphology and crypt cell proliferation rate (CCPR) were then evaluated. RESULTS: The villus height of the ileum in the SMOF group was significantly higher than in the SO group. The crypt depth of the intestine in the SMOF group was significantly lower than in the SO group. The CCPRs of the intestine in the FO and SMOF groups were both higher than in the SO group. CONCLUSIONS: Lipid emulsion affected the bowel morphology, such as the mucosa as well as the intestinal smooth muscle. Further studies are needed to clarify the mechanisms.

DOI： 10.1016/j.jpedsurg.2018.08.019

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桝屋 隆太, 連 利博, 川野 正人, 矢野 圭輔, 山田 耕嗣, 山田 和歌, 町頭 成郎, 川野 孝文, 中目 和彦, 向井 基, 加治 建, 谷本 昭英, 家入 里志 .  胆道閉鎖症肝生検検体における門脈低形成所見の検討 .  日本小児外科学会雑誌54 ( 7 ) 1408 - 1409   2018.12

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Yuki Nomoto, Yuko Kijima, Yoshiaki Shinden, Munetugu Hirata, Yuka Eguchi, Heiji Yoshinaka, Ikumi Kitazono, Tsubasa Hiraki, Akihide Tanimoto, Shoji Natsugoe .  Two cases of radiation-associated angiosarcoma of the breast. .  Surgical case reports4 ( 1 ) 132 - 132   2018.11Reviewed International journal

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BACKGROUND: The incidence of radiation-associated angiosarcoma (RAA) of the breast has been increasing, and its prognosis is reportedly poor. It is important to remove tumor tissues completely to prevent recurrence. CASE PRESENTATION: We report two cases of patients with RAA of the breast. Both patients had a nodule in their remaining breast a few years after undergoing breast-conserving surgery and radiation therapy for breast cancer. The nodules were diagnosed as angiosarcoma by skin biopsy and open biopsy, respectively. To determine the extent of lesion spread, mapping biopsy was performed before surgery. Both patients underwent mastectomy, extensive skin resection, and split skin grafting. Pathological findings showed that their tumors could be completely resected. After surgery, chemotherapy was performed. CONCLUSION: In our cases, no local or distant recurrence has been detected in either patient for over 4 years. We identified the range of tumor invasion by preoperative mapping biopsy and completely resected all tumor tissue.

DOI： 10.1186/s40792-018-0539-8

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有馬 大智, 佐々木 裕美, 嶋田 博文, 永野 聡, 天辰 愛弓, 瀬戸口 啓夫, 後藤 優子, 平木 翼, 谷本 昭英, 小宮 節郎 .  背部に発生した紡錘形細胞脂肪腫の1例 .  整形外科と災害外科67 ( 4 ) 857 - 860   2018.9

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【はじめに】紡錘形細胞脂肪腫spindle cell lipomaは脂肪腫の特殊型で、中年男性の後頸部、肩、背部に好発する稀な腫瘍である。【症例】70歳男性、背部皮下に弾性軟、約8cm大の腫瘤を認めた。MRI上T2強調画像にて著明な高信号を主体とし、漸増性の増強効果を呈し内部に微小な脂肪成分を認め、分葉状の形態を呈していた。粘液型脂肪肉腫との鑑別が必要と考え、生検術を施行。肉眼的に粘液性の成分と一部線維性の組織を採取した。病理所見では粘液腫様の間質内に存在する短紡錘形の腫瘍細胞はCD34陽性、ロープ状膠原線維の存在やMDM2陰性から紡錘形細胞脂肪腫と診断し、辺縁切除術を施行した。【まとめ】紡錘形細胞脂肪腫は術前診断が難しく、他の脂肪系腫瘍である粘液型脂肪肉腫や異型脂肪腫様腫瘍との鑑別が重要である。画像所見や病理所見、臨床所見について文献的考察を加え報告する。(著者抄録)

有馬 大智, 佐々木 裕美, 嶋田 博文, 永野 聡, 天辰 愛弓, 瀬戸口 啓夫, 後藤 優子, 平木 翼, 谷本 昭英, 小宮 節郎 .  背部に発生した紡錘形細胞脂肪腫の1例 .  整形外科と災害外科67 ( 4 ) 857 - 860   2018.9

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【はじめに】紡錘形細胞脂肪腫spindle cell lipomaは脂肪腫の特殊型で、中年男性の後頸部、肩、背部に好発する稀な腫瘍である。【症例】70歳男性、背部皮下に弾性軟、約8cm大の腫瘤を認めた。MRI上T2強調画像にて著明な高信号を主体とし、漸増性の増強効果を呈し内部に微小な脂肪成分を認め、分葉状の形態を呈していた。粘液型脂肪肉腫との鑑別が必要と考え、生検術を施行。肉眼的に粘液性の成分と一部線維性の組織を採取した。病理所見では粘液腫様の間質内に存在する短紡錘形の腫瘍細胞はCD34陽性、ロープ状膠原線維の存在やMDM2陰性から紡錘形細胞脂肪腫と診断し、辺縁切除術を施行した。【まとめ】紡錘形細胞脂肪腫は術前診断が難しく、他の脂肪系腫瘍である粘液型脂肪肉腫や異型脂肪腫様腫瘍との鑑別が重要である。画像所見や病理所見、臨床所見について文献的考察を加え報告する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00766&link_issn=&doc_id=20181017080058&doc_link_id=130007507272&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007507272&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Jing Zhang, Xin Guo, Taiji Hamada, Seiya Yokoyama, Yuka Nakamura, Jianbo Zheng, Nozomu Kurose, Yasuhito Ishigaki, Hidetaka Uramoto, Akihide Tanimoto, Sohsuke Yamada .  Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury. .  International journal of molecular sciences19 ( 9 )   2018.8Reviewed International journal

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Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

DOI： 10.3390/ijms19092509

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Shun Onishi, Tatsuru Kaji, Waka Yamada, Kazuhiko Nakame, Seiro Machigashira, Masato Kawano, Keisuke Yano, Toshio Harumatsu, Koji Yamada, Ryuta Masuya, Takafumi Kawano, Motoi Mukai, Taiji Hamada, Masakazu Souda, Takako Yoshioka, Akihide Tanimoto, Satoshi Ieiri .  Ghrelin stimulates intestinal adaptation following massive small bowel resection in parenterally fed rats. .  Peptides106   59 - 67   2018.8Reviewed International journal

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BACKGROUND: Since short bowel syndrome (SBS) patients face life-threatening conditions, the development of therapeutic strategies to induce intestinal adaptation has been investigated. Ghrelin, a ligand of growth hormone (GH) secretagogue-receptor that stimulates the release of GH and insulin like growth factor-1 (IGF-1), has several pleiotropic effects. We investigated whether ghrelin induces intestinal adaptation in parenterally fed rats with SBS. METHODS: Sprague-Dawley rats underwent venous catheterization and were divided into 3 groups: those receiving 90% small bowel resection while leaving the proximal jejunum and distal ileum (90% SBR) with TPN (SBS/TPN group), those receiving 90% SBR with TPN + ghrelin (SBS/TPN/ghrelin group), and those receiving sham operation and fed chow (sham group). Ghrelin was administered intravenously at 10 μg/kg/day. On Day 13, the rats were euthanized and the small intestine harvested, and the histology and crypt cell proliferation rates (CCPR), apoptosis, and nutrient transporter protein levels were analyzed and the plasma hormones were measured. RESULTS: The villus height and crypt depth of the ileum in the SBS/TPN/ghrelin group were significantly higher than in the SBS/TPN group. The CCPR of the jejunum and the ileum significantly increased by the administration of ghrelin; however, the apoptosis rates did not significantly differ between the SBS/TPN and SBS/TPN/ghrelin groups. Significant differences did not exist in the plasma IGF-1 and nutrient transporter protein levels among three groups. CONCLUSIONS: The intravenous administration of ghrelin stimulated the morphological intestinal adaptation of the ileum to a greater degree than the jejunum due to the direct effect of ghrelin.

DOI： 10.1016/j.peptides.2018.06.009

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宮本 陽子, 川口 博明, 谷本 昭英 .  雄ラット乳腺の発達とホルモン・レセプターの関連性(Relationship between morphological development and sex hormone receptor expression of mammary glands with age in male rats) .  Experimental Animals67 ( 3 ) 361 - 371   2018.7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本実験動物学会  

14-100日齢の雄Sprague-Dawleyラットの乳腺における経時的形態学的変化とホルモン・レセプター発現の関連について、性成熟後に出現する"oxyphilic cells(OCs)"(豊富な好酸性細胞質を有する細胞)を主体に形態学的検索を行った。肉眼的観察、Whole mount標本及びHE標本を用いた観察を行い、OCsについては透過型電子顕微鏡(TEM)を用いて精査した。更に、アンドロゲン・レセプター(AR)、エストロゲン・レセプター(ER)及びプロゲステロン・レセプター(PgR)について免疫組織学的検索を行った。肉眼的に成熟期(50-100日齢)の乳腺は褐色を帯びており、組織学的には若齢期(14-35日齢)と成熟期では構成細胞の形態が異なり、成熟期ではOCsが認められた。ER及びPgRはすべての時期で、ARは成熟期のみで発現した。OCsではAR発現が優位であり、その割合は経時的に増加した。以上の結果から成熟期の乳腺発達とAR発現は強く関連していると示唆された。また、TEMでは、OCsの細胞質に多数の脂肪滴、変形・大型化したミトコンドリア等が認められた。(著者抄録)

DOI： 10.1538/expanim.17-0134

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J04703&link_issn=&doc_id=20180802220007&doc_link_id=130007423739&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007423739&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Kie Honjo, Taiji Hamada, Takuya Yoshimura, Seiya Yokoyama, Sohsuke Yamada, Yan-Qin Tan, Lai K Leung, Norifumi Nakamura, Yasuyo Ohi, Michiyo Higashi, Akihide Tanimoto .  PCP4/PEP19 upregulates aromatase gene expression via CYP19A1 promoter I.1 in human breast cancer SK-BR-3 cells. .  Oncotarget9 ( 51 ) 29619 - 29633   2018.7Reviewed International journal

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The Purkinje cell protein 4/peptide 19 (PCP4/PEP19) is a novel breast cancer cell expressing peptide, originally found in the neural cells as an anti-apoptotic factor, could inhibit cell apoptosis and enhance cell migration and invasion in human breast cancer cell lines. The expression of PCP4/PEP19 is induced by estrogens in estrogen receptor-positive (ER+) MCF-7 cells but also highly expressed in ER- SK-BR-3 cells. In this study, we investigated the effects of PCP4/PEP19 on aromatase gene expression in MCF-7 and SK-BR-3 human breast cancer cells. In SK-BR-3 cells but not in MCF-7 cells, PCP4/PEP19 knockdown by siRNA silencing decreased the aromatase expression in gene transcriptional level. When PCP4/PEP19 was overexpressed by CMV promoter-driven PCP4/PEP19 expressing plasmid transfection, aromatase gene transcription increased in SK-BR-3 cells. This aromatase gene transcription is mainly mediated through promoter region PI.1, which is usually active in the placental tissue but not in the breast cancer tissue. These results indicate a new function of PCP4/PEP19 that would enhance aromatase gene upregulation to supply estrogens in heterogeneous cancer microenvironment.

DOI： 10.18632/oncotarget.25651

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宮本 陽子, 川口 博明, 谷本 昭英 .  雄ラット乳腺の発達とホルモン・レセプターの関連性(Relationship between morphological development and sex hormone receptor expression of mammary glands with age in male rats) .  Experimental Animals67 ( 3 ) 361 - 371   2018.7

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Publisher：(公社)日本実験動物学会  

14-100日齢の雄Sprague-Dawleyラットの乳腺における経時的形態学的変化とホルモン・レセプター発現の関連について、性成熟後に出現する"oxyphilic cells(OCs)"(豊富な好酸性細胞質を有する細胞)を主体に形態学的検索を行った。肉眼的観察、Whole mount標本及びHE標本を用いた観察を行い、OCsについては透過型電子顕微鏡(TEM)を用いて精査した。更に、アンドロゲン・レセプター(AR)、エストロゲン・レセプター(ER)及びプロゲステロン・レセプター(PgR)について免疫組織学的検索を行った。肉眼的に成熟期(50-100日齢)の乳腺は褐色を帯びており、組織学的には若齢期(14-35日齢)と成熟期では構成細胞の形態が異なり、成熟期ではOCsが認められた。ER及びPgRはすべての時期で、ARは成熟期のみで発現した。OCsではAR発現が優位であり、その割合は経時的に増加した。以上の結果から成熟期の乳腺発達とAR発現は強く関連していると示唆された。また、TEMでは、OCsの細胞質に多数の脂肪滴、変形・大型化したミトコンドリア等が認められた。(著者抄録)

宮本 陽子, 川口 博明, 谷本 昭英 .  雄ラット乳腺の発達とホルモン・レセプターの関連性(Relationship between morphological development and sex hormone receptor expression of mammary glands with age in male rats) .  Experimental Animals67 ( 3 ) 361 - 371   2018.7

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Language：English   Publisher：(公社)日本実験動物学会  

14-100日齢の雄Sprague-Dawleyラットの乳腺における経時的形態学的変化とホルモン・レセプター発現の関連について、性成熟後に出現する&quot;oxyphilic cells(OCs)&quot;(豊富な好酸性細胞質を有する細胞)を主体に形態学的検索を行った。肉眼的観察、Whole mount標本及びHE標本を用いた観察を行い、OCsについては透過型電子顕微鏡(TEM)を用いて精査した。更に、アンドロゲン・レセプター(AR)、エストロゲン・レセプター(ER)及びプロゲステロン・レセプター(PgR)について免疫組織学的検索を行った。肉眼的に成熟期(50-100日齢)の乳腺は褐色を帯びており、組織学的には若齢期(14-35日齢)と成熟期では構成細胞の形態が異なり、成熟期ではOCsが認められた。ER及びPgRはすべての時期で、ARは成熟期のみで発現した。OCsではAR発現が優位であり、その割合は経時的に増加した。以上の結果から成熟期の乳腺発達とAR発現は強く関連していると示唆された。また、TEMでは、OCsの細胞質に多数の脂肪滴、変形・大型化したミトコンドリア等が認められた。(著者抄録)

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Yoshinobu Saitoh, Takao Setoguchi, Takako Yoshioka, Junichiro Nishi, Akihide Tanimoto, Setsuro Komiya .  Intraoperative evaluation of polymorphonuclear leukocyte during second-stage revision surgery promote overdiagnosis of persistent periprosthetic joint infection. .  Acta orthopaedica et traumatologica turcica52 ( 3 ) 191 - 195   2018.5Reviewed International journal

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OBJECTIVE: The aim of this study was to evaluate whether intraoperative histopathological examination could predict the risk of relapse of infection in periprosthetic joint infections (PJI). METHODS: The study included 25 patients (14 women and 11 men, with a mean age of 67.0 years (range, 37-83 years)), who had two-staged revision surgery for a PJI. Following prosthetic removal in the first stage, all patient underwent an intraoperative histopathological examination during the second stage. The patients were divided into PMNs-positive group (≥five PMNs per high-powered field) or -negative group (<five PMNs). A relapse was defined as the occurrence of PJI. Median follow-up was 51 months (range, 32-80 months) following second-stage revision surgery. RESULTS: Intraoperative histopathological revealed that 8.0% of cases were PMNs-positive. Postoperative histopathological examination revealed that 28.0% of cases were PMNs-positive. 28.0% of cases showed discrepancy between the PMNs-positivity. Intraclass correlation coefficient indicates poor reproducibility. Infection relapse after revision surgery occurred in two cases (8.0%); both relapse cases were from the PMNs-negative group. There was no statistical relationship between the presence of PMNs in periprosthetic tissue by intraoperative or postoperative histopathological examination and relapse of infection. CONCLUSIONS: Our findings showed that intraoperative histopathological examination could not predict the relapse of infection. Intraoperative histopathological examination promotes overdiagnosis of the requirement for re-implantation of antibiotic-impregnated cement and prolonged treatment periods. LEVEL OF EVIDENCE: Level III, diagnostic study.

DOI： 10.1016/j.aott.2018.02.002

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横山 勢也, 東 美智代, 谷本 昭英, 米澤 傑 .  【肝胆膵疾患のエピジェネティクスを学ぶ】 膵疾患のエピジェネティクス 膵癌におけるメチル化によるムチン発現調節 .  肝・胆・膵76 ( 5 ) 945 - 950   2018.5

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横山 勢也, 東 美智代, 谷本 昭英, 米澤 傑 .  【肝胆膵疾患のエピジェネティクスを学ぶ】膵疾患のエピジェネティクス 膵癌におけるメチル化によるムチン発現調節 .  肝胆膵76 ( 5 ) 945 - 950   2018.5

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野元 裕輔, 山筋 好子, 川平 尚生, 指宿 敦子, 内田 洋平, 多田 浩一, 藤井 一恭, 東 裕子, 井内 寛之, 宮下 圭一, 大堀 純一郎, 平木 翼, 西 正行, 谷本 昭英, 金蔵 拓郎 .  右前額部原発のmalignant spiradenomaの1例 .  西日本皮膚科80 ( 2 ) 164 - 165   2018.4

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小倉 葉月, 新田 吉陽, 大井 秀之, 平田 宗嗣, 田上 聖徳, 江口 裕可, 中条 哲浩, 喜島 祐子, 霧島 茉莉, 谷本 昭英, 夏越 祥次 .  急激に増大した若年性乳房悪性葉状腫瘍の1例 .  鹿児島県臨床外科学会誌29   16 - 17   2018.3

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Publisher：鹿児島県臨床外科学会  

症例は24歳女性で、手拳大の右乳房腫瘤が出現し、次第に小児頭大に増大した。右乳房に皮膚露出と出血を伴う腫瘍を認め、針生検にて悪性葉状腫瘍、紡錘細胞癌、間質肉腫などが疑われたため、貧血管理と手術目的で当院に緊急入院となった。右乳房に31×26×16cm大の巨大腫瘤を認めた。長径25cmにわたって腫瘍が露出しており、壊死と出血を認めた。造影CTで、右乳房に26cm大の内部不均一な腫瘤と右腋窩リンパ節の腫大を認めた。針生検病理像から悪性葉状腫瘍、紡錘細胞癌、間質肉腫が疑われたため、右乳房悪性腫瘍の術前診断で手術を施行した。術中の肉眼所見でも胸壁浸潤は認めず、腫瘍の完全切除が可能であった。病理組織学的所見では、大部分で強い核異型と多数の核分裂像を認め、悪性葉状腫瘍の診断であった。切除断端は陰性、摘出リンパ節にも転移は認めなかった。

小倉 葉月, 新田 吉陽, 大井 秀之, 平田 宗嗣, 田上 聖徳, 江口 裕可, 中条 哲浩, 喜島 祐子, 霧島 茉莉, 谷本 昭英, 夏越 祥次 .  急激に増大した若年性乳房悪性葉状腫瘍の1例 .  鹿児島県臨床外科学会誌29   16 - 17   2018.3

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Language：Japanese   Publisher：鹿児島県臨床外科学会  

症例は24歳女性で、手拳大の右乳房腫瘤が出現し、次第に小児頭大に増大した。右乳房に皮膚露出と出血を伴う腫瘍を認め、針生検にて悪性葉状腫瘍、紡錘細胞癌、間質肉腫などが疑われたため、貧血管理と手術目的で当院に緊急入院となった。右乳房に31×26×16cm大の巨大腫瘤を認めた。長径25cmにわたって腫瘍が露出しており、壊死と出血を認めた。造影CTで、右乳房に26cm大の内部不均一な腫瘤と右腋窩リンパ節の腫大を認めた。針生検病理像から悪性葉状腫瘍、紡錘細胞癌、間質肉腫が疑われたため、右乳房悪性腫瘍の術前診断で手術を施行した。術中の肉眼所見でも胸壁浸潤は認めず、腫瘍の完全切除が可能であった。病理組織学的所見では、大部分で強い核異型と多数の核分裂像を認め、悪性葉状腫瘍の診断であった。切除断端は陰性、摘出リンパ節にも転移は認めなかった。

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Kie Honjo, Tsubasa Hiraki, Michiyo Higashi, Hirotsugu Noguchi, Mitsuharu Nomoto, Takuya Yoshimura, Surinder K Batra, Suguru Yonezawa, Ichiro Semba, Norifumi Nakamura, Akihide Tanimoto, Sohsuke Yamada .  Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase. .  Histology and histopathology33 ( 2 ) 201 - 213   2018.2Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

DOI： 10.14670/HH-11-913

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Kaichiro Takeishi, Hiroaki Kawaguchi, Kohei Akioka, Michiko Noguchi, Emi Arimura, Masaharu Abe, Miharu Ushikai, Shinobu Okita, Akihide Tanimoto, Masahisa Horiuchi .  Effects of dietary and lighting conditions on diurnal locomotor activity and body temperature in microminipigs .  In Vivo32 ( 1 ) 55 - 62   2018.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

The effects of dietary and lighting conditions on diurnal rhythm of locomotor activity (LA) and body temperature (BT) using four adult male microminipigs were investigated. Different feeding times, diet and lighting conditions were applied sequentially for 3 weeks in each phase as follows: Phase I: Morning mealtime, normal diet, 12-h lights on
phase II: mealtime changed to afternoon
phase III: diet changed to high-fat diet
phase IV: lighting changed to 20-h on
and phase V: phase I repeated. LA was measured by an actigraph which was worn on the body of each pig. A BT recording module (Thermochron Type-SL) was implanted in the neck subcutaneously. Phase II increased BT compared with phase I. Phase III increased LA and BT compared with phase II. Phase IV increased LA compared with phase III. LA in phase V was higher compared with phase I. These results can be extrapolated to other diurnal animals such as humans. This study provides an example of the effects of diet and lighting on biological activities in microminipigs under low-invasive procedures measuring LA and BT, leading to low variations in these measures.

DOI： 10.21873/invivo.11204

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後藤 優子, 山田 壮亮, 霧島 茉莉, 北薗 育美, 平木 翼, 東 美智代, 畑中 一仁, 谷本 昭英 .  右肺静脈内に主座を置き左心房内まで達したグロムス腫瘍の稀少な1手術症例 .  診断病理35 ( 1 ) 25 - 30   2018.1

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Publisher：(一社)日本病理学会  

症例は32歳女性。胸部CTで右肺上葉の末梢から右上肺静脈を経て左心房内に達する数珠状の腫瘍を認め、右肺上葉切除が行われた。切除検体では最大4×2cmの白色充実性の腫瘍であった。組織学的には比較的均一な円形核を有する腫瘍細胞が充実性、シート状構造を呈し、免疫組織化学的にはvimentin、α-SMAにびまん性に強陽性、laminin、h-caldesmonは一部陽性であった。悪性度不明なグロムス腫瘍が肺静脈を経て心房内に達した症例は過去に報告がない。(著者抄録)

北薗 育美, 山田 壮亮, 上村 豪, 霧島 茉莉, 後藤 優子, 平木 翼, 東 美智代, 田中 和彦, 松山 篤二, 谷本 昭英 .  捺印細胞診所見の得られたPrimary pulmonary myxoid sarcoma with EWSR1-CREB1 translocationの1例 .  診断病理35 ( 1 ) 79 - 84   2018.1

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Publisher：(一社)日本病理学会  

症例は60歳代、女性。右肺上葉の18mm大の腫瘍が切除された。組織学的に、豊富な粘液腫状基質を背景に小型類円形〜卵円形核を有する腫瘍細胞の増殖が認められた。RT-PCRでEWSR1-CREB1融合遺伝子が検出され、primary pulmonary myxoid sarcoma with EWSR1-CREB1 translocationと診断した。捺印細胞診では、粘液状基質や炎症細胞を混じる短紡錘形から多角形の異型に乏しい細胞集塊を認め、炎症性変化との鑑別が必要であった。(著者抄録)

後藤 優子, 山田 壮亮, 霧島 茉莉, 北薗 育美, 平木 翼, 東 美智代, 畑中 一仁, 谷本 昭英 .  右肺静脈内に主座を置き左心房内まで達したグロムス腫瘍の稀少な1手術症例 .  診断病理35 ( 1 ) 25 - 30   2018.1Reviewed

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本病理学会  

症例は32歳女性。胸部CTで右肺上葉の末梢から右上肺静脈を経て左心房内に達する数珠状の腫瘍を認め、右肺上葉切除が行われた。切除検体では最大4×2cmの白色充実性の腫瘍であった。組織学的には比較的均一な円形核を有する腫瘍細胞が充実性、シート状構造を呈し、免疫組織化学的にはvimentin、α-SMAにびまん性に強陽性、laminin、h-caldesmonは一部陽性であった。悪性度不明なグロムス腫瘍が肺静脈を経て心房内に達した症例は過去に報告がない。(著者抄録)

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北薗 育美, 山田 壮亮, 上村 豪, 霧島 茉莉, 後藤 優子, 平木 翼, 東 美智代, 田中 和彦, 松山 篤二, 谷本 昭英 .  捺印細胞診所見の得られたPrimary pulmonary myxoid sarcoma with EWSR1-CREB1 translocationの1例 .  診断病理35 ( 1 ) 79 - 84   2018.1Reviewed

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本病理学会  

症例は60歳代、女性。右肺上葉の18mm大の腫瘍が切除された。組織学的に、豊富な粘液腫状基質を背景に小型類円形〜卵円形核を有する腫瘍細胞の増殖が認められた。RT-PCRでEWSR1-CREB1融合遺伝子が検出され、primary pulmonary myxoid sarcoma with EWSR1-CREB1 translocationと診断した。捺印細胞診では、粘液状基質や炎症細胞を混じる短紡錘形から多角形の異型に乏しい細胞集塊を認め、炎症性変化との鑑別が必要であった。(著者抄録)

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Haesu Lee Motoyama, Sohsuke Yamada, Satoko Nakada, Nozomu Kurose, Akihide Tanimoto .  Intraorbital ancient pilocytic astrocytoma of the optic nerve in neurofibromatosis type 1 patient presenting with sudden ocular pain. .  SAGE open medical case reports6   2050313X18761310   2018Reviewed International journal

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Language：English  

Optic nerve pilocytic astrocytoma is an uncommon but well-known entity; however, intraorbital ancient pilocytic astrocytoma of the optic nerve is extremely rarely reported. To our knowledge, this is the first detailed description regarding the intraorbital ancient pilocytic astrocytoma, reported in available English literature, to date. We presented an extremely unusual neurofibromatosis type 1 case of a 17-year-old male's sudden ocular pain secondary to intraorbital pilocytic astrocytoma of the optic nerve with markedly cystic degeneration, fluid production, and hemorrhage, due to ancient and possibly ruptured glioma. Future prospective studies are required to validate the significance of intraorbital ancient pilocytic astrocytoma arising from the optic nerve and the close correlation with ruptured cystic degeneration and ocular pain, after collecting and investigating a larger number of its cases examined.

DOI： 10.1177/2050313X18761310

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有馬 大智, 小宮 節郎, 佐々木 裕美, 嶋田 博文, 永野 聡, 天辰 愛弓, 瀬戸口 啓夫, 後藤 優子, 平木 翼, 谷本 昭英 .  背部に発生した紡錘形細胞脂肪腫の1例 .  整形外科と災害外科67 ( 4 ) 857 - 860   2018

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Publisher：西日本整形・災害外科学会  

<p>【はじめに】紡錘形細胞脂肪腫spindle cell lipomaは脂肪腫の特殊型で，中年男性の後頚部，肩，背部に好発する稀な腫瘍である．【症例】70歳男性，背部皮下に弾性軟，約8 cm大の腫瘤を認めた．MRI上T2強調画像にて著明な高信号を主体とし，漸増性の増強効果を呈し内部に微小な脂肪成分を認め，分葉状の形態を呈していた．粘液型脂肪肉腫との鑑別が必要と考え，生検術を施行．肉眼的に粘液性の成分と一部線維性の組織を採取した．病理所見では粘液腫様の間質内に存在する短紡錘形の腫瘍細胞はCD34陽性，ロープ状膠原線維の存在やMDM2陰性から紡錘形細胞脂肪腫と診断し，辺縁切除術を施行した．【まとめ】紡錘形細胞脂肪腫は術前診断が難しく，他の脂肪系腫瘍である粘液型脂肪肉腫や異型脂肪腫様腫瘍との鑑別が重要である．画像所見や病理所見，臨床所見について文献的考察を加え報告する．</p>

DOI： 10.5035/nishiseisai.67.857

CiNii Research

Masahiro Sato, Kazuchika Miyoshi, Shingo Nakamura, Masato Ohtsuka, Takayuki Sakurai, Satoshi Watanabe, Hiroaki Kawaguchi, Akihide Tanimoto .  Efficient Generation of Somatic Cell Nuclear Transfer-Competent Porcine Cells with Mutated Alleles at Multiple Target Loci by Using CRISPR/Cas9 Combined with Targeted Toxin-Based Selection System. .  International journal of molecular sciences18 ( 12 )   2017.12Reviewed International journal

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The recent advancement in genome editing such a CRISPR/Cas9 system has enabled isolation of cells with knocked multiple alleles through a one-step transfection. Somatic cell nuclear transfer (SCNT) has been frequently employed as one of the efficient tools for the production of genetically modified (GM) animals. To use GM cells as SCNT donor, efficient isolation of transfectants with mutations at multiple target loci is often required. The methods for the isolation of such GM cells largely rely on the use of drug selection-based approach using selectable genes; however, it is often difficult to isolate cells with mutations at multiple target loci. In this study, we used a novel approach for the efficient isolation of porcine cells with at least two target loci mutations by one-step introduction of CRISPR/Cas9-related components. A single guide (sg) RNA targeted to GGTA1 gene, involved in the synthesis of cell-surface α-Gal epitope (known as xenogenic antigen), is always a prerequisite. When the transfected cells were reacted with toxin-labeled BS-I-B₄ isolectin for 2 h at 37 C to eliminate α-Gal epitope-expressing cells, the surviving clones lacked α-Gal epitope expression and were highly expected to exhibit induced mutations at another target loci. Analysis of these α-Gal epitope-negative surviving cells demonstrated a 100% occurrence of genome editing at target loci. SCNT using these cells as donors resulted in the production of cloned blastocysts with the genotype similar to that of the donor cells used. Thus, this novel system will be useful for SCNT-mediated acquisition of GM cloned piglets, in which multiple target loci may be mutated.

DOI： 10.3390/ijms18122610

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保坂 優斗, 盛 真一郎, 馬場 研二, 喜多 芳昭, 又木 雄弘, 上之園 芳一, 内門 泰斗, 前村 公成, 北園 育美, 谷本 昭英, 新地 洋之, 夏越 祥次 .  盲腸軸捻転症と続発性小腸軸捻転症を発症した混合性結合組織病の1例 .  日本消化器外科学会雑誌50 ( 12 ) 1008 - 1015   2017.12

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Publisher：(一社)日本消化器外科学会  

膠原病は結合組織の障害による消化管の運動異常により,しばしば消化管病変を合併する.症例は60歳の女性で,17年前に混合性結合組織病(mixed connective tissue disease;以下,MCTDと略記)の診断を受け,以後当院膠原病内科で加療を行っていた.腹痛を主訴に来院され,盲腸軸捻転症と診断し緊急手術を施行した.回結腸動脈を軸に360°捻転していたため,捻転解除術と盲腸固定術を行った.退院後の術後37日目に腹痛を来し,腹部CTで腸管捻転の所見を認めたため,緊急手術を施行した.捻転は解除されたが広範囲の回腸の拡張を認め,減圧処置後に腸管を切除する方針とした.初回手術から51日目に再々手術を行い,拡張し蠕動低下を認めた回腸を30cm切除した.病理検査で固有筋層の萎縮を認めた.限局した固有筋層の萎縮が限局性の蠕動低下,腸管内容物の停滞を起こし,軸捻転症が発症したものと推測した.MCTDに腸管軸捻転症の合併を認めた報告例はなく,病理所見も合わせて報告する.(著者抄録)

Sohsuke Yamada, Hiroaki Kawaguchi, Tomonobu Yamada, Xin Guo, Kei Matsuo, Taiji Hamada, Naoki Miura, Takashi Tasaki, Akihide Tanimoto .  Cholic Acid Enhances Visceral Adiposity, Atherosclerosis and Nonalcoholic Fatty Liver Disease in Microminipigs. .  Journal of atherosclerosis and thrombosis24 ( 11 ) 1150 - 1166   2017.11Reviewed

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AIM: We have recently established a novel swine model for studies of atherosclerosis using MicrominipigsTM (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries. METHODS: The µMPs were fed HcD supplemented with 0.7% CA (HcD＋CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated. RESULTS: The HcD＋CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD＋CA-fed µMPs. CONCLUSION: To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.

DOI： 10.5551/jat.39909

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Md Zahorul Islam, Hiroaki Kawaguchi, Naoki Miura, Noriaki Miyoshi, Emi Yamazaki-Himeno, Mitsuya Shiraishi, Atsushi Miyamoto, Akihide Tanimoto .  Hypertension alters the endothelial-dependent biphasic response of bradykinin in isolated Microminipig basilar artery. .  Microvascular research114   52 - 57   2017.11Reviewed International journal

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Angiotensin (Ang) II is known to promote vascular disease and hypertension, partly through its effect on vascular endothelium. Bradykinin (BK) is an endothelium-dependent agonist that induces relaxation followed by contraction of the porcine basilar artery through release of NO and PGF2α, respectively. In this study, we evaluated the effect of Ang II-induced hypertension on basilar artery responsiveness to BK in the Microminipig (MMPig). Ang II (200ng/kg/min) or vehicle was infused into MMPigs for 14days using an osmotic mini-pump and blood pressure was monitored regularly. The responsiveness of subsequently isolated basilar arteries was then measured using a micro organ bath system. MMPig basilar artery endothelial cells were cultured and stimulated with Ang II or vehicle for 48h. Mean blood pressure was significantly (P<0.05; n=5) higher in Ang II-infused MMPigs than in vehicle-infused MMPigs. In vitro, BK-induced endothelium-dependent dilation of isolated basilar artery specimens was abolished and BK-induced contraction was significantly increased (Emax: 15.85±2.42% and 56.54±2.71% of 60mM KCl in control and Ang II group respectively at 10-7M concentration of BK; P<0.01; n=5) in Ang II-infused MMPigs. Ang II stimulation of the endothelial cells significantly decreased (54.15% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited NO and increased (44.27% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited PGF2α. These results suggest that the decrease of NO and increase of PGF2α production from endothelial cells are responsible for cerebrovascular dysfunction in hypertension, possibly causing cerebrovascular contraction and thus increasing the risk of brain infarction.

DOI： 10.1016/j.mvr.2017.06.001

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Takashi Tasaki, Kazuhito Hatanaka, Mari Kirishima, Shun Ohnishi, Yuko Goto, Ikumi Kitazono, Tsubasa Hiraki, Sohsuke Yamada, Michiyo Higashi, Akihide Tanimoto .  Aortic fibromuscular dysplasia complicated by dissection: a case report and review of literature .  CARDIOVASCULAR PATHOLOGY31   41 - 46   2017.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Fibromuscular dysplasia (FMD) is an idiopathic, segmental, nonatherosclerotic, non-inflammatory vascular disease, which is often complicated by the occurrence of dissection. Although it is known to occur in all arteries, aortic involvement is relatively rare. To date, 33 cases of aortic FMD have been reported in available English literature, among which only three cases have been complicated by the occurrence of dissection. We describe the case of a 40-year-old woman diagnosed with aortic FMD complicated by the occurrence of a type A aortic dissection. Non-invasive imaging revealed an ascending to descending thoracic aneurysm measuring 8 cm in diameter associated with dissection. Histopathologically, a segment of the wall of the aneurysm showed architectural disorganization of the aortic wall with loss of elastic fibers, collagen deposition, and irregular proliferation of smooth muscle cells in the intima and media-features suggesting FMD. No atheromatous plaque or medial cystic degeneration was observed in the aorta. Although aortic FMD is sometimes fatal, it is often very difficult to diagnose using imaging techniques. Therefore, performing a histopathological diagnosis is very important and should be emphasized. (C) 2017 Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2017.07.007

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Shuhei Ota, Tsuyoshi Sunagawa, Morikazu Shimabukuro, Youjirou Mitsumoto, Akihide Tanimoto .  [Bowel Perforation in a Patient with Adult T-Cell Leukemia/Lymphoma]. .  Gan to kagaku ryoho. Cancer & chemotherapy44 ( 12 ) 1494 - 1496   2017.11Reviewed

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Adult T-cell leukemia/lymphoma(ATLL)can infiltrate throughout various organs and frequently involves the gastrointestinal tract. However, bowel perforation in ATLL patients is rare. Herein, we present a case of ATLL with bowel perforation. A 75-year-old man presented with bowel distension. Computed tomography showed a large mass of the cecum. Edema and stenosis of the ascending colon was seen on colonoscopy, and tumor on the anal side of the stenosis was also found. After admission, the patient complained of abdominal pain with a peritoneal irritation sign. Free air was seen around a large mass of the cecum on computed tomography and an emergency operation was performed under the diagnosis of bowel perforation. Microscopic examination revealed bowel infiltration of ATLL. Gastrointestinal perforation can be caused by ATLL itself and is associated with a poor prognosis. The standard treatment for ATLL is chemotherapy but emergency surgery is necessary in case of perforation. It is important to observe the patient with ATLL carefully.

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Michiko Noguchi, Masaya Hirata, Hiroaki Kawaguchi, Akihide Tanimoto .  Corpus luteum Regression Induced by Prostaglandin F-2 alpha in Microminipigs During the Normal Estrous Cycle .  IN VIVO31 ( 6 ) 1097 - 1101   2017.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Induction of corpus luteum regression and subsequent estrus using prostaglandin F-2 alpha (PGF(2 alpha)) in microminipigs was investigated. Microminipigs with normal estrous cycle were treated with PGF(2 alpha) as 0.75 mg (0.75 PG group, n=3) or 1.5 mg (1.5 PG group, n=4) dinoprost injected into the vulva at 24-h intervals at 10 days after the onset of estrus (D0), D1 and D2. Three microminipigs were not treated (control group). The estrous interval in the 1.5 PG group was significantly shortened compared to the control and 0.75 PG groups. Plasma progesterone levels started to decline and reached the base line in the 1.5 PG group significantly faster than in the control group. In conclusion, we demonstrate that multiple PGF(2 alpha) treatments can induce corpus luteum regression and estrous synchronization in female microminipigs.

DOI： 10.21873/invivo.11175

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大田 修平, 砂川 剛, 島袋 盛一, 満元 洋二郎, 谷本 昭英 .  経過中穿孔を来した成人T細胞性白血病リンパ腫の1例 .  癌と化学療法44 ( 12 ) 1494 - 1496   2017.11

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成人T細胞性白血病リンパ腫(ATLL)は、全身諸臓器へ浸潤し、消化管へも高率に浸潤するが、穿孔を来すことはまれである。ATLLの消化管浸潤により、穿孔を来した症例を経験したため報告する。患者は腹部膨満感を主訴に受診した75歳、男性。腹部造影CTで回盲部に粗大な腫瘤を認め、下部消化管内視鏡検査では上行結腸に浮腫、狭窄があり、スコープは通過できず、上行結腸狭窄部肛門側に腫瘤を認めた。入院後、腹膜刺激症状を伴う腹痛が出現した。腹部造影CTで回盲部腫瘍周囲にfree airを認め、消化管穿孔の診断で緊急手術を施行した。術後の病理組織検査でATLLの消化管浸潤と診断された。ATLLの消化管浸潤は消化管穿孔を来すことがあり、穿孔を来した場合は予後不良である。ATLLの治療の主体は化学療法であるが、穿孔を来した場合は早急に手術が必要であり、慎重に経過をみる必要があると考えられた。(著者抄録)

大田 修平, 砂川 剛, 島袋 盛一, 満元 洋二郎, 谷本 昭英 .  経過中穿孔を来した成人T細胞性白血病リンパ腫の1例 .  癌と化学療法44 ( 12 ) 1494 - 1496   2017.11Reviewed

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成人T細胞性白血病リンパ腫(ATLL)は、全身諸臓器へ浸潤し、消化管へも高率に浸潤するが、穿孔を来すことはまれである。ATLLの消化管浸潤により、穿孔を来した症例を経験したため報告する。患者は腹部膨満感を主訴に受診した75歳、男性。腹部造影CTで回盲部に粗大な腫瘤を認め、下部消化管内視鏡検査では上行結腸に浮腫、狭窄があり、スコープは通過できず、上行結腸狭窄部肛門側に腫瘤を認めた。入院後、腹膜刺激症状を伴う腹痛が出現した。腹部造影CTで回盲部腫瘍周囲にfree airを認め、消化管穿孔の診断で緊急手術を施行した。術後の病理組織検査でATLLの消化管浸潤と診断された。ATLLの消化管浸潤は消化管穿孔を来すことがあり、穿孔を来した場合は予後不良である。ATLLの治療の主体は化学療法であるが、穿孔を来した場合は早急に手術が必要であり、慎重に経過をみる必要があると考えられた。(著者抄録)

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Takuya Yoshimura, Sohsuke Yamada, Takayuki Ishida, Kazuhiko Tanaka, Ikumi Kitazono, Kenichi Kume, Hiroshi Hijioka, Ichiro Semba, Norifumi Nakamura, Akihide Tanimoto .  Cystadenocarcinoma of the minor salivary gland arising in the upper lip: A surgical case of an inadequate cytology specimen hampering conclusive diagnosis .  Human Pathology: Case Reports9   64 - 68   2017.9Reviewed

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Cystadenocarcinoma (CAC) of the salivary gland poses a diagnostic challenge to us, as this uncommon entity is extremely difficult to diagnose pre-operatively on an inadequate sample. However, markedly few papers have described the cytological features of CAC. An 82-year-old male presented with a history of a gradual increase in size and occasional mucous drainage from a swollen reddish nodule on the right upper lip. A retrospective examination of the cytological specimens from the drainage revealed a small number of clusters and scattered single cells of severely degenerated and mildly atypical epithelial cells with hyperchromatic dense nuclei and abundant clear cytoplasm, in a background of a large amount of mucinous material. We first interpreted this finding merely as the presence of atypical cells. However, a gross examination revealed a non-capsulated and relatively well-demarcated cystic lesion, grayish to whitish in color and measuring 13 × 9 mm in diameter, filled with mucin. A microscopic examination showed that the tumor had a central cystic cavity filled with mucinous material and was predominantly composed of the papillary proliferation of atypical columnar mucous epithelial cells with enlarged hyperchromatic nuclei, mixed with mitotic hot spots often projecting and melting into the mucinous cystic lumen, and focally involving the surrounding connective tissue. Therefore, we ultimately made a diagnosis of CAC of the minor salivary gland arising in the upper lip. Given the characteristic features of CAC, cytopathologists should be able to correctly diagnose this lesion based on multiple adequate fine needle aspiration samples.

DOI： 10.1016/j.ehpc.2016.08.006

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谷本 昭英, 山田 壮亮 .  【血管生物学と疾患】 日常業務でよく遭遇する血管病変の最新知見 粥状動脈硬化症の最新知見と病理 .  病理と臨床35 ( 8 ) 700 - 706   2017.8

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Tsubasa Hiraki, Kazuhito Hatanaka, Kazunobu Sueyoshi, Yuko Goto, Ikumi Kitazono, Mari Kirishima, Sohsuke Yamada, Michiyo Higashi, Akihide Tanimoto .  Unusual morphology of a pulmonary blastoma having an epithelial component with focally significant nuclear pleomorphism. .  Pathology international67 ( 7 ) 370 - 372   2017.7Reviewed International journal

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DOI： 10.1111/pin.12541

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宿里 亜李沙, 田中 和彦, 窪田 恵美, 竹下 かおり, 西田 ゆかり, 平木 翼, 山田 壮亮, 東 美智代, 畑中 一仁, 谷本 昭英 .  腎細胞癌根治術後20年で甲状腺内孤立性転移を来たした1例 .  日本臨床細胞学会九州連合会雑誌48   89 - 93   2017.7

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背景:術後長期を経た腎細胞癌の甲状腺への孤立性転移は非常に稀である。今回、我々は右腎細胞癌術後20年を経過して甲状腺内に孤立性転移を来たした症例を経験したので報告する。症例:70歳代、男性。前医のエコー検査にて甲状腺右葉内に45×41×32mm大の腫瘤を指摘され、当院を紹介受診された。穿刺吸引細胞診では、血性背景に濃縮コロイドや濾胞上皮細胞集塊に混じて、異型細胞が孤在性からシート状にごく少数認められた。異型細胞は淡明で豊富な細胞質と軽度腫大した核を有し、N/C比は小さいながらも核形不整と中心性の明瞭な核小体を認めた。異型細胞はごく少数で、且つ由来が不明であったため、「鑑別困難」(現:意義不明)と報告したところ、経過観察となっていた。その後、嗄声が出現したため再受診され、甲状腺癌による右反回神経麻痺と診断された。生検の結果、腎細胞癌の転移と判明し、CTにて周囲組織への広汎な浸潤が疑われたため、甲状腺全摘出術及び喉頭摘出術が施行された。結論:再検討では淡明細胞型腎細胞癌の細胞像であり、スクリーニング時に充分な情報があれば、腎細胞癌の転移を指摘しえた症例であった。甲状腺の単発性腫瘤であっても、病歴に留意し、腎細胞癌の転移も念頭においたスクリーニングが望まれる。(著者抄録)

宿里 亜李沙, 田中 和彦, 窪田 恵美, 竹下 かおり, 西田 ゆかり, 平木 翼, 山田 壮亮, 東 美智代, 畑中 一仁, 谷本 昭英 .  腎細胞癌根治術後20年で甲状腺内孤立性転移を来たした1例 .  日本臨床細胞学会九州連合会雑誌48   89 - 93   2017.7Reviewed

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Authorship：Last author   Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景:術後長期を経た腎細胞癌の甲状腺への孤立性転移は非常に稀である。今回、我々は右腎細胞癌術後20年を経過して甲状腺内に孤立性転移を来たした症例を経験したので報告する。症例:70歳代、男性。前医のエコー検査にて甲状腺右葉内に45×41×32mm大の腫瘤を指摘され、当院を紹介受診された。穿刺吸引細胞診では、血性背景に濃縮コロイドや濾胞上皮細胞集塊に混じて、異型細胞が孤在性からシート状にごく少数認められた。異型細胞は淡明で豊富な細胞質と軽度腫大した核を有し、N/C比は小さいながらも核形不整と中心性の明瞭な核小体を認めた。異型細胞はごく少数で、且つ由来が不明であったため、「鑑別困難」(現:意義不明)と報告したところ、経過観察となっていた。その後、嗄声が出現したため再受診され、甲状腺癌による右反回神経麻痺と診断された。生検の結果、腎細胞癌の転移と判明し、CTにて周囲組織への広汎な浸潤が疑われたため、甲状腺全摘出術及び喉頭摘出術が施行された。結論:再検討では淡明細胞型腎細胞癌の細胞像であり、スクリーニング時に充分な情報があれば、腎細胞癌の転移を指摘しえた症例であった。甲状腺の単発性腫瘤であっても、病歴に留意し、腎細胞癌の転移も念頭においたスクリーニングが望まれる。(著者抄録)

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Tsubasa Hiraki, Sohsuke Yamada, Michiyo Higashi, Kazuhito Hatanaka, Seiya Yokoyama, Ikumi Kitazono, Yuko Goto, Mari Kirishima, Surinder K. Batra, Suguru Yonezawa, Akihide Tanimoto .  Immunohistochemical expression of mucin antigens in gallbladder adenocarcinoma: MUC1-positive and MUC2-negative expression is associated with vessel invasion and shortened survival .  HISTOLOGY AND HISTOPATHOLOGY32 ( 6 ) 585 - 596   2017.6Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

Mucins play pivotal roles in influencing cancer biology, for example affecting carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to investigate the significance of expression profiles of two mucins in particular, MUC1 and MUC2, their correlations with various clinicopathological features, and prognosis in gallbladder adenocarcinoma (GBAC). We performed immunohistochemistry from patients with surgically resected GBAC, using antibodies against mucin core proteins MUC1/DF3 and MUC2/Ccp58 in 81 paraffin-embedded tumor samples. MUC1 or MUC2 expression was considered to be high when &gt;= 20% or 10% of the GBAC cells showed positive staining, respectively. High MUC1 expression was revealed to have a significant relationship to the presence of pathologically lymphatic and vascular invasion, and regional lymph node metastasis. By contrast, high MUC2 expression showed a significant correlation with pathologically perineural invasion, T stage &gt;= 3, and post-operative recurrence. Moreover, MUC1 showed significantly positive co-expression and potentially complementary correlations with MUC2. Multivariate analyses demonstrated that the high MUC1 expression group had significantly shorter disease-specific survival times. However, the combination of both high MUC1 and MUC2 expression did not predict worse outcome in GBACs. Therefore, although each mucin has a somewhat important role in the pathogenesis of GBAC progression, MUC1 can independently predict vessel invasion and poor prognosis in patients with GBAC. The detection of MUC1 might well offer a useful parameter for providing clinical management and treatment against postsurgical GBACs.

DOI： 10.14670/HH-11-824

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Mika Kina-Tanada, Mayuko Sakanashi, Akihide Tanimoto, Tadashi Kaname, Toshihiro Matsuzaki, Katsuhiko Noguchi, Taro Uchida, Junko Nakasone, Chisayo Kozuka, Masayoshi Ishida, Haruaki Kubota, Yuji Taira, Yuichi Totsuka, Shin-Ichiro Kina, Hajime Sunakawa, Junichi Omura, Kimio Satoh, Hiroaki Shimokawa, Nobuyuki Yanagihara, Shiro Maeda, Yusuke Ohya, Masayuki Matsushita, Hiroaki Masuzaki, Akira Arasaki, Masato Tsutsui .  Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice. .  Diabetologia60 ( 6 ) 1138 - 1151   2017.6Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

AIMS/HYPOTHESIS: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. METHODS: To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. RESULTS: Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. CONCLUSIONS/INTERPRETATION: These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

DOI： 10.1007/s00125-017-4259-6

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Ke-Yong Wang, Sohsuke Yamada, Shohei Shimajiri, Ryuji Nakano, Naoki Yamashita, Tetsuya So, Akihide Tanimoto .  Calcifying giant cell cardiomyopathy: a possible new entity. Images in Cardiovascular Pathology .  CARDIOVASCULAR PATHOLOGY28   68 - 70   2017.5Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

We demonstrated an extremely unusual case of an 83-year-old male's sudden death secondary to characteristic myocardial necrosis and fibrosis with calcification and multinucleated giant cells infiltration, possibly due to sepsis and Stage IV pulmonary pleomorphic carcinoma-induced cachexia after postmortem study. We propose that this calcifying giant cell cardiomyopathy (CGC) would be a new entity especially from the pathological viewpoints and should be considered in the classification of noninfectious myocarditis. Further prospective studies are needed to validate the presence and significance of CGC and the association with any triggers of somewhat microvascular dysfunction and/or toxic agents, after collecting and investigating a larger number of CGC cases examined. (C) 2017 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2017.03.004

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Yuko Higashi, Takako Yoshioka, Kazuhiro Kawai, Kazuyasu Fujii, Makoto Yoshimitsu, Joji Kusuyama, Kaori Shima, Akihide Tanimoto, Takuro Kanekura .  Lymphomatoid granulomatosis initially presenting as ulcerated subcutaneous and muscle lesions without pulmonary involvement. .  The Journal of dermatology44 ( 5 ) e107 - e108   2017.5Reviewed International journal

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DOI： 10.1111/1346-8138.13712

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Sohsuke Yamada, Hirotsugu Noguchi, Akihide Tanimoto .  Critical and diverse in vivo roles of apoptosis signal-regulating kinase 1 in animal models of atherosclerosis and cholestatic liver injury .  HISTOLOGY AND HISTOPATHOLOGY32 ( 5 ) 433 - 444   2017.5Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

Apoptosis plays pivotal in vivo roles in not only vital processes, such as cell turnover and embryonic development, but also various inflammatory disorders. However, the role of apoptosis by vascular and hepatic cells in the respective progression of atherosclerosis and liver injury remains controversial. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase family member that is activated through distinct mechanisms in response to various cytotoxic stressors. ASK1, ubiquitously expressed, is situated in an important upstream position for many signal transduction pathways, which subsequently induce inflammation and/or apoptosis. Our serial in vivo studies have uniquely reported that the expression of phosphorylated ASK1 is variably seen in atherosclerotic lesions or bile-duct- ligation (BDL)induced injury livers. In mice genetically deficient of ASK1 (ASK1(-/-)), activated ASK1 signaling accelerates high-cholesterol-diet-induced necrotic lipid core formation by inducing macrophage apoptosis and enhances ligation injury-induced vascular remodeling via pro-inflammatory reactions and by stimulating apoptosis of smooth muscle cells. In contrast, in models of BDL-induced cholestatic liver injury, the pathogenic roles of ASK1-mediated early necro-inflammation, but not apoptosis, and the proliferation of hepatocytes and cholangiocytes are crucial in subsequent peribiliary fibrosis/fibrogenesis. These animal models of acute to chronic inflammatory diseases show that stimulated ASK1 signaling critically and diversely regulates not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also the acute and subacute-to-chronic phase of BDL-induced cholestasis. We herein review the diverse, key in vivo roles of ASK1 signaling in the pathogenesis of inflammatory disorders closely related to metabolic syndrome.

DOI： 10.14670/HH-11-840

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平木 翼, 山田 壮亮, 霧島 茉莉, 後藤 優子, 北薗 育美, 畑中 一仁, 東 美智代, 谷本 昭英 .  基底細胞腺腫、篩状亜型の1例 .  診断病理34 ( 2 ) 102 - 105   2017.4

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40代、男性。右耳下腺部に20mm大の可動性良好な腫瘤を認め、摘出術が施行された。周囲とは境界明瞭で、一部に菲薄な線維性被膜を認めた。病変の大部分は基底細胞様細胞が大小の篩状構造を呈し増殖しており、胞巣内には好酸性細胞質を有する導管上皮様細胞からなる真の腺腔も散見された。腺様嚢胞癌や基底細胞腺癌等、篩状構造を示す悪性上皮性唾液腺腫瘍との鑑別が問題となったが、肉眼的に境界明瞭な病変であり、組織学的にも明らかな浸潤性増殖や神経侵襲、脈管侵襲を認めない事から基底細胞腺腫、篩状亜型と診断した。(著者抄録)

平木 翼, 山田 壮亮, 霧島 茉莉, 後藤 優子, 北薗 育美, 畑中 一仁, 東 美智代, 谷本 昭英 .  基底細胞腺腫、篩状亜型の1例 .  診断病理34 ( 2 ) 102 - 105   2017.4Reviewed

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40代、男性。右耳下腺部に20mm大の可動性良好な腫瘤を認め、摘出術が施行された。周囲とは境界明瞭で、一部に菲薄な線維性被膜を認めた。病変の大部分は基底細胞様細胞が大小の篩状構造を呈し増殖しており、胞巣内には好酸性細胞質を有する導管上皮様細胞からなる真の腺腔も散見された。腺様嚢胞癌や基底細胞腺癌等、篩状構造を示す悪性上皮性唾液腺腫瘍との鑑別が問題となったが、肉眼的に境界明瞭な病変であり、組織学的にも明らかな浸潤性増殖や神経侵襲、脈管侵襲を認めない事から基底細胞腺腫、篩状亜型と診断した。(著者抄録)

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Seiya Yokoyama, Michiyo Higashi, Hideaki Tsutsumida, Jouji Wakimoto, Tomofumi Hamada, Edwin Wiest, Kei Matsuo, Ikumi Kitazono, Yuko Goto, Xin Guo, Taiji Hamada, Sohsuke Yamada, Tsubasa Hiraki, Suguru Yonezawa, Surinder K Batra, Michael A Hollingsworth, Akihide Tanimoto .  TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. .  Genes & cancer8 ( 3-4 ) 517 - 527   2017.3Reviewed International journal

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Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.

DOI： 10.18632/genesandcancer.139

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Xin Guo, Zhiming Dong, Sohsuke Yamada, Yuanyuan Li, Yanli Guo, Supeng Shen, Jia Liang, Akihide Tanimoto, Wei Guo .  Association of Casp3 microRNA Target Site (1049216) SNP With the Risk and Progress of Cervical Squamous Cell Carcinoma. .  International journal of gynecological cancer : official journal of the International Gynecological Cancer Society27 ( 2 ) 206 - 213   2017.2Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: In the present study, we investigated the relationship between the single-nucleotide polymorphism (SNP) of caspase-3 rs1049216 (C > T), a miRNA target site, and the risk and progression of cervical cancer. MATERIALS AND METHODS: Using polymerase chain reaction-restriction fragment length polymorphism, we evaluated the genotype and distribution of caspase-3 rs1049216 in 515 patients with cervical squamous cell cancer and 415 controls. In additional experiments, we transfected luciferase reporter plasmids carrying T or C allele and/or miRNA mimics into the human cervical cell lines (HeLa and C-33A) to analyze its roles in the regulation of caspase-3 expression. By immunohistochemistry, the protein level of caspase-3 expression was examined in tumor tissues from 515 patients with cervical squamous cell cancer. RESULTS: We found that the TT genotype of caspase-3 rs1049216 conferred a significantly decreased risk of cervical cancer (adjusted odds ratio, 0.35; 95% confidence interval, 0.154-0.581) and may be associated with the progression of this cancer. Although the expression of caspase-3 in the TT genotype was higher than that in CC/CT genotype in peripheral blood mononuclear cells and tumor tissues. Additional luciferase analysis showed that the rs1049216 variant T allele was associated with significantly higher luciferase activity, compared with the C allele in the transfected cells, and when cotransfected with miRNAs, miRNA-181a could downregulate the luciferase activity in the cells that transfected the construct containing C allele, compared with T allele, which had not happened in the presence of other miRNAs selected. CONCLUSIONS: These data indicate that through upregulating the expression of caspase-3, the TT genotype of caspase-3 rs1049216 can be associated with not only the risk of cervical cancer but also the progression of this cancer.

DOI： 10.1097/IGC.0000000000000881

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筒井 正人, 下川 宏明, 谷本 昭英, 柳原 延章, 尾辻 豊 .  NOと代謝・循環器・腎臓疾患 NOSs完全欠損マウスの解析から .  腎臓内科・泌尿器科5 ( 2 ) 177 - 184   2017.2

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Kan Tanabe, Yoshinari Shinsato, Tatsuhiko Furukawa, Yoshiaki Kita, Kazuhito Hatanaka, Kentaro Minami, Kohichi Kawahara, Masatatsu Yamamoto, Kenji Baba, Shinichiro Mori, Yasuto Uchikado, Kosei Maemura, Akihide Tanimoto, Shoji Natsugoe .  Filamin C promotes lymphatic invasion and lymphatic metastasis and increases cell motility by regulating Rho GTPase in esophageal squamous cell carcinoma. .  Oncotarget8 ( 4 ) 6353 - 6363   2017.1Reviewed International journal

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To establish treatments to improve the prognosis of cancer patients, it is necessary to find new targets to control metastasis. We found that expression of FilaminC (FLNC), a member of the actin binding and cross-linking filamin protein family is correlated with lymphatic invasion and lymphatic metastasis in esophageal squamous cell carcinoma (ESCC) by increasing cell motility through activation of Rho GTPase.Immunohistochemistry analysis showed that FLNC expression in ESCC is associated with lymphatic invasion, metastasis, and prognosis. FLNC knockdown in esophageal cancer cell lines decreased cell migration in wound healing and transwell migration assays, and invasion in transwell migration assays. Furthermore, FLNC knockdown reduced the amount of activated Rac-1 (GTP-Rac1) and activated Cdc42 (GTP-Cdc42). Our results suggest that FLNC expression is a useful biomarker of ESCC metastatic tendency and that inhibiting FLNC function may be useful to control the metastasis of ESCC.

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Sohsuke Yamada, Mari Kirishima, Tsubasa Hiraki, Michiyo Higashi, Kazuhito Hatanaka, Akihide Tanimoto .  Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review. .  Diagnostic pathology12 ( 1 ) 11 - 11   2017.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

BACKGROUND: Epithelioid schwannoma as a rare variant poses a challenge to all pathologists, as this uncommon entity is extremely difficult to conclusively diagnose by morphological analyses on a resected sample alone owing to its unique histopathological features. However, few papers have described the detailed clinicopathological characteristics of epithelioid schwannoma. CASE PRESENTATION: A 65-year-old female presented with a history of a flat and slightly elevated firm and tan plaque accompanied by occasional tenderness, measuring 10 × 8 mm, in the right joint of her hand 1 year before resection. A gross examination of a locally resected specimen revealed an encapsulated nodular lesion, yellow-whitish in color, partly filled with blood. A microscopic examination showed that the tumor predominantly consisted of a solid proliferation of epithelioid cells having mildly enlarged and round to partially spindled nuclei and abundant vacuolated or clear cytoplasm with very few mitotic figures and modest nuclear size variation, associated with focal hyalinized, cystic and hemorrhagic degeneration. This well-demarcated tumor was surrounded by dense, hyalinized and layered fibrocollagenous stroma. Immunohistochemically, these tumor cells were diffusely positive for S-100 protein and had a very low MIB-1 labeling index, and type IV collagen was strongly reactive with reduplicated basal lamina of them. We ultimately made a diagnosis of cutaneous epithelioid schwannoma. CONCLUSION: We should be aware that, since pathologists might misinterpret epithelioid schwannoma as other soft tissue tumors, including its malignant counterpart, a wide panel of immunohistochemical antibodies can be powerful supplementary tools for identifying a very rare entity of conventional schwannoma.

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喜名 美香, 坂梨 まゆ子, 谷本 昭英, 松崎 俊博, 野口 克彦, 仲宗根 淳子, 下川 宏明, 喜名 振一郎, 砂川 元, 大屋 祐輔, 新崎 章, 筒井 正人 .  食事中のnitriteおよびnitrateの不足は代謝症候群、内皮機能不全、および心血管死を惹起する .  血管40 ( 1 ) 60 - 60   2017.1

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Hozaka Yuto, Tanimoto Akihide, Shinchi Hiroyuki, Natsugoe Shoji, Mori Shinichiro, Baba Kenji, Kita Yoshiaki, Mataki Yuko, Uenosono Yoshikazu, Uchikado Yasuto, Maemura Kosei, Kitazono Ikumi .  Mixed Connective Tissue Disease with Cecal Volvulus and Secondary Ileal Volvulus .  The Japanese Journal of Gastroenterological Surgery50 ( 12 ) 1008 - 1015   2017Reviewed

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Language：Japanese   Publisher：The Japanese Society of Gastroenterological Surgery  

<p>A 60-year-old woman with mixed connective tissue disease (MCTD) was admitted because of abdominal pain and vomiting. Abdominal CT showed "whirl sign" around the cecum, so the patient was given a diagnosis of cecal volvulus. The patient underwent emergency operation. The cecum was twisted 360° clockwise around the ileocolic vessels. Although the jejunum and ileum were dilated, the cecum and intestine caused no ischemic change. The patient underwent detorsion of the cecum and cecopexy. The patient was discharged twelve days after surgery. Thirty-seven days after discharge, the patient was admitted for abdominal pain again. The patient underwent emergency operation since we diagnosed recurrence cecum volvulus. The ileum twisted 360° clockwise and detorsion of the twisting ileum was performed. We decided to reoperate the intestinal resection after decompression treatment, because the patient had a possibility of ileal volvulus again. Fifty-one days later from the initial surgery, we operated again. We resected the extended ileum 30 cm. Atrophy of the muscle layer was observed corresponding to the extend site pathologically. There was some possibility of hypoperistalsis due to atrophy of intestinal muscle of MCTD. It is better to evaluate peristalsis using gastrointestinal series in case of bowel volvulus with MCTD.</p>

DOI： 10.5833/jjgs.2016.0186

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Sohsuke Yamada, Akihide Tanimoto, Yasuyuki Sasaguri .  Critical in vivo roles of histamine and histamine receptor signaling in animal models of metabolic syndrome. .  Pathology international66 ( 12 ) 661 - 671   2016.12Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Histamine, a classic low-molecular-weight amine, is synthesized from L-histidine by histidine decarboxylase (HDC), and histamine-specific receptors (HRs) are essential for its actions. Our serial in vivo studies have uniquely reported that expression of histamine/HRs is variably identified in atherosclerotic lesions, and that HDC-gene knockout mice without histamine/HRs signaling show a marked reduction of atherosclerotic progression. These data have convinced us that histamine plays a pivotal role in the pathogenesis of atherosclerosis. Among four subclasses of HRs, the expression profile of the main receptors (H1/2R) has been shown to be switched from H2R to H1R during monocyte to macrophage differentiation, and H1R is also predominant in smooth muscle and endothelial cells of atheromatous plaque. Using various animal models of H1/2R-gene knockout mice, H1R and H2R were found to reciprocally but critically regulate not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also hyperlipidemia-induced nonalcoholic fatty liver disease (NAFLD). Metabolic syndrome manifests obesity, dyslipidemia, insulin resistance, atherosclerosis, and/or NAFLD, i.e. the dysregulation of lipid/bile acid/glucose metabolism. Therefore, although its etiology is complicated and multifactorial, histamine/HRs signaling has a close relationship with the development of metabolic syndrome. We herein review diverse, key in vivo roles of histamine/HR signaling in the pathogenesis of metabolic syndrome.

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Waka Yamada, Tatsuru Kaji, Shun Onishi, Kazuhiko Nakame, Koji Yamada, Takafumi Kawano, Motoi Mukai, Masakazu Souda, Takako Yoshioka, Akihide Tanimoto, Satoshi Ieiri .  Ghrelin improves intestinal mucosal atrophy during parenteral nutrition: An experimental study. .  Journal of pediatric surgery51 ( 12 ) 2039 - 2043   2016.12Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

BACKGROUND/PURPOSE: Total parenteral nutrition (TPN) has been reported to be associated with mucosal atrophy of the small intestine. Ghrelin has hormonal, orexigenic, and metabolic activities. We investigated whether ghrelin improved intestinal mucosal atrophy using a TPN-supported rat model. METHODS: Rats underwent jugular vein catheterization and were divided into four groups: TPN alone (TPN), TPN plus low-dose ghrelin (TPNLG), TPN plus high-dose ghrelin (TPNHG), and oral feeding with normal chow (OF). Ghrelin was administered continuously at dosages of 10 or 50 μg/kg/day. On day 6 rats were euthanized, and the small intestine was harvested and divided into the jejunum and ileum. Then the villus height (VH) and crypt depth (CD) were evaluated. RESULTS: The jejunal and ileal VH and CD in the TPN group were significantly decreased compared with those in the OF group. TPNHG improved only VH of the jejunum. TPNLG improved VH and CD of the jejunum and CD of the ileum. The improvement of TPNLG was significantly stronger than that in CD of the jejunum and ileum. CONCLUSIONS: TPN was more strongly associated with mucosal atrophy in the jejunum than in the ileum. Low-dose intravenous administration of ghrelin improved TPN-associated intestinal mucosal atrophy more effectively than high-dose administration.

DOI： 10.1016/j.jpedsurg.2016.09.035

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Shun Onishi, Tatsuru Kaji, Waka Yamada, Kazuhiko Nakame, Tomoe Moriguchi, Koushirou Sugita, Koji Yamada, Takafumi Kawano, Motoi Mukai, Masakazu Souda, Sohsuke Yamada, Takako Yoshioka, Akihide Tanimoto, Satoshi Ieiri .  The administration of ghrelin improved hepatocellular injury following parenteral feeding in a rat model of short bowel syndrome .  PEDIATRIC SURGERY INTERNATIONAL32 ( 12 ) 1165 - 1171   2016.12Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Long-term parenteral nutrition following massive bowel resection causes liver dysfunction, such as intestinal failure-associated liver disease (IFALD). IFALD includes two different states, cholestasis and steatosis, which represents a life-threatening complication. The previous reports have shown the protective role of ghrelin in the liver. The aim of this study was to evaluate the effects of the administration of ghrelin in the liver in a parenterally fed rat model of short bowel syndrome (SBS).
Rats underwent jugular vein catheterization, and were divided into three groups: 90 % small bowel resection (90 % SBR) and TPN (SBS/TPN group), 90 % SBR and TPN plus ghrelin (SBS/TPN/ghrelin group), and sham operation with normal chow (sham group). Ghrelin was administered continuously at a dose of 10 mu g/kg/day. On day 13, all rats were euthanized. The serum chemistry was analyzed, the lipid content of the liver was measured, and the liver tissue was histologically analyzed.
The AST and LDH levels significantly increased, and the accumulation of lipids in the liver was observed in the TPN/SBS group. The accumulation of lipids in the liver of the rats in the SBS/TPN group was attenuated by the administration of ghrelin.
The administration of ghrelin has a therapeutic potential for IFALD.

DOI： 10.1007/s00383-016-3975-1

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坂江 遥, 玉井 努, 小田 耕平, 鈴木 紳介, 平木 翼, 谷山 央樹, 伊集院 翔, 大西 容雅, 椨 一晃, 室町 香織, 馬渡 誠一, 森内 昭博, 石塚 賢治, 谷本 昭英, 井戸 章雄 .  脾破裂を伴い急性肝不全様の経過を呈した悪性リンパ腫の一例 .  肝臓57 ( 12 ) 674 - 683   2016.12Reviewed

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Language：Japanese   Publisher：(一社)日本肝臓学会  

症例は66歳、男性。全身倦怠感、発熱、腹痛、食思不振で近医を受診し、血小板減少、肝腎機能障害を認め、当院へ緊急入院となった。腹部超音波検査、CT検査で著明な肝脾腫と脾内占拠性病変、脾出血を認めた。急速に肝不全が進行、播種性血管内凝固症候群(disseminated intravascular coagulation:DIC)も合併し、全身状態は増悪した。第3病日には腹腔内出血を来し、第5病日に死亡した。家族の同意を得て、剖検を行った。肝腫大、著明な脾腫大を認め、脾臓は被膜の破綻、出血を伴い脾破裂をきたしていた。肝臓、脾臓には腫瘍細胞がびまん性に増殖しており、免疫染色にて悪性リンパ腫(diffuse large B-cell lymphoma:DLBCL)と診断した。今回、我々は脾破裂を伴い急性肝不全様の急激な経過を呈した悪性リンパ腫の一例を経験したので文献的考察を含めて報告する。(著者抄録)

DOI： 10.2957/kanzo.57.674

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Kazuchika Miyoshi, Hiroaki Kawaguchi, Kosuke Maeda, Masahiro Sato, Kohei Akioka, Michiko Noguchi, Masahisa Horiuchi, Akihide Tanimoto .  Birth of Cloned Microminipigs Derived from Somatic Cell Nuclear Transfer Embryos That Have Been Transiently Treated with Valproic Acid. .  Cellular reprogramming18 ( 6 ) 390 - 400   2016.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

In our previous study, we found that treatment of miniature pig somatic cell nuclear transfer (SCNT) embryos with 4 mM valproic acid (VPA), a histone deacetylase inhibitor, for 48 hours after activation enhanced blastocyst formation rate and octamer-binding transcription factor-3/4 (Oct-3/4) gene expression at the late blastocyst stage; however, the production of viable cloned pups failed, when those VPA-treated SCNT embryos were transferred to recipients. This failure suggests that the present VPA treatment is suboptimal. In the present study, we explored the optimal conditions for VPA to have beneficial effects on the development of SCNT embryos. When miniature pig SCNT embryos were treated with 8 mM VPA for 24 hours after activation, both the rates of blastocyst formation and blastocysts expressing the Oct-3/4 gene were significantly (p < 0.05) improved. A similar increase in blastocyst formation was also observed when microminipig-derived cells were used as SCNT donors. Five cloned piglets were obtained after the transfer of 152 microminipig SCNT embryos that had been treated with 8 mM VPA for 24 hours. The results indicated that a short duration of treatment with VPA improves the development of both miniature pig and microminipig SCNT embryos, possibly via an enhanced reprogramming mechanism.

DOI： 10.1089/cell.2016.0025

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田崎 貴嗣, 畑中 一仁, 平木 翼, 北薗 育美, 後藤 優子, 霧島 茉莉, 山田 壮亮, 東 美智代, 宮園 明典, 谷本 昭英 .  フィンランド型先天性ネフローゼ症候群の1症例 .  診断病理33 ( 4 ) 320 - 324   2016.10Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

稀なフィンランド型先天性ネフローゼ症候群の1例を報告する。症例は4ヵ月、男児。緊急帝王切開により出生した低出生体重児で、出生直後より低アルブミン血症、高蛋白尿、発育不良、浮腫、甲状腺機能低下症、脂質異常症および胸腹水を認めたが、腎機能低下はみられなかった。蛋白尿コントロール目的に片腎摘出術が行われた。腎は腫大し、組織学的には特徴的な小嚢胞状に拡張した尿細管が皮質表層から皮髄境界部にかけて認められ、糸球体メサンギウム細胞の増加がみられた。また本疾患の責任遺伝子であるNPHS1遺伝子変異が確認された。(著者抄録)

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田崎 貴嗣, 平木 翼, 北薗 育美, 後藤 優子, 霧島 茉莉, 山田 壮亮, 東 美智代, 畑中 一仁, 東 裕子, 金蔵 拓郎, 谷本 昭英 .  四肢遠位側に多発したEccrine angiomatous hamartomaの1症例 .  診断病理33 ( 4 ) 325 - 328   2016.10Reviewed

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Eccrine angiomatous hamartomaの1症例を報告する。症例は12歳男児。1年前より両手指背と右足背に多発する、淡紅色の結節が指摘された。自覚症状はなく、胼胝を疑われ、足背の皮疹から生検された。組織学的に、真皮中層から皮下脂肪組織にかけて、粘液腫状変性を示す線維性間質を背景に、境界不明瞭な結節性病変を認めた。病変部ではエクリン腺や導管が増加し、周囲に毛細血管の増生や脂肪組織、末梢神経線維の混在を認めた。(著者抄録)

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筒井 正人, 迎 寛, 矢寺 和博, 谷本 昭英, 下川 宏明, 尾辻 豊 .  一酸化窒素合成酵素の多様な役割 .  血管39 ( 3 ) 81 - 91   2016.9

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Michiko Noguchi, Tomonobu Ikedo, Hiroaki Kawaguchi, Akihide Tanimoto .  Estrus synchronization in microminipig using estradiol dipropionate and prostaglandin F-2 alpha .  The Journal of Reproduction and Development62 ( 4 ) 373 - 378   2016.8Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOCIETY REPRODUCTION & DEVELOPMENT-SRD  

The induction of pseudopregnancy by the exogenous administration of estradiol dipropionate (EDP) was investigated in cyclic Microminipigs (MMpigs) and the effects of exogenous administration of prostaglandin (PG) F-2 alpha on estrus exhibition were assessed in pseudopregnant MMpigs. In experiment 1, ovariectomized MMpigs were given a single intramuscular injection of 0.5, 1.5, or 2.5 mg of EDP. The estradiol-17 beta level at each of these doses was significantly higher 1 to 3 days after EDP administration than on the day of the injection. In experiment 2, animals were given 1.5 mg of EDP once at 9 to 12 days after the end of estrus (D0) and then no (1.5 mg x 1 group), one (D0 and D4; 1.5 mg x 2 group), or two (D0, D4 and D7; 1.5 mg x 3 group) additional treatments. The pseudopregnancy rate was significantly higher in the 1.5 mg x 3 than in the 1.5 mg x 1 group. In experiment 3, PGF(2 alpha) was administered twice between 26 and 28 days after EDP treatment to five pseudopregnant gilts with a 24-h interval between the two injections. Estrus after PGF(2 alpha) treatment and LH surge were observed in 100% and 80% pseudopregnant MMpigs, respectively. The interval from the day of the first PGF(2 alpha) treatment to the onset of estrus was 6.5 +/- 0.2 days. These results indicate that multiple EDP treatments are required for induction of pseudopregnancy in MMpigs and estrus exhibition can be controlled in MMpigs by treatment with EDP and PGF(2 alpha).

DOI： 10.1262/jrd.2015-169

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Takuya Yoshimura, Taiji Hamada, Hiroshi Hijioka, Masakazu Souda, Kazuhito Hatanaka, Takako Yoshioka, Sohsuke Yamada, Masato Tsutsui, Yoshihisa Umekita, Norifumi Nakamura, Akihide Tanimoto .  PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells .  ONCOTARGET7 ( 31 ) 49065 - 49074   2016.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Purkinje cell protein (PCP) 4/peptide (PEP) 19 is expressed in Purkinje cells where it has a calmodulin-binding, anti-apoptotic function. We recently demonstrated that PCP4/PEP19 is expressed and inhibit apoptosis in human breast cancer cell lines. In the present study we investigated the role of PCP4/PEP19 in cell morphology, adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cell lines. Knockdown of PCP4/PEP19 reduced the formation of filopodia-like cytoplasmic structures and vinculin expression, and enhanced E-cadherin expression. Activities of migration, invasion, and cell adhesion were also decreased after the knockdown of PCP4/PEP19 in MCF-7 and T47D cells. These results suggested that PCP4/PEP19 promotes cancer cell adhesion, migration, and invasion and that PCP4/PEP19 may be a potential target for therapeutic agents in breast cancer treatment which act by inhibiting epithelial-mesenchymal transition and enhancing apoptotic cell death.

DOI： 10.18632/oncotarget.7529

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Sohsuke Yamada, Aya Nawata, Manabu Yoshioka, Tsubasa Hiraki, Michiyo Higashi, Kazuhito Hatanaka, Akihide Tanimoto .  Complete regression of primary cutaneous malignant melanoma associated with distant lymph node metastasis: A teaching case mimicking blue nevus .  BMC Research Notes9 ( 1 ) 366 - 366   2016.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Malignant melanoma (MM) tends to be spontaneously regressed, however, complete regression of primary cutaneous MM is an extremely rare phenomenon. Our aim is to be aware that pathologists and/or dermatologists can readily misinterpret it as the other benign or malignant lesions. Case presentation: A gradually growing and verrucous hypopigmented macule had been noticed in the right sole of a 65-year-old Japanese male since 2 years before, and it turned to be a solitary bluish to black patch with surrounding depigmentation and was recently decreased in size. In parallel, the patient had a rapidly growing black-pigmented mass lesion at the right inguen. The cutaneous specimen from the sole showed an aggregation of many melanophages predominantly in the middle to deep layer of dermis, associated with surrounding fibrosis, reactive vascular proliferation and CD8-positive T-lymphocytic infiltrate, covered by attenuated epidermis with absence of rete ridge. However, no remnant MM cells were completely seen in the step-serial sections. We first interpreted it as blue nevus. By contrast, the inguinal mass revealed a diffuse proliferation of highly atypical mono- to multi-nucleated large cells having abundant eosinophilic cytoplasm in the enlarged lymph node tissue. Immunohistochemical findings demonstrated that these atypical cells were specifically positive for HMB45 and Melan A. Therefore, we finally made a diagnosis of complete regression of primary cutaneous MM associated with distant lymph node metastasis of MM. Conclusion: Careful, not only general/cutaneous but histopathological, examinations should be necessary and adjunctive aids for reaching the correct diagnosis of complete regression of cutaneous MM.

DOI： 10.1186/s13104-016-2174-4

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Seiya Yokoyama, Michiyo Higashi, Sho Kitamoto, Monika Oeldorf, Uwe Knippschild, Marko Kornmann, Kosei Maemura, Hiroshi Kurahara, Edwin Wiest, Tomofumi Hamada, Ikumi Kitazono, Yuko Goto, Takashi Tasaki, Tsubasa Hiraki, Kazuhito Hatanaka, Yuko Mataki, Hiroki Taguchi, Shinichi Hashimoto, Surinder K. Batra, Akihide Tanimoto, Suguru Yonezawa, Michael A. Hollingsworth .  Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas .  ONCOTARGET7 ( 27 ) 42553 - 42565   2016.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

DOI： 10.18632/oncotarget.9924

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Sohsuke Yamada, Xin Guo, Ke-Yong Wang, Akihide Tanimoto, Yasuyuki Sasaguri .  Novel function of histamine signaling via histamine receptors in cholesterol and bile acid metabolism: Histamine H2 receptor protects against nonalcoholic fatty liver disease .  PATHOLOGY INTERNATIONAL66 ( 7 ) 376 - 385   2016.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

We have reported that the function of histamine and its receptors (HRs) has a close relationship with the development of nonalcoholic fatty liver disease (NAFLD). However, much less is known regarding its pathogenic and molecular mechanism (s), including the early stage of hepatic and intestinal function for lipid and bile acid (BA) metabolism. We used H1R and H2R knockout mice (H1/2R-KO) to clarify those pivotal roles in cholesterol/BA metabolism, in which H1/2R-KO mice were separately fed a short-term 1% cholesterol or cholic acid (CA) diet. [H-3]Cholesterol absorption study revealed that significantly enhanced accumulation occurred in the jejunum, blood and liver, but not in the feces, of H2R-KO mice, compared to wild-type and H1R-KO mice. Furthermore, four weeks after the high-cholesterol diet, the H2R-KO jejunum but not liver exhibited increased expressions of cholesterol transporters, consistent with higher plasma lipoprotein levels. Five days after CA diet, the H2R-KO mice showed significantly higher expressions of ileal BA-reabsorption and hepatic BA-efflux factors, corresponding to higher serum but lower fecal BA levels. The following long-term CA diets resulted in severe injury to the H2R-KOliver. Histamine/H2R signaling might have a protective role in the initial phase during NAFLD progression, correlated with cholesterol and BA metabolism in the liver/intestine.

DOI： 10.1111/pin.12423

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窪田 恵美, 西田 ゆかり, 竹下 かおり, 田中 和彦, 平木 翼, 義岡 孝子, 東 美智代, 畑中 一仁, 谷本 昭英 .  右側胸壁に発生した明細胞肉腫の1例 .  日本臨床細胞学会九州連合会雑誌47   69 - 72   2016.7Reviewed

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景:明細胞肉腫は軟部悪性黒色腫とも呼ばれ、若年成人に多く、四肢の遠位部に好発する。今回、稀な右胸壁発生の明細胞肉腫を経験したので報告する。症例:30代、女性。半年前より背部痛があり、右胸壁に増大傾向のある腫瘤を認めた。穿刺吸引細胞診では、比較的きれいな背景に、N/C比の高い類円形から紡錐形の細胞が散在性から小集塊状にみられた。細胞は類円形ないし円形核を有し、核小体は明瞭で微細顆粒状のクロマチン増量を認めた。明細胞肉腫、悪性末梢神経腫瘍、滑膜肉腫などが疑われたが組織型の推定は困難であった。摘出された腫瘍は、組織学的に淡明から弱好酸性の胞体および核小体明瞭な類円形核を有する腫瘍細胞のシート状充実性増殖からなり、メラニン色素は認められなかった。免疫組織化学ではHMB-45及びS-100蛋白が陽性であった。遺伝子検索は行っていないが、細胞所見、免疫組織化学を含む組織所見および臨床情報より明細胞肉腫と診断した。結論:明細胞肉腫の細胞像ではメラニン色素や明瞭な核小体に着目することが重要と考えられるが、メラニン色素が認められない場合には遺伝子解析とともに既往歴や発生部位などの臨床情報が鑑別に重要である。(著者抄録)

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馬場 淳徳, 北山 香澄, 朝倉 哲郎, 瀬筒 秀樹, 谷本 昭英, 金蔵 拓郎 .  研究最前線 シルクフィブロインを用いた新規創傷被覆材の開発 .  西日本皮膚科78 ( 3 ) 288 - 289   2016.6Reviewed

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Aya Nawata, Hirotsugu Noguchi, Yuichi Mazaki, Toshihiro Kurahashi, Hiroto Izumi, Ke-Yong Wang, Xin Guo, Hidetaka Uramoto, Kimitoshi Kohno, Hatsumi Taniguchi, Yoshiya Tanaka, Junichi Fujii, Yasuyuki Sasaguri, Akihide Tanimoto, Toshiyuki Nakayama, Sohsuke Yamada .  Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease .  PLOS ONE11 ( 4 ) e0152549   2016.4Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear.
Methods & Results
Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wildtype (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-alpha, but lower expression of microsomal triglyceride-transfer protein.
Conclusion
Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.

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Tsubasa Hiraki, Yuko Goto, Ikumi Kitazono, Takashi Tasaki, Michiyo Higashi, Kazuhito Hatanaka, Akihide Tanimoto .  The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma .  INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY24 ( 2 ) 135 - 138   2016.4Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma.

DOI： 10.1177/1066896915614893

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Satoru Morishita, Hiroaki Kawaguchi, Tomoji Ono, Naoki Miura, Michiaki Murakoshi, Keikichi Sugiyama, Hisanori Kato, Akihide Tanimoto, Hoyoku Nishino .  Enteric lactoferrin attenuates the development of high-fat and high-cholesterol diet-induced hypercholesterolemia and atherosclerosis in Microminipigs .  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY80 ( 2 ) 295 - 303   2016.2Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Previously, we found that enteric lactoferrin (eLF) could reduce the visceral fat accumulation known to associate strongly with metabolic syndrome symptoms and consequently with an increased risk of atherosclerosis. In this study, the atherosclerosis-preventive potential of LF was assessed in a high-fat and high-cholesterol diet (HFCD)-induced hypercholesterolemia and atherosclerosis model using Microminipig. Eight-week orally administered eLF remarkably reduced the HFCD-induced serum total and low-density lipoprotein cholesterol levels but not high-density lipoprotein cholesterol levels. A histological analysis of 15 arteries revealed that eLF systemically inhibited the development of atherosclerotic lesions. Pathway analysis using identified genes that characterized eLF administration in liver revealed significant changes in the steroid biosynthesis pathway (ssc00100) and all affected genes in this pathway were upregulated, suggesting that cholesterol synthesis inhibited by HFCD was recovered by eLF. In summary, eLF could potentially prevent the hypercholesterolemia and atherosclerosis through protecting homeostasis from HFCD-induced dysfunction of cholesterol metabolism.

DOI： 10.1080/09168451.2015.1091713

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Yoshinobu Saitoh, Takao Setoguchi, Masahito Nagata, Arisa Tsuru, Shunsuke Nakamura, Satoshi Nagano, Yasuhiro Ishidou, Hiroko Nagao-Kitamoto, Masahiro Yokouchi, Shingo Maeda, Akihide Tanimoto, Tatsuhiko Furukawa, Setsuro Komiya .  Combination of Hedgehog inhibitors and standard anticancer agents synergistically prevent osteosarcoma growth .  INTERNATIONAL JOURNAL OF ONCOLOGY48 ( 1 ) 235 - 242   2016.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

High-dose chemotherapy and surgical intervention have improved long-term prognosis for non-metastatic osteosarcoma to 50-80%. However, metastatic osteosarcoma exhibits resistance to standard chemotherapy. We and others have investigated the function of Hedgehog pathway in osteosarcoma. To apply our previous findings in clinical settings, we examined the effects of Hedgehog inhibitors including arsenic trioxide (ATO) and vismodegib combined with standard anticancer agents. We performed WST-1 assays using ATO, cisplatin (CDDP), ifosfamide (IFO), doxorubicin (DOX), and vismodegib. Combination-index (CI) was used to examine synergism using CalcuSyn software. Xenograft models were used to examine the synergism in vivo. WST-1 assays showed that 143B and Saos2 cell proliferation was inhibited by ATO combined with CDDP, IFO, DOX, and vismodegib. Combination of ATO and CDDP, IFO, DOX or vismodegib was synergistic when the two compounds were used on proliferating 143B and Saos2 human osteosarcoma cells. An osteosarcoma xenograft model showed that treatment with ATO and CDDP, IFO, or vismodegib significantly prevented osteosarcoma growth in vivo compared with vehicle treatment. Our findings indicate that combination of Hedgehog pathway inhibitors and standard FDA-approved anticancer agents with established safety for human use may be an attractive therapeutic method for treating osteosarcoma.

DOI： 10.3892/ijo.2015.3236

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Sohsuke Yamada, Yoshikazu Harada, Hirotsugu Noguchi, Naoko Satoh, Satoshi Kimura, Toshiyuki Nakayama, Akihide Tanimoto .  Embryonal rhabdomyosarcoma arising from the uterine corpus in a postmenopausal female: a surgical case challenging the genuine diagnosis on a cytology specimen .  DIAGNOSTIC PATHOLOGY11   3 - 3   2016.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

A 55-year-old postmenopausal female presented with genital bleeding and lower abdominal mass. An abdominal MRI revealed a heterogeneously enhanced, 15 x 10 cm mass, completely filling the lumen of the enlarged uterus. The cytologic analysis of the mass showed tumor cells in small clusters and as individual cells showing hyperchromatic round to oval nuclei, and pleomorphic and occasionally unipolar "tadpole"-shaped cytoplasm, in a background of severe necrosis and many degenerated squamous cells. We first interpreted it merely as atypical cells, possibly originated from sarcoma. A total abdominal hysterectomy and salpingo-oophorectomy were performed, and gross examination showed an exophytic polypoid mass with a whitish to white-grayish, necrotic appearance, protruding from the endometrial mucosa. Microscopically, the tumor was composed of a diffuse proliferation of highly atypical spindle-shaped cells, admixed with many characteristic rhabdomyoblasts having abundant densely eosinophilic cytoplasm with sometimes distinct cross-striations, coexisted with cellular primitive small blue round to oval cells foci. However, neither carcinoma nor additional heterologous sarcoma components were completely seen within our thorough investigation. Therefore, we finally made a diagnosis of embryonal rhabdomyosarcoma arising from the uterine corpus. We should be aware that owing to its characteristic features, cytopathologists might be able to determine a genuine diagnosis, based on multiple and adequate cytology samplings.

DOI： 10.1186/s13000-016-0451-0

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Takao Setoguchi, Hirotaka Kawakami, Yasuhiro Ishidou, Hideki Kawamura, Junichiro Nishi, Takako Yoshioka, Hironori Kakoi, Satoshi Nagano, Masahiro Yokouchi, Akihide Tanimoto, Setsuro Komiya .  Cut-off values of latent infection in patients with rapid migration following bipolar hip hemiarthroplasty .  BMC MUSCULOSKELETAL DISORDERS17   37 - 37   2016.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Although most patients achieve favorable results following bipolar hip hemiarthroplasty (BHA), some experience rapid migration of the prosthesis. We retrospectively reviewed 18 patients with BHA that necessitated revision.
Methods: We examined soft tissues obtained from periprosthetic lesions. In total, 18 patients with pain and acetabular migration of the BHA prosthesis were included. The patients were divided into a polymorphonuclear leukocyte (PMN)-positive (&gt;= 5 PMNs per high-power field [HPF]) and PMN-negative (&lt; 5 PMNs/HPF) group.
Results: Pathological findings showed that 11 patients were PMN-positive, which was indicative of infection. All patients in the PMN-positive group showed no polyethylene particles or foreign body giant cells, while all patients in the PMN-negative group showed polyethylene debris or foreign body giant cells (p &lt; 0.001). BHA survival, C-reactive protein (CRP) levels, and the Japanese Orthopaedic Association (JOA) hip score were significantly different between the PMN-positive and PMN-negative group (p &lt; 0.01). A BHA survival cut-off value of 3270 days was diagnostic for PMN positivity (sensitivity: 100 %; specificity: 100 %). The cut-off values for CRP and the JOA hip score were 0.43 mg/dl and 56 points, respectively. Four of 11 PMN-positive patients showed no clinical symptoms of infection (asymptomatic PMN-positive group). BHA survival, CRP levels, and JOA hip scores were significantly different between the asymptomatic PMN-positive and PMN-negative group (p &lt; 0.05). A BHA survival cut-off of 3270 days was diagnostic for asymptomatic PMN positivity (sensitivity: 100 %; specificity: 100 %). The cut-off values for CRP and the JOA hip score were 0.43 mg/dl and 57 points, respectively.
Conclusion: Our findings suggest that some portion of rapid BHA prosthesis migration is caused by mild infection. Careful pathological examination should be performed to identify infection before removal of the BHA prosthesis in patients who develop migration within 9 years.

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Yoshimura T, Yamada S, Shima K, Nakamura N, Tanimoto A .  An elastofibromatous lesion at the tip of the sublingual fold .  J Dent & Oral Disord2 ( 6 ) 1031   2016Reviewed

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Hirofumi Shimada, Miguel Otero, Kaneyuki Tsuchimochi, Satoshi Yamasaki, Harutoshi Sakakima, Fumiyo Matsuda, Megumi Sakasegawa, Takao Setoguchi, Lin Xu, Mary B. Goldring, Akihide Tanimoto, Setsuro Komiya, Kosei Ijiri .  CCAAT/enhancer binding protein beta (C/EBP beta) regulates the transcription of growth arrest and DNA damage-inducible protein 45 beta (GADD45 beta) in articular chondrocytes .  PATHOLOGY RESEARCH AND PRACTICE212 ( 4 ) 302 - 309   2016Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Osteoarthritis (OA) is a whole joint disease characterized by cartilage degradation, which causes pain and disability in older adults. Our previous work showed that growth arrest and DNA damage-inducible protein 45 beta (GADD45 beta) is upregulated in chondrocyte clusters in OA cartilage, especially in the early stage of this disease. CCAAT/enhancer binding protein beta (C/EBP beta) is expressed in the hypertrophic growth plate chondrocytes and functions in synergy with GADD45 beta. Here, the presence and localization of these proteins was assessed by immunohistochemistry using articular cartilage from OA patients, revealing colocalization of C/EBP beta and GADD45 beta in OA chondrocytes. GADD45 beta promoter analysis was performed to determine whether C/EBP beta directly regulates GADD45 beta transcription. Furthermore, we analyzed the effect of C/EBP beta on Gadd45 beta gene regulation in articular chondrocytes in vivo and in vitro. Immunohistochemical analysis of C/ebp beta-haploinsufficient mice (C/ebp beta(+/-)) cartilage showed that C/ebp beta haploinsufficiency led to reduced Gadd45 beta gene expression in these cells. In vitro, we evaluated the effects of conditional C/EB1 beta overexpression driven by the cartilage oligomeric matrix protein (Comp) promoter in mComp-tTA;pTRE-Tight-BI-DsRed-mC/ebp beta transgenic mice. C/EBP beta overexpression significantly stimulated Gadd45 beta gene expression in articular chondrocytes. Taken together, our data demonstrate that C/EBPP plays a central role in controlling Gadd45 beta gene expression in these cells. (C) 2016 The Authors. Published by Elsevier GmbH.

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KAWAGUCHI Hiroaki, HORIUCHI Masahisa, TANIMOTO Akihide .  Toxicologic pathology of Microminipig .  Annual Meeting of the Japanese Society of Toxicology43   S9 - 3   2016Reviewed

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

DOI： 10.14869/toxpt.43.1.0_S9-3

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北薗 育美, 東 美智代, 平木 翼, 後藤 優子, 田崎 貴嗣, 義岡 孝子, 畑中 一仁, 藤尾 信吾, 平野 宏文, 有田 和徳, 谷本 昭英 .  第三脳室脊索腫様膠腫の1例 .  診断病理32 ( 4 ) 285 - 288   2015.10Reviewed

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Language：Japanese   Publisher：(一社)日本病理学会  

第三脳室脊索腫様膠腫の1例を報告する。症例は44歳女性。12年前に無月経、頭痛があり精査。第三脳室内腫瘤性病変を指摘され、生検されたが、炎症所見のみで確定診断には至らなかった。病変の増大を認めたため摘出された。組織学的に、粘液腫状基質や炎症細胞浸潤を伴った上皮様腫瘍細胞の増殖を認めた。免疫組織学的検討では腫瘍細胞はGFAP、Vimentinにびまん性に陽性でCD34に部分的に陽性、EMAに一部が弱陽性を示した。以上の所見から第三脳室脊索腫様膠腫と診断した。(著者抄録)

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Arisa Tsuru, Takao Setoguchi, Naoya Kawabata, Masataka Hirotsu, Takuya Yamamoto, Satoshi Nagano, Masahiro Yokouchi, Hironori Kakoi, Hideki Kawamura, Yasuhiro Ishidou, Akihide Tanimoto, Setsuro Komiya .  Enrichment of bacteria samples by centrifugation improves the diagnosis of orthopaedics-related infections via real-time PCR amplification of the bacterial methicillin-resistance gene .  BMC Research Notes8 ( 1 ) 288 - 288   2015.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: To effectively treat orthopaedic infections by methicillin-resistant strains, an early diagnosis is necessary. Bacterial cultures and real-time polymerase chain reaction (PCR) have been used to define methicillin-resistant staphylococci. However, even when patients display clinical signs of infections, bacterial culture and real-time PCR often cannot confirm infection. The aim of this study was to prospectively compare the utility of real-time PCR for the mecA gene detection following centrifugation of human samples with suspected orthopaedic infections. Results: In addition to the conventional real-time PCR method, we performed real-time PCR following centrifugation of the sample at 4,830xg for 10 min in a modified real-time PCR (M-PCR) method. We suspended cultured methicillin-resistant Staphylococcus aureus and generated standard dilution series for in vitro experiments. The in vitro detection sensitivity of the M-PCR method was approximately 5.06 times higher than that of the conventional real-time PCR method. We performed bacterial culture, pathological examination, real-time PCR, and M-PCR to examine the infectious fluids and tissues obtained from 36 surgical patients at our hospital. Of these, 20 patients who had undergone primary total hip arthroplasty were enrolled as negative controls. In addition, 15 patients were examined who were clinically confirmed to have an infection, including periprosthetic joint infection (eight patients), pyogenic spondylitis (two patients), infectious pseudoarthrosis (two patients), and after spine surgery (three patients). In one sample from a patient who developed infectious pseudoarthrosis and two samples from surgical site infections after spine surgery, the mecA gene was detected only by the M-PCR method. In one patient with infectious pseudoarthrosis, one patient with infection after arthroplasty, and two patients with purulent spondylitis, the detection sensitivity of the M-PCR method was increased compared with PCR (clinical sample average: 411.6 times). Conclusions: These findings suggest that the M-PCR method is useful to detect methicillin-resistant strains infections. In addition, the centrifugation process only takes 10 min longer than conventional real-time PCR methods. We believe that the M-PCR method could be clinically useful to detect orthopaedic infections caused by methicillin-resistant strains.

DOI： 10.1186/s13104-015-1180-2

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谷本 昭英 .  【病理診断クイックリファレンス】 (第1章)心・血管 嚢胞状中膜壊死 .  病理と臨床33 ( 臨増 ) 10 - 10   2015.4

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谷本 昭英 .  【病理診断クイックリファレンス】 (第1章)心・血管 肥大型心筋症 .  病理と臨床33 ( 臨増 ) 8 - 8   2015.4

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谷本 昭英 .  【病理診断クイックリファレンス】 (第1章)心・血管 心筋炎 .  病理と臨床33 ( 臨増 ) 7 - 7   2015.4

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谷本 昭英, 川口 博明 .  第三の家畜 実験動物としてのミニブタ マイクロミニピッグ疾患モデル .  病理と臨床33 ( 3 ) 330 - 332   2015.3

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Sohsuke Yamada, Ke-Yong Wang, Akihide Tanimoto, Yasuyuki Sasaguri .  Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis .  PATHOLOGY INTERNATIONAL65 ( 2 ) 67 - 80   2015.2Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Histamine is not only essential for acute inflammatory reactions, but it also participates in a chronic inflammatory disorder. We generated apolipoprotein E (apoE) and histamine receptors (HHRs), including the major H1 and H2 receptors (HH1R, HH2R) double knockout mice (DKO) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis, in which apoE-KO and DKO mice were fed a high cholesterol diet. We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in HH1R/apoE-DKO mice, but in HH2R/apoE-DKO mice less atherosclerosis, despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice. Furthermore, the increased expressions of scavenger receptors (SRs), such as SR-A, CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), nuclear factor-kappa B (NFB), monocyte chemoattractant protein (MCP-1), matrix metalloproteinases (MMPs) or liver X receptor (LXR)-related inflammatory signaling factors, were consistent with the pro-atherogenic phenotype of HH2R/apoE-DKO mice. We hypothesize that histamine/HH1R and HH2R signaling has conflicting innate functions, inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions, and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis, independently of serum cholesterol metabolism. Specific histamine signaling blockers, in particular, HH2R blockers, are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis.

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Noguchi M, Miura N, Ando T, Kubota C, Hobo S, Kawaguchi H, Tanimoto A. .  Profiles of reproductive hormone in the microminipig during the normal estrous cycle. .  In Vivo.29 ( 1 ) 176 - 22   2015.1Reviewed

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Yamada S, Wang KY, Tanimoto A, Sasaguri Y. .  Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis. .  Pathol Int.65 ( 2 ) 67 - 80   2015.1Reviewed

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Masato Tsutsui, Akihide Tanimoto, Masahito Tamura, Hiroshi Mukae, Nobuyuki Yanagihara, Hiroaki Shimokawa, Yutaka Otsuji .  Significance of nitric oxide synthases: Lessons from triple nitric oxide synthases null mice .  JOURNAL OF PHARMACOLOGICAL SCIENCES127 ( 1 ) 42 - 52   2015.1Reviewed

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Nitric oxide (NO) is synthesized by three distinct NO synthases (neuronal, inducible, and endothelial NOSs), all of which are expressed in almost all tissues and organs in humans. The regulatory roles of NOSs in vivo have been investigated in pharmacological studies with non-selective NOS inhibitors. However, the specificity of the inhibitors continues to be an issue of debate, and the authentic significance of NOSs is still poorly understood. To address this issue, we generated mice in which all three NOS genes are completely disrupted. The triple NOSs null mice exhibited cardiovascular abnormalities, including hypertension, arteriosclerosis. myocardial infarction, cardiac hypertrophy, diastolic heart failure, and reduced EDHF responses, with a shorter survival. The triple NOSs null mice also displayed metabolic abnormalities, including metabolic syndrome and high-fat diet-induced severe dyslipidemia. Furthermore, the triple NOSs null mice showed renal abnormalities (nephrogenic diabetes insipidus and pathological renal remodeling), lung abnormalities (accelerated pulmonary fibrosis), and bone abnormalities (increased bone mineral density and bone turnover). These results provide evidence that NOSs play pivotal roles in the pathogenesis of a wide variety of disorders. This review summarizes the latest knowledge on the significance of NOSs in vivo, based on lessons learned from experiments with our triple mutant model. (C) 2015 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

DOI： 10.1016/j.jphs.2014.10.002

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Michiko Noguchi, Naoki Miura, Takaaki Ando, Chikara Kubota, Seiji Hobo, Hiroaki Kawaguchi, Akihide Tanimoto .  Profiles of Reproductive Hormone in the Microminipig During the Normal Estrous Cycle .  IN VIVO29 ( 1 ) 17 - 22   2015.1Reviewed

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We investigated changes in the peripheral plasma concentrations of ovarian steroids and gonadotropins throughout the estrous cycle of the Microminipig (MMpig), a novel experimental animal model. The mean (+/- standard error of the mean (SEM)) duration of estrous and the estrous cycle in seven animals was 66.0 +/- 5.2 h and 20.6 +/- 0.3 days, respectively. A luteinizing hormone (LH) surge was observed 16.5 +/- 6.5 h after the onset of estrous in six out of the seven animals. The LH peak and the duration of the LH surge were 14.0 +/- 4.5 ng/ml and 34.0 +/- 2.0 h, respectively. Plasma progesterone concentrations started to decline on Day 7 (Day 0 = the day of the LH peak) and increased from Day 4. Estradiol-17 beta levels increased from Day 3 and reached a maximum (37.0 +/- 1.6 pg/ml) on Day 0.75. Follicle-stimulating hormone (FSH) concentrations showed a first and second surge on Days 0 and 1.75. An inverse relationship between FSH and estradiol-17 beta concentrations was noted before the LH surge. The characteristics of estrous and the gonadotropin and ovarian steroid profiles throughout the estrous cycle of MMpigs are similar to those of domestic pigs and other miniature pig strains.

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Michiko Noguchi, Naoki Miura, Takaaki Ando, Chikara Kubota, Seiji Hobo, Hiroaki Kawaguchi, Akihide Tanimoto .  Profiles of Reproductive Hormone in the Microminipig During the Normal Estrous Cycle .  IN VIVO29 ( 1 ) 17 - 22   2015.1Reviewed

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We investigated changes in the peripheral plasma concentrations of ovarian steroids and gonadotropins throughout the estrous cycle of the Microminipig (MMpig), a novel experimental animal model. The mean (+/- standard error of the mean (SEM)) duration of estrous and the estrous cycle in seven animals was 66.0 +/- 5.2 h and 20.6 +/- 0.3 days, respectively. A luteinizing hormone (LH) surge was observed 16.5 +/- 6.5 h after the onset of estrous in six out of the seven animals. The LH peak and the duration of the LH surge were 14.0 +/- 4.5 ng/ml and 34.0 +/- 2.0 h, respectively. Plasma progesterone concentrations started to decline on Day 7 (Day 0 = the day of the LH peak) and increased from Day 4. Estradiol-17 beta levels increased from Day 3 and reached a maximum (37.0 +/- 1.6 pg/ml) on Day 0.75. Follicle-stimulating hormone (FSH) concentrations showed a first and second surge on Days 0 and 1.75. An inverse relationship between FSH and estradiol-17 beta concentrations was noted before the LH surge. The characteristics of estrous and the gonadotropin and ovarian steroid profiles throughout the estrous cycle of MMpigs are similar to those of domestic pigs and other miniature pig strains.

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Taro Uchida, Yumi Furuno, Akihide Tanimoto, Yumiko Toyohira, Kumiko Arakaki, Mika Kina-Tanada, Haruaki Kubota, Mayuko Sakanashi, Toshihiro Matsuzaki, Katsuhiko Noguchi, Junko Nakasone, Tomonori Igarashi, Susumu Ueno, Masayuki Matsushita, Shogo Ishiuchi, Hiroaki Masuzaki, Yusuke Ohya, Nobuyuki Yanagihara, Hiroaki Shimokawa, Yutaka Otsuji, Masahito Tamura, Masato Tsutsui .  Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse .  JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY77   29 - 41   2014.12Reviewed International journal

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We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4 months after the surgery. The 2/3NX triple NOSs(-/-) mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1 alpha (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs(-/-) mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin-angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs(-/-) mouse is a new experimentally useful model of AMI. Renin-angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1 alpha-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2014.09.021

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Naoki Miura, Ken-Ichi Kucho, Michiko Noguchi, Noriaki Miyoshi, Toshiki Uchiumi, Hiroaki Kawaguchi, Akihide Tanimoto .  Comparison of the Genomic Sequence of the Microminipig, a Novel Breed of Swine, with the Genomic Database for Conventional Pig .  IN VIVO28 ( 6 ) 1107 - 1111   2014.11Reviewed International journal

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The microminipig, which weighs less than 10 kg at an early stage of maturity, has been reported as a potential experimental model animal. Its extremely small size and other distinct characteristics suggest the possibility of a number of differences between the genome of the microminipig and that of conventional pigs. In this study, we analyzed the genomes of two healthy microminipigs using a next-generation sequencer SOLiD (TM) system. We then compared the obtained genomic sequences with a genomic database for the domestic pig (Sus scrofa). The mapping coverage of sequenced tag from the microminipig to conventional pig genomic sequences was greater than 96% and we detected no clear, substantial genomic variance from these data. The results may indicate that the distinct characteristics of the microminipig derive from small-scale alterations in the genome, such as Single Nucleotide Polymorphisms or translational modifications, rather than large-scale deletion or insertion polymorphisms. Further investigation of the entire genomic sequence of the microminipig with methods enabling deeper coverage is required to elucidate the genetic basis of its distinct phenotypic traits.

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Sohsuke Yamada, Tomoyuki Koyama, Hirotsugu Noguchi, Yuki Ueda, Ryo Kitsuyama, Hiroya Shimizu, Akihide Tanimoto, Ke-Yong Wang, Aya Nawata, Toshiyuki Nakayama, Yasuyuki Sasaguri, Takumi Satoh .  Marine Hydroquinone Zonarol Prevents Inflammation and Apoptosis in Dextran Sulfate Sodium-Induced Mice Ulcerative Colitis .  PLOS ONE9 ( 11 ) e113509   2014.11Reviewed International journal

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Background and Aim: We previously identified an anti-inflammatory compound, zonarol, a hydroquinone isolated from the brown algae Dictyopteris undulata as a marine natural product. To ascertain the in vivo functions of zonarol, we examined the pharmacological effects of zonarol administration on dextran sulfate sodium (DSS)-induced inflammation in a mouse model of ulcerative colitis (UC). Our goal is to establish a safe and effective cure for inflammatory bowel disease (IBD) using zonarol.
Methods and Results: We subjected Slc:ICR mice to the administration of 2% DSS in drinking water for 14 days. At the same time, 5-aminosalicylic acid (5-ASA) at a dose of 50 mg/kg (positive control) and zonarol at doses of 10 and 20 mg/kg, were given orally once a day. DSS-treated animals developed symptoms similar to those of human UC, such as severe bloody diarrhea, which were evaluated by the disease activity index (DAI). Treatment with 20 mg/kg of zonarol, as well as 5-ASA, significantly suppressed the DAI score, and also led to a reduced colonic ulcer length and/or mucosal inflammatory infiltration by various immune cells, especially macrophages. Zonarol treatment significantly reduced the expression of pro-inflammatory signaling molecules, and prevented the apoptosis of intestinal epithelial cells. Finally, zonarol protected against in vitro lipopolysaccharide (LPS)-induced activation in the RAW264.7 mouse macrophage cell line.
Conclusions: This is the first report that a marine bioproduct protects against experimental UC via the inhibition of both inflammation and apoptosis, very similar to the standard-of-care sulfasalazine, a well-known prodrug that releases 5-ASA. We believe that the oral administration of zonarol might offer a better treatment for human IBDs than 5-ASA, or may be useful as an alternative/additive therapeutic strategy against UC, without any evidence of side effects.

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Takehiro Yamaguchi, Takanori Yamazaki, Hiroaki Kawaguchi, Masashi Tawa, Yasuhiro Nakamura, Masayuki Shiota, Mayuko Osada-Oka, Akihide Tanimoto, Tomio Okamura, Katsuyuki Miura, Hiroshi Iwao, Minoru Yoshiyama, Yasukatsu Izumi .  A Noninvasive Metabolic Syndrome Model Using an Extremely Small Minipig, the Microminipig .  JOURNAL OF PHARMACOLOGICAL SCIENCES126 ( 2 ) 168 - 171   2014.10Reviewed

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Metabolic syndrome (MetS) induces serious complications; therefore, we developed a noninvasive MetS model using an extremely small minipig, the Microminipig. For 8 weeks, Microminipigs were administrated a high-fat and high-cholesterol diet (HFCD) for atherosclerosis and N-G-nitro-L-arginine methyl ester (L-NAME) for inhibiting nitric oxide synthase. HFCD significantly increased serum low-density lipoprotein levels, L-NAME increased blood pressure and cardiac hypertrophy, and HFCD-induced aortal arteriosclerosis was accelerated by L-NAME administration. Endothelium-dependent relaxation of the coronary artery was remarkably decreased by L-NAME administration. This model may be useful for elucidating the mechanisms of MetS and developing new therapeutic medicines for its treatment.

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Kazuhito Hatanaka, Takako Yoshioka, Takashi Tasaki, Akihide Tanimoto .  The Hyaline Vascular Type of Castleman's Disease of the Ovary: A Case Report .  INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY22 ( 7 ) 652 - 655   2014.10Reviewed International journal

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Castleman's disease in the pelvic cavity is rare. We present a 72-year-old woman with hyaline vascular type of Castleman's disease of the right ovary. Right ovarian enlargement was detected in the medical examination. Computed tomography revealed a solid mass, measured 2.5 cm in size, in the right ovary. A bilateral salpingo-oophorectomy was performed. Morphologically, lymphoid follicles with regressed germinal centers (GCs) were surrounded by a broad mantle zone composed of concentric rings of small lymphocytes, and the hyalinized blood vessels with plump endothelial cells penetrated radially into GCs. Proliferation of follicular dendritic cells, which were positive for CD21 and epidermal growth factor receptor, were detected in GCs and mantle zone. No other lesions were found. To the best of our knowledge, this is the first case of hyaline vascular type of Castleman's disease of ovarian primary.

DOI： 10.1177/1066896913517936

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Taiji Hamada, Masakazu Souda, Takuya Yoshimura, Shoko Sasaguri, Kazuhito Hatanaka, Takashi Tasaki, Takako Yoshioka, Yasuyo Ohi, Sohsuke Yamada, Masato Tsutsui, Yoshihisa Umekita, Akihide Tanimoto .  Anti-apoptotic Effects of PCP4/PEP19 in Human Breast Cancer Cell Lines: A Novel Oncotarget .  ONCOTARGET5 ( 15 ) 6076 - 6086   2014.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-Akt(Thr308), enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-Akt(Thr308) and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.

DOI： 10.18632/oncotarget.2161

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Tsubasa Hiraki, Michiyo Higashi, Yuko Goto, Ikumi Kitazono, Seiya Yokoyama, Hiroyuki Iuchi, Hiromi Nagano, Akihide Tanimoto, Suguru Yonezawa .  A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1 .  CARDIOVASCULAR PATHOLOGY23 ( 4 ) 244 - 247   2014.7Reviewed International journal

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Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal. (C) 2014 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2014.02.001

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Toshiaki Kakimoto, Akira Otsuka, Hiroaki Kawaguchi, Kenji Ogata, Akihide Tanimoto, Hiroaki Kanouchi .  Plasma Homocysteine Concentrations in Novel Microminipigs .  IN VIVO28 ( 4 ) 579 - 582   2014.7Reviewed International journal

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A novel microminipig has been recently developed for use in biomedical research. In the present study, age- and sex-related differences, as well as 24-h fluctuations in plasma total homocysteine concentrations (tHcy), were investigated in these microminipigs. tHcy (mean +/- SD) was 10.2 +/- 3.4 mu M and significantly correlated with age. By contrast, neither the differences in tHcy between sexes nor the 24-h fluctuations in tHcy after feeding were significant. The kinetics of plasma tHcy after intravenous injection of reduced Hcy showed that its levels peaked within 5 min post-injection, as did the levels of tHcy. These results suggested that reduced Hcy is rapidly oxidized or metabolized. The half-lives of reduced Hcy, tHcy, and reduced cysteine in the blood were 47, 71, and 141 min, respectively. In conclusion, there was a significantly positive correlation between age and plasma tHcy in microminipigs. After intravenous injection of reduced Hcy, plasma tHcy quickly returned to pre-injection levels.

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Masahiro Yokouchi, Satoshi Nagano, Yuko Kijima, Takako Yoshioka, Akihide Tanimoto, Shoji Natsugoe, Setsuro Komiya .  Solitary breast metastasis from myxoid liposarcoma .  BMC CANCER14   482 - 482   2014.7Reviewed International journal

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Background: Metastasis to the breast from nonmammary malignancies is rare, and mostly involves patients in a pre-terminal condition with systemic metastases outside the breast. Lymphoma and leukemia, melanoma, and lung carcinoma are the most common primary malignancies to cause breast metastasis; metastasis of soft tissue sarcoma to the breast is very rare. Here, we report a case of primary lower-extremity myxoid liposarcoma with the development of a solitary metastasis to the breast. To the best of our knowledge, no isolated case reports of solitary breast metastasis by myxoid liposarcoma have been previously reported in the English-language literature.
Case presentation: The patient, a 66-year-old woman, had been previously diagnosed with myxoid liposarcoma of the right thigh. At 21 months after complete surgical resection of the primary tumor with negative margins, a palpable tumor was identified in the patient's left breast. Needle biopsy revealed the presence of metastatic liposarcoma; positron emission tomography/computed tomography examination confirmed the metastasis as solitary, and no local recurrence of the primary tumor was identified. The patient underwent lumpectomy with negative margins and did not provide consent for adjuvant chemotherapy. As with the biopsy specimen and the total cleavage specimen, myxoid liposarcoma with metastasis to the breast was diagnosed. No recurrence or new metastases were observed five years after resection of the metastatic breast lesion.
Conclusions: We have presented an extremely rare case of a solitary metastatic breast tumor arising from myxoid liposarcoma of the lower limbs. There is no standard treatment for the management of solitary breast metastasis from myxoid liposarcoma. Therefore, treatment should be guided by consideration of an individual patient's overall condition.

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Yuichiro Sakamoto, Masahiro Yokouchi, Satoshi Nagano, Hirofumi Shimada, Shunsuke Nakamura, Takao Setoguchi, Ichiro Kawamura, Yasuhiro Ishidou, Akihide Tanimoto, Setsuro Komiya .  Metastasis of osteosarcoma to the trapezius muscle: a case report .  WORLD JOURNAL OF SURGICAL ONCOLOGY12   176 - 176   2014.6Reviewed International journal

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Metastasis of a primary osteosarcoma to the muscles is extremely rare. As there have been few reported cases, the necessity of surgical treatment for such metastatic lesions remains controversial. We present the case of a primary osteosarcoma with development of a solitary metastasis to the trapezius muscle during chemotherapy for pulmonary metastasis. The patient was a 51-year-old man diagnosed with osteosarcoma of the right tibia. After undergoing chemotherapy and femoral amputation, he developed pulmonary metastasis. Chemotherapy was reinitiated, however, after approximately 1 year a palpable tumor was identified in the patient's right shoulder. This tumor grew and was associated with pain in the right shoulder. It was surgically removed 3 years after the reinitiation of chemotherapy. The pathological diagnosis was osteosarcoma with metastasis to the trapezius muscle. Although the patient died of respiratory failure due to pulmonary metastasis 14 months after resection of the metastatic lesion in the trapezius muscle, no new extrapulmonary metastasis was observed after the resection.

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早田 正和, 巌谷 織絵, 大井 恭代, 谷本 昭英 .  病理技術 迅速FISH検査システムHER2 IQFISH pharmDxの有用性の検討 .  病理と臨床32 ( 5 ) 583 - 586   2014.5Reviewed

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Masatatsu Yamamoto, Hiroshi Arimura, Tomoko Fukushige, Kentarou Minami, Yukihiko Nishizawa, Akihide Tanimoto, Takuro Kanekura, Masayuki Nakagawa, Shin-ichi Akiyama, Tatsuhiko Furukawa .  Abcb10 Role in Heme Biosynthesis In Vivo: Abcb10 Knockout in Mice Causes Anemia with Protoporphyrin IX and Iron Accumulation .  MOLECULAR AND CELLULAR BIOLOGY34 ( 6 ) 1077 - 1084   2014.3Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Abcb10, member 10 of the ABC transporter family, is reportedly a part of a complex in the mitochondrial inner membrane with mitoferrin-1 (Slc25a37) and ferrochelatase (Fech) and is responsible for heme biosynthesis in utero. However, it is unclear whether loss of Abcb10 causes pathological changes in adult mice. Here, we show that Abcb10(-/-) mice lack heme biosynthesis and erythropoiesis abilities and die in midgestation. Moreover, we generated Abcb10(F/-); Mx1-Cre mice, with Abcb10 in hematopoietic cells deleted, which showed accumulation of protoporphyrin IX and maturation arrest in reticulocytes. Electron microscopy images of Abcb10(-/-) hematopoietic cells showed a marked increase of iron deposits at the mitochondria. These results suggest a critical role for Abcb10 in heme biosynthesis and provide new insights into the pathogenesis of erythropoietic protoporphyria and sideroblastic anemia.

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Hirotsugu Noguchi, Sohsuke Yamada, Atsunori Nabeshima, Xin Guo, Akihide Tanimoto, Ke-Yong Wang, Shohei Kitada, Takashi Tasaki, Tatsuo Takama, Shohei Shimajiri, Hasita Horlad, Yoshihiro Komohara, Hiroto Izumi, Kimitoshi Kohno, Hidenori Ichijo, Yasuyuki Sasaguri .  Depletion of Apoptosis Signal-Regulating Kinase 1 Prevents Bile Duct Ligation-Induced Necroinflammation and Subsequent Peribiliary Fibrosis .  AMERICAN JOURNAL OF PATHOLOGY184 ( 3 ) 644 - 661   2014.3Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bite duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK/-deficient (ASK(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribitiary fibrogenic cells and petibitiary fibrosis. These observations indicate that ASK1-mediated hepatic necroinfiammation and proliferation, but not apoptosis, are closely linked to Liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.

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Yamada S, Koyama T, Noguchi H, Ueda Y, Kitsuyama R, Shimizu H, Tanimoto A, Wang KY, Nawata A, Nakayama T, Sasaguri Y, Satoh T. .  Marine hydroquinone zonarol prevents inflammation and apoptosis in dextran sulfate sodium-induced mice ulcerative colitis. .  PLoS One9 ( 11 )   2014.1Reviewed

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Miura N, Kucho K, Noguchi M, Miyoshi N, Uchiumi T, Kawaguchi H, Tanimoto A. .  Comparison of the genomic sequence of the microminipig, a novel breed of swine, with the genomic database for conventional pig. .  In Vivo.28 ( 6 ) 1107 - 1111   2014.1Reviewed

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Uchida T, Furuno Y, Tanimoto A, Toyohira Y, Arakaki K, Kina-Tanada M, Kubota H, Sakanashi M, Matsuzaki T, Noguchi K, Nakasone J, Igarashi T, Ueno S, Matsushita M, Ishiuchi S, Masuzaki H, Ohya Y, Yanagihara N, Shimokawa H, Otsuji Y, Tamura M, Tsutsui M. .  Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse. .  J Mol Cell Cardiol.77   29 - 41   2014.1Reviewed

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Yamaguchi T, Yamazaki T, Kawaguchi H, Tawa M, Nakamura Y, Shiota M, Osada-Oka M, Tanimoto A, Okamura T, Miura K, Iwao H, Yoshiyama M, Izumi Y. .  A noninvasive metabolic syndrome model using an extremely small minipig, the microminipig. .  J Pharmacol Sci.126 ( 2 ) 168 - 171   2014.1Reviewed

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Yokouchi M, Nagano S, Kijima Y, Yoshioka T, Tanimoto A, Natsugoe S, Komiya S. .  Solitary breast metastasis from myxoid liposarcoma. .  BMC Cancer. 2014 Jul 4;14:482. doi: 10.1186/1471-2407-14-482.14 ( 482 )   2014.1Reviewed

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Hiraki T, Higashi M, Goto Y, Kitazono I, Yokoyama S, Iuchi H, Nagano H, Tanimoto A, Yonezawa S .  A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1. .  Cardiovasc Pathol. 23 ( 4 ) 244 - 247   2014.1Reviewed

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Hatanaka K, Yoshioka T, Tasaki T, Tanimoto A .  The hyaline vascular type of Castleman's disease of the ovary: a case report. .  Int J Surg Pathol.22 ( 7 ) 652 - 655   2014.1Reviewed

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Kakimoto T, Otsuka A, Kawaguchi H, Ogata K, Tanimoto A, Kanouchi H. .  Plasma homocysteine concentration in novel microminipigs. .  In Vivo 28   579 - 582   2014.1Reviewed

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Hamada T, Souda M, Yoshimura T, Sasaguri S, Hatanaka K, Tasaki T, Yoshioka T, Ohi Y, Yamada S, Tsutsui M, Umekita Y, Tanimoto A .  Anti-apoptotic Effects of PCP4/PEP19 in Human Breast Cancer Cell Lines: A Novel Oncotarget .  Oncotarget 5   6076 - 6086   2014.1Reviewed

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Hatanaka K, Yoshioka T, Tasaki T, Tanimoto A. .  Pulmonary rhabdomyomatous dysplasia of the newborn in neurofibromatosis type 1. .  Pathol Res Pract. 210: 318-320 ( 1 ) 318 - 320   2014.1Reviewed

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Kawaguchi H, Yamada T, Miura N, Ayaori M, Uto-Kondo H, Ikegawa M, Noguchi M, Wang KY, Izumi H, Tanimoto A. .  Rapid Development of Atherosclerosis in the World's Smallest Microminipig fed a high-fat/high cholesterol diet: A Useful Animal Model Because of its Size and Similarity to Human Pathophysiology. .  J Atheroscler Thromb. 21 ( 1 ) 186 - 203   2014.1Reviewed

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Noguchi H, Yamada S, Nabeshima A, Guo X, Tanimoto A, Wang KY, Kitada S, Tasaki T, Takama T, Shimajiri S, Horlad H, Komohara Y, Izumi H, Kohno K, Ichijo H, Sasaguri Y. .  Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necro-inflammation and subsequent peribiliary fibrosis. .  Am J Pathol. 184 ( 1 ) 644 - 661   2014.1Reviewed

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Yamamoto M, Arimura H, Fukushige T, Minami K, Nshizawa Y, Tanimoto A, Kanekura T, Nakagawa M, Akiyama SI, Furukawa T. .  Abcb10 knockout mice causes anemia with protoporphyrin IX and iron accumulation: Abcb10 is essential for heme biosynthesis in vivo. .  Mol Cell Biol.34 ( 1 ) 1077 - 1084   2014.1Reviewed

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Akioka K, Kawaguchi H, Kitajima S, Miura N, Noguchi M, Horiuchi M, Miyoshi N, Tanimoto A. .  Investigation of Necessity of Sodium Cholate and Minimal Required Amount of Cholesterol for Dietary Induction of Atherosclerosis in Microminipigs. .  In Vivo. 28 ( 1 ) 81 - 90   2014.1Reviewed

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Kohei Akioka, Hiroaki Kawaguchi, Sawako Kitajima, Naoki Miura, Michiko Noguchi, Masahisa Horiuchi, Noriaki Miyoshi, Akihide Tanimoto .  Investigation of Necessity of Sodium Cholate and Minimal Required Amount of Cholesterol for Dietary Induction of Atherosclerosis in Microminipigs .  IN VIVO28 ( 1 ) 81 - 90   2014.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Recently we established a Microminipig (MMPig) model of atherosclerosis induced by high fat/high cholesterol (Cho) diet containing sodium cholate (SC), which is known to cause hepatotoxicity. In the present study, we investigated whether SC is necessary as well as the minimum amount of dietary Cho required to induce atherosclerosis. Experiment A: Six MMPigs were divided into three groups of two, and were fed for 12 weeks as follows: a diet containing 12% fat and 5% Cho with or without 0.7% SC, or the diet including 12% fat and 0.5% Cho with SC. Although each diet induced a similar degree of hypercholesterolemia and atherosclerosis, the liver weights and severity of fatty change in the hepatocytes were maximal in the animals fed 5% Cho and SC. Experiment B: Six MMPigs were divided into two groups of three, and fed for 18 weeks as follows: normal diet, and a diet of increasing dose of Cho (0.03, 0.1, 0.3, 0.5, 1.5 and 5%) for the initial 14 weeks and 0.5% Cho/12% fat diet for the final four weeks. Serum levels of total Cho and low-density lipoprotein-Cho reached a plateau with 0.5% Cho diet, suggesting that the minimum amount of Cho required is 0.5%. The absorption of Cho in MMPigs was enhanced by 0.5% Cho and 12% fat diet compared to the 5% Cho-alone diet. In conclusion, a diet with 0.5% Cho and 12% fat without SC appears to be sufficient to induce atherosclerosis in the MMPig.

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谷本 昭英, 川口 博明, 野口 倫子, 三浦 直樹, 大竹 正剛 .  第三の家畜 実験動物としてのミニブタ 世界最小のマイクロミニピッグ .  病理と臨床32 ( 1 ) 92 - 96   2014.1

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Md Zahorul Islam, Emi Yamazaki-Himeno, Mitsuya Shiraishi, Atsushi Miyamoto, Hiroaki Kawaguchi, Noriaki Miyoshi, Naoki Miura, Akihide Tanimoto .  Angiotensin II decreases bradykinin-induced NO and increases prostaglandin F-2 alpha release from cultured Microminipig basilar arterial endothelial cells .  JOURNAL OF PHARMACOLOGICAL SCIENCES124   104P - 104P   2014Reviewed

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Hiroaki Kawaguchi, Tomonobu Yamada, Naoki Miura, Makoto Ayaori, Harumi Uto-Kondo, Masaya Ikegawa, Michiko Noguchi, Ke-Yong Wang, Hiroyuki Izumi, Akihide Tanimoto .  Rapid Development of Atherosclerosis in the World's Smallest Microminipig Fed a High-Fat/High-Cholesterol Diet A Useful Animal Model Due to its Size and Similarity to Human Pathophysiology .  JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS21 ( 3 ) 186 - 203   2014Reviewed

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Aim: Experimental studies of human atherogenesis require an appropriate animal model that mimics human physiology and pathology. Because swine physiology is similar to human physiology, we developed a hyperlipidemia-induced atherosclerosis model using the recently developed world's smallest Microminipig (TM).
Methods: These animals weigh only 5 kg at 3 months of age, much smaller than any other miniature pig. We found that the administration of a high-fat/high-cholesterol diet containing at least 0.2% cholesterol without cholic acid for as little as eight weeks induces hypercholesterolemia and subsequent atherosclerosis in these animals.
Results: The serum levels of low-density lipoprotein cholesterol (LDL-C) and the percent distribution of cholesterol in the LDL fractions were markedly increased. The hepatic expression of LDL receptor and hydroxymethylglutaryl-CoA reductase was coordinately decreased. The cholesteryl ester transfer protein activity, which plays a role in reverse cholesterol transport, was detected in the serum of the Microminipigs. Niemann-Pick C1-like 1 protein was expressed in both the liver and small intestine; however, hepatic apoB mRNA editing enzyme was not expressed. As in humans, and in contrast to that observed in mice, most of the hepatic lipase activity was localized in the liver. These results suggest that the hyperlipidemia-induced gene expression profile linked to cholesterol homeostasis and atherogenesis is similar in Microminipigs and humans.
Conclusion: We conclude that the characteristics of the Microminipig, including its easy handling size, make it an appropriate model for studies of atherosclerosis and related conditions.

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Izumi Yasukatsu, Yamaguchi Takehiro, Kawaguchi Hiroaki, Tawa Masashi, Shiota Masayuki, Oka Mayuko, Tanimoto Akihide, Miura Katsuyuki, Iwao Hiroshi .  The establishment of a noninvasive metabolic syndrome model using an extremely small size minipig .  JOURNAL OF PHARMACOLOGICAL SCIENCES124   234P - 234P   2014Reviewed

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Masato Tsutsui, Hiroaki Shimokawa, Akihide Tanimoto, Nobuyuki Yanagihara, Masahito Tamura, Yutaka Otsuji .  Roles of nitric oxide synthases in arteriosclerotic vascular disease: Insights from murine genetic models .  Journal of Clinical and Experimental Cardiology5 ( 6 )   2014

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Nitric Oxide (NO) exerts a variety of biological actions under both physiological and pathological conditions. NO is synthesized by three distinct NO synthase (NOS) isoforms, encoded by three distinct NOS genes, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS), all of which are expressed in the human vascular system. Although the roles of the NOSs in arteriosclerotic vascular diseases have been described in pharmacological studies with selective and non-selective NOS inhibitors, the selectivity and specificity of the NOS inhibitors continue to be an issue of debate. To solve this issue, genetically altered animals have been established. All types of NOS gene-deficient animals have been developed, including singly, doubly, and triply NOS-deficient mice and various types of NOS Gene-Transgenic (TG) animals have also been generated, including conditional and non-conditional TG mice bearing site-specific overexpression of each NOS gene. The roles of individual NOS isoforms as well as the entire NOSs system in arteriosclerotic vascular diseases have been extensively investigated in those mice, providing pivotal insights into an understanding of the pathophysiological significance of the NOSs in human arteriosclerotic vascular diseases. The present review, which is based on studies with the murine NOS genetic models, summarizes the latest knowledge about the NOSs and arteriosclerotic vascular diseases. © 2014 Tsutsui M, et al.

DOI： 10.4172/2155-9880.1000318

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Kazuhito Hatanaka, Takako Yoshioka, Takashi Tasaki, Akihide Tanimoto .  Pulmonary rhabdomyomatous dysplasia of the newborn in neurofibromatosis type 1 .  PATHOLOGY RESEARCH AND PRACTICE210 ( 5 ) 318 - 320   2014Reviewed International journal

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Proliferation of non-neoplastic striated muscle cells in the lung is rare and has been frequently observed in cases of cardiovascular and pulmonary congenital malformations. We present an extremely rare case of pulmonary rhabdomyomatous dysplasia (RD) in neurofibromatosis type 1 (NF-1). A male neonate was born at 35 weeks' gestation after normal pregnancy. Postnatally, besides patent ductus arteriosus and posterior mediastinal mass, abnormal cystic lesions in the left upper and lower lung were detected. No bronchial atresia and stenosis were identified. Partial lobectomy specimens showed hypoplastic lung parenchyma with cystic lesions resembling terminal bronchioles and distinctive proliferation of non-neoplastic striated muscle fibers in the interstitium. The posterior mediastinal mass consisted of neurofibroma. Considering that cafe au lait spots and freckling occurred at 2 months of age, a diagnosis of NF-1 was made. The patient died of aspiration pneumonia at the age of 30 months. To the best of our knowledge, this is the first case of pulmonary RD in NF-1. (C) 2013 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2013.10.008

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Atsunori Nabeshima, Sohsuke Yamada, Xin Guo, Akihide Tanimoto, Ke-Yong Wang, Shohei Shimajiri, Satoshi Kimura, Takashi Tasaki, Hirotsugu Noguchi, Shohei Kitada, Teruo Watanabe, Junichi Fujii, Kimitoshi Kohno, Yasuyuki Sasaguri .  Peroxiredoxin 4 protects against nonalcoholic steatohepatitis and type 2 diabetes in a nongenetic mouse model .  Antioxidants and Redox Signaling19 ( 17 ) 1983 - 1998   2013.12Reviewed International journal

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Aims: Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. Results: To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. Innovation and Conclusion: Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury. Antioxid. Redox Signal. 19, 1983-1998. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

DOI： 10.1089/ars.2012.4946

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Sohsuke Yamada, Ke-Yong Wang, Akihide Tanimoto, Xin Guo, Atsunori Nabeshima, Takeshi Watanabe, Yasuyuki Sasaguri .  Histamine receptors expressed in circulating progenitor cells have reciprocal actions in ligation-induced arteriosclerosis .  PATHOLOGY INTERNATIONAL63 ( 9 ) 435 - 447   2013.9Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Histamine is synthesized as a low-molecular-weight amine from L-histidine by histidine decarboxylase (HDC). Recently, we demonstrated that carotid artery-ligated HDC gene-deficient mice (HDC-/-) showed less neointimal formation than wild-type (WT) mice, indicating that histamine participates in the process of arteriosclerosis. However, little is known about the roles of histamine-specific receptors (HHRs) in arteriosclerosis. To define the roles of HHRs in arteriosclerosis, we investigated intimal remodeling in ligated carotid arteries of HHR-deficient mice (H1R(-/-) or H2R(-/-)). Quantitative analysis showed that H1R(-/-) mice had significantly less arteriosclerogenesis, whereas H2R(-/-) mice had more, as compared with WT mice. Bone marrow transplantation from H1R(-/-) or H2R(-/-) to WT mice confirmed the above observation. Furthermore, the increased expression of monocyte chemoattractant protein (MCP-1), platelet-derived growth factor (PDGF), adhesion molecules and liver X receptor (LXR)-related inflammatory signaling factors, including Toll-like receptor (TLR3), interleukin-1 receptor (IL-1R) and tumor necrosis factor receptor (TNF-R), was consistent with the arteriosclerotic phenotype of H2R(-/-) mice. Peripheral progenitor cells in H2R(-/-) mice accelerate ligation-induced arteriosclerosis through their regulation of MCP-1, PDGF, adhesion molecules and LXR-related inflammatory signaling factors. In contrast, peripheral progenitor cells act to suppress arteriosclerosis in H1R(-/-) mice, indicating that HHRs reciprocally regulate inflammation in the ligation-induced arteriosclerosis.

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Hiroaki Kawaguchi, Tomonobu Yamada, Naoki Miura, Michiko Noguchi, Hiroyuki Izumi, Noriaki Miyoshi, Akihide Tanimoto .  Sex Differences of Serum Lipid Profile in Novel Microminipigs .  IN VIVO27 ( 5 ) 617 - 621   2013.9Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Swine have been used extensively in biomedical research, with a significant increase in recent decades. Minipigs are increasingly becoming an especially attractive animal model in life science research because of their physiological and anatomical similarities to humans. The Microminipig (MMPig) has emerged as a novel and small minipig for non-clinical pharmacological/toxicological use. The MMPig is docile, weighs less than 10 kg in early maturity, and has an easily manageable size. In this study, we report on sex and age patterns in serum biochemistry parameters, including lipid analysis items and lipid profiles in healthy MMPigs. In total, 58 males and 67 females aged 034 months underwent serum biochemistry parameter measurements. Most parameters showed no effect of age or sex (although some did). Lipid analyses showed that the serum levels of total cholesterol, but not those of triglycerides (TG), were consistently higher in females at 0-34 months of age. Lipid profiles in 5-month-old MMPigs were investigated in greater detail. Serum low-density lipoprotein-cholesterol (LDL-C) values were higher in females. The percentage of LDL-C against total cholesterol was also higher, although high-density lipoprotein-cholesterol was lower, in females. There were no sex differences in the TG fraction. Although the sex difference in the serum lipid profile remains unexplained, the reference values obtained in this study could help facilitate the use of MMPigs in life science research.

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山本 謙一郎, 倉本 正文, 池嶋 聡, 増田 稔郎, 宮田 辰徳, 浦田 昌幸, 吉松 眞一, 江藤 健一郎, 谷本 昭英, 馬場 秀夫, 島田 信也 .  腹腔鏡下に切除した骨盤内後腹膜平滑筋肉腫の1例 .  日本外科系連合学会誌38 ( 4 ) 909 - 915   2013.8

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症例は63歳女性.4年前,前医における尿路結石診断のためのCT検査にて,左腸骨前面に存在する2cm大の腫瘍を指摘されていた.徐々に増大してきたため当科紹介となった.左腸骨前面に接する4cm大の腫瘍を認めたが,経過ならびにCT・MRI検査にて積極的に悪性の所見を認めないことから骨盤内良性後腹膜腫瘍の術前診断にて,腹腔鏡下に腫瘍摘出術を施行した.特に周囲への癒着・浸潤はなく,腫瘍は完全に切除しえた.切除標本の病理組織学的診断にて,紡錘形の大型核多形性細胞を混在する腫瘍が束状増殖しており,免疫染色も併施し平滑筋肉腫と診断した.後腹膜腫瘍は症状もなく,CT検査にて偶然発見されることも多く,良悪性の術前診断に苦慮する場合も少なくない.画像診断の進歩により,比較的小さな腫瘍径で診断された後腹膜腫瘍は腹腔鏡下に安全かつ低侵襲に切除が可能であるが,悪性腫瘍を念頭においた完全切除が重要である.(著者抄録)

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Kazuhito Hatanaka, Takako Yoshioka, Takashi Tasaki, Akihide Tanimoto .  Paratesticular dedifferentiated liposarcoma with leiomyosarcomatous differentiation: a case report with a review of literature .  DIAGNOSTIC PATHOLOGY8   142 - 142   2013.8Reviewed International journal

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Paratesticular liposarcoma is a rare neoplasm, described in single case studies or components of larger studies, as histologically well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL). However, leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL. We report a case of leiomyosarcomatous differentiation in a 77-year-old man. The patient presented with a painless right scrotal mass. Magnetic resonance imaging showed a large mass along the right spermatic cord. The resected mass, measuring 17.5 x 12 x 5 cm, was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis. Atypical smooth muscle differentiation was also detected. Additional tumor sampling revealed the presence of a WDL component. Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4, and negative staining for alpha smooth muscle actin (alpha SMA) and desmin. The smooth muscle component was positive for alpha SMA and desmin, and negative for MDM2 and CDK4. Extension from primary retroperitoneal sarcoma was not proved. We diagnosed of DL with leiomyosarcomatous differentiation.

DOI： 10.1186/1746-1596-8-142

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Mayuko Sakanashi, Toshihiro Matsuzaki, Katsuhiko Noguchi, Junko Nakasone, Makiko Sakanashi, Taro Uchida, Mika Kina-Tanada, Haruaki Kubota, Kumiko Arakaki, Akihide Tanimoto, Nobuyuki Yanagihara, Matao Sakanashi, Yusuke Ohya, Hiroaki Masuzaki, Shogo Ishiuchi, Kazuhiro Sugahara, Masato Tsutsui .  Long-Term Treatment With San'o-Shashin-To, a Kampo Medicine, Markedly Ameliorates Cardiac Ischemia-Reperfusion Injury in Ovariectomized Rats via the Redox-Dependent Mechanism .  CIRCULATION JOURNAL77 ( 7 ) 1827 - 1837   2013.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san'o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model.
Methods and Results: Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes. Myocardial inducible nitric oxide synthase (iNOS) expression and peroxynitrite levels were significantly higher in ovariectomized rats compared with sham-operated rats, and long-term TJ-113 treatment significantly reduced these oxidative changes. Furthermore, myocardial manganese superoxide dismutase (Mn-SOD) activity was significantly lower in ovariectomized than in sham-operated rats, and long-term TJ-113 treatment significantly restored antioxidant activity. Importantly, those beneficial actions of TJ-113 were significantly inhibited by the estrogen receptor antagonist, fulvestrant, and the phytoestrogen, emodin, a TJ-113 ingredient, mimicked the actions of TJ-113, suggesting involvement of emodin in the effects of TJ-113.
Conclusions: These results provide the first evidence that long-term treatment with a clinical dosage of TJ-113 markedly ameliorates cardiac IR injury in ovariectomized rats via inhibition of iNOS expression, suppression of peroxynitrite formation, and restoration of Mn-SOD activity. TJ-113 may be a novel therapeutic option in the treatment of ischemic heart disease in climacteric women.

DOI： 10.1253/circj.CJ-12-1434

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Naoki Miura, Hiroaki Kawaguchi, Tomoka Nagasato, Tomonobu Yamada, Takashi Ito, Hiroyuki Izumi, Hisayo Shameshima, Noriaki Miyoshi, Akihide Tanimoto, Ikuro Maruyama .  Coagulation activity and white thrombus formation in the microminipig .  In Vivo27 ( 3 ) 357 - 361   2013.5Reviewed International journal

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Swine are becoming increasingly attractive as animal models for clinical research and the recently developed Microminipig (MMPig) has emerged as a possible experimental animal model. In this study, we demonstrated age-dependent changes in hematological parameters and coagulation activity in healthy MMPigs (58 male and 67 females, aged 0-34 months), and investigated white thrombus formation (WTF) using an in vitro microchip flow-chamber system (four males and four females, aged 22-23 months). There was no clear sex or age-dependent differences in any hematological parameters. While activated partial thromboplastin time (APTT) was shorter than prothrombin time (PT), with APTT:PT of 0.88:1, microchip flow-chamber system analysis showed that WTF time was shorter than that in humans, suggesting a possible thrombotic tendency in the MMPig. These results could be useful to life science researchers in the use of the MMPig as an experimental model animal for thrombus formation.

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Mitsuru Muto, Tatsuru Kaji, Motoi Mukai, Kazuhiko Nakame, Takako Yoshioka, Akihide Tanimoto, Hiroshi Matsufuji .  Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection .  PEPTIDES43   160 - 166   2013.5Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Children with short bowel syndrome face life-threatening complications. Therefore, there is an urgent need for a new therapy to induce effective adaptation of the remnant intestine. Adaptation occurs only during feeding. We focused on preprandial acyl ghrelin and des-acyl ghrelin, and postprandial glucagon-like peptide-2 (GLP-2), which are known to have active orexigenic and trophic actions. This study aims to clarify the secretion trends of these hormones after massive small bowel resection and to obtain basic data for developing a new treatment. Sixty-three growing male rats were used: 3 were designated as controls receiving no operation and 60 were randomized into the 80% small bowel resection (80% SBR) group and the transection and re-anastomosis group. Changes in body weight, food intake, and remnant intestine morphology were also assessed for 15 days after the operation. Acyl ghrelin and des-acyl ghrelin levels increased immediately, equivalently in both operation groups (P = 0.09 and 0.70). Interestingly, in 80% SBR animals, des-acyl ghrelin peaked on day 1 and acyl ghrelin peaked on day 4 (P = 0.0007 and P = 0.049 vs controls). GLP-2 secretion was obvious in 80% SBR animals (P = 2.25 x 10(-6)), which increased immediately and peaked on day 4 (P = 0.009 vs. controls). Body weight and food intake in 80% SBR animals recovered to preoperative levels on day 4. Morphological adaptations were evident after day 4. Our results may suggest a management strategy to reinforce these physiological hormone secretion patterns in developing a new therapy for short bowel syndrome. (C) 2013 Elsevier Inc. All rights reserved.

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山本 謙一郎, 蔵元 一崇, 倉本 正文, 池嶋 聡, 増田 稔郎, 宮田 辰徳, 吉松 眞一, 浦田 昌幸, 門田 正貴, 谷本 昭英, 馬場 秀夫, 島田 信也 .  内臓逆位症に合併した十二指腸乳頭部癌に対して膵頭十二指腸切除術を施行した1例 .  胆と膵34 ( 4 ) 335 - 338   2013.4

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Publisher：医学図書出版(株)  

症例は73歳女性。黄疸を指摘され当院受診。胸腹部造影CTにて総胆管と膵管の拡張と完全内臓逆位を認めた。上部消化管内視鏡検査では十二指腸乳頭部に表面不整で発赤腫大した易出血性の腫瘍を認めた。生検にて十二指腸乳頭部癌と診断し、亜全胃温存膵頭十二指腸切除術(Child変法再建)を施行した。病理検査所見にてtubular adenocarcinoma、pT3N0M0であった。術後4年3ヵ月無再発生存中である。内臓逆位症は内臓の一部または全部が左右逆転し正常位に対して鏡面的位置関係にある比較的まれな先天疾患であるが、それ自体に病的意義はないといわれている。悪性疾患合併の報告も散見されるが、高難度手術の一つである膵頭十二指腸切除施行例の報告は極めて少ない。今回われわれは完全内臓逆位症に合併した十二指腸乳頭部癌に対して、安全に膵頭十二指腸切除術を遂行し得たので、若干の文献的考察を加えて報告する。(著者抄録)

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Takashi Tasaki, Sohsuke Yamada, Xin Guo, Akihide Tanimoto, Ke-Yong Wang, Atsunori Nabeshima, Shohei Kitada, Hirotsugu Noguchi, Satoshi Kimura, Shohei Shimajiri, Kimitoshi Kohno, Hidenori Ichijo, Yasuyuki Sasaguri .  Apoptosis Signal-Regulating Kinase 1 Deficiency Attenuates Vascular Injury-Induced Neointimal Hyperplasia by Suppressing Apoptosis in Smooth Muscle Cells .  AMERICAN JOURNAL OF PATHOLOGY182 ( 2 ) 597 - 609   2013.2Reviewed International journal

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Apoptosis signal regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and Less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of Luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-alpha-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model. (Am J Pathol 2013, 182: 597-609; http://dx.doi.org/10.1016/j.ajpath.2012.10.008)

DOI： 10.1016/j.ajpath.2012.10.008

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Sakanashi M, Matsuzaki T, Noguchi K, Nakasone J, Sakanashi M, Uchida T, Kina-Tanada M, Kubota H, Arakaki K, Tanimoto A, Yanagihara N, Sakanashi M, Ohya Y, Masuzaki H, Ishiuchi S, Sugahara K, Tsutsui M. .  Long-Term Treatment With San'o-Shashin-To, a Kampo Medicine, Markedly Ameliorates Cardiac Ischemia-Reperfusion Injury in Ovariectomized Rats via the Redox-Dependent Mechanism. .  Circ J.77   1827 - 1837   2013.1Reviewed

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Kawaguchi H, Yamada T, Miura N, Noguchi M, Izumi H, Miyoshi N, Tanimoto A. .  Sex Differences in Serum Lipid Profile in Novel Microminipigs. .  In Vivo.27   617 - 621   2013.1Reviewed

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Yoshikawa T, Takahashi Y, Kawaguchi H, Utsunomiya S, Miura N, Izumi H, Miyoshi N, Tanimoto A. .  A Dermal Phototoxicity Study Following Intravenous Infusion Administration of Ciprofloxacin Hydrochloride in the Novel Microminipigs. .  Toxicol Pathol41   109 - 113   2013.1Reviewed

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Miura N, Kawaguchi H, Nagasato T, Yamada T, Ito T, Izumi H, Shameshima H, Miyoshi N, Tanimoto A, Maruyama I. .  Coagulation activity and white thrombus formation in the Microminipig. .  In Vivo. 24   671 - 680   2013.1Reviewed

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Muto M, Kaji T, Mukai M, Nakame K, Yoshioka T, Tanimoto A, Matsufuji H. .  Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection. .  Peptides. 43C   160 - 166   2013.1Reviewed

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Tasaki T, Yamada S, Guo X, Tanimoto A, Wang KY, Nabeshima A, Kitada S, Noguchi H, Kimura S, Shimajiri S, Kohno K, Ichijo H, Sasaguri Y. .  Apoptosis Signal-Regulating Kinase 1 Deficiency Attenuates Vascular Injury-Induced Neointimal Hyperplasia By Suppressing Apoptosis In Smooth Muscle Cells. .  Am J Pathol. 182   597 - 609   2013.1Reviewed

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Nabeshima A, Yamada S, Guo X, Tanimoto A, Wang KY, Shimajiri S, Kimura S, Tasaki T, Noguchi H, Kitada S, Watanabe T, Fujii J, Kohno K, Sasaguri Y. .  Peroxiredoxin 4 protects against nonalcoholic steatohepatitis and type 2 diabetes in a nongenetic mouse model. .  Antioxid Redox Signal 19 ( 1 ) 1983 - 1998   2013.1Reviewed

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Hatanaka K, Yoshioka T, Tasaki T, Tanimoto A. .  Paratesticular dedifferentiated liposarcoma with leiomyosarcomatous differentiation: A case report with a review of literature .  Diagn Pathol. 0.333333333333333 ( 1 ) 142 doi: 10.1186/1746-1596-8-142.   2013.1Reviewed

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Yamada S, Wang KY, Tanimoto A, Guo X, Nabeshima A,Watanabe T, Sasaguri Y. .  Histamine receptors expressed in circulating progenitor cells have reciprocal actions in ligation-induced arteriosclerosis. .  Pathol Int. 63 ( 1 ) 435 - 447   2013.1Reviewed

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Tsuyoshi Yoshikawa, Yoshihiro Takahashi, Hiroaki Kawaguchi, Shinji Utsunomiya, Naoki Miura, Hiroyuki Izumi, Noriaki Miyoshi, Akihide Tanimoto .  A Dermal Phototoxicity Study Following Intravenous Infusion Administration of Ciprofloxacin Hydrochloride in the Novel Microminipigs .  TOXICOLOGIC PATHOLOGY41 ( 1 ) 109 - 113   2013.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

The authors evaluated dermal phototoxicity using the world smallest minipig (MMPig: Microminipig). MMPigs were administered 100 mg/kg ciprofloxacin hydrochloride with an infusion pump. The dorsal area of each animal was irradiated with ultraviolet-A irradiation. The left dorsal skin was irradiated at intensities of 5, 10, 15, and 20 J/cm(2), and the right dorsal back skin was set as a nonirradiated site. Gross and histopathological examinations were conducted before irradiation and from 1 to 72 hr after irradiation. Initial changes in the skin were necrosis of the basal and/or prickle cell layer and cellular infiltration from 24 hr after irradiation. Vesicle formation observed from 48 hr after irradiation was considered similar to bullous eruptions, a known side effect of fluoroquinolones in humans. Therefore, the authors suggest that the MMPig may be a useful experimental animal model for dermal phototoxicity studies.

DOI： 10.1177/0192623312452489

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Atsushi Miyamoto, Md. Zahorul Islam, Hiroaki Kawaguchi, Naoki Miura, Emi Yamzaki-Himeno, Mitsuya Shiraishi, Noriaki Miyoshi, Akihide Tanimoto .  Effect of continuous intravenous infusion of angiotensin II on Microminipig basilar arterial responsiveness .  JOURNAL OF PHARMACOLOGICAL SCIENCES121   22P - 22P   2013Reviewed

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谷本 昭英, 川口 博明 .  第三の家畜 実験動物としてのミニブタ ブタの研究利用の現状 .  病理と臨床30 ( 11 ) 1276 - 1279   2012.11

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Xin Guo, Sohsuke Yamada, Akihide Tanimoto, Yan Ding, Ke-Yong Wang, Shohei Shimajiri, Yoshitaka Murata, Satoshi Kimura, Takashi Tasaki, Atsunori Nabeshima, Teruo Watanabe, Kimitoshi Kohno, Yasuyuki Sasaguri .  Overexpression of Peroxiredoxin 4 Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice .  ANTIOXIDANTS & REDOX SIGNALING17 ( 10 ) 1362 - 1375   2012.11Reviewed International journal

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Aim: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. Results: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4(+/+)/apoE(-/-)). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE(-/-) mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4(+/+)/apoE(-/-) mice than in apoE(-/-) mice. Bone marrow transplantation from hPRDX4(+/+) donors to apoE(-/-) mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. Innovation: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE(-/-) mice fed a high-cholesterol diet. Conclusion: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. Antioxid. Redox Signal. 17, 1362-1375.

DOI： 10.1089/ars.2012.4549

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Satoshi Kimura, Akihide Tanimoto, Ke-Yong Wang, Shohei Shimajiri, Xin Guo, Takashi Tasaki, Sohsuke Yamada, Yasuyuki Sasaguri .  Expression of macrophage-derived chemokine (CCL22) in atherosclerosis and regulation by histamine via the H2 receptor .  PATHOLOGY INTERNATIONAL62 ( 10 ) 675 - 683   2012.10Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines and is synthesized by monocyte-derived macrophages and dendritic cells (DCs). In this study, we investigate the relationship between monocytes/macrophages and histamine in atherosclerosis and discover that histamine levels regulate various immunologically important molecules and influences atherosclerotic progression. Immunohistochemical analysis of human atherosclerotic lesions revealed that macrophages and DCs express CCL22. The human acute monocytic leukemia cell line (THP-1) adhered to culture plates and morphologically changed to macrophage-like cells when treated with tetradecanoylphorbol-13-acetate (TPA). Macrophage-like cells derived from THP-1 cells and cultivated peripheral blood mononuclear cells (PBMCs) show similar expression of CCL22. Gene expression of CCL22 was also detected in THP-1 cells treated with histamine and the expression of the protein produced by the CCL22 gene is similar in PBMCs and THP-1 cells. In addition, the histamine H2 receptor mediated these reactions. Our results suggest that CCL22 expression in monocytes is regulated by histamine, and that CCL22 is involved centrally in the development of human atherosclerotic lesions. In conclusion, CCL22 is a marker that is a characteristic of the monocytes/ macrophages migrating into atherosclerotic lesions and histamine plays a role in regulating its expression.

DOI： 10.1111/j.1440-1827.2012.02854.x

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Y. Ohi, Y. Umekita, Y. Sagara, Y. Rai, D. Yotsumoto, A. Matsukata, S. Baba, S. Tamada, Y. Matsuyama, M. Ando, Y. Sagara, M. Sasaki, S. Tsuchimochi, A. Tanimoto, Y. Sagara .  Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer .  BRITISH JOURNAL OF CANCER107 ( 8 ) 1239 - 1243   2012.10Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a rapid procedure for the detection of lymph node (LN) metastases using molecular biological techniques. The aim of this study was to assess the reliability of the whole sentinel lymph node (SLN) analysis by the OSNA assay as a predictor of non-SLN metastases.
METHODS: Consecutive 742 patients with breast cancer were enroled in the study. The association of non-SLN or &gt;= 4 LN metastases with clinicopathological variables was investigated using multivariate logistic analysis.
RESULTS: In total, 130 patients with a positive SLN who underwent complete axillary LN dissection were investigated. The frequency of non-SLN metastases in patients who were OSNA+ and + + was 19.3% and 53.4%, respectively, and that in patients with &gt;= 4 LN metastases who were OSNA+ and + + was 7.0% and 27.4%, respectively. The cytokeratin 19 (CK19) mRNA copy number (&gt;= 5.0 x 10(3); OSNA+ +) in the SLN was the most significant predictors of non-SLN metastases (P = 0.003). The CK19 mRNA copy number (&gt;= 1.0 x 10(5)) in the SLN was the only independent predictor of &gt;= 4 LN metastases (P = 0.014).
CONCLUSION: Whole SLN analysis using the OSNA assay could become a valuable method for predicting non-SLN and &gt;= 4 LN metastases. British Journal of Cancer (2012) 107, 1239-1243. doi:10.1038/bjc.2012.387 www.bjcancer.com Published online 28 August 2012 (C) 2012 Cancer Research UK

DOI： 10.1038/bjc.2012.387

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Sohsuke Yamada, Akihide Tanimoto, Atsunori Nabeshima, Takashi Tasaki, Ke-Yong Wang, Shohei Kitada, Hirotsugu Noguchi, Yasuyuki Sasaguri .  Diffuse large B-cell lymphoma presenting with neurolymphomatosis and intravascular lymphoma: a unique autopsy case with diverse neurological symptoms .  DIAGNOSTIC PATHOLOGY7   94 - 94   2012.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

A 78-year-old Japanese male noticed a difficulty in the beginning of standing up, followed by 7a progressive numbness of extremities with pain, Bell's palsy, dysarthria, and difficulty in swallowing. A clinician had suspected cancer of unknown primary origin, accompanied by the diverse and elusive neurological symptoms, likely presenting as painful mononeuropathy simplex and cranial neuropathy. He developed dysbasia over weeks and died 1 month after the symptom onset. At autopsy, an ill-defined large and soft tumor mass in the right lobe of the liver with direct invasion into the right adrenal gland was observed. The left adrenal gland or right iliopsoas muscle was also involved. Microscopic findings showed a monotonous proliferation of medium-sized to large atypical lymphoid cells, which were diffusely positive for CD20 in immunohistochemistry, consistent with diffuse large B-cell lymphoma (DLBL). Furthermore, the lymphoma cells aggressively infiltrated endoneurial and subperineurial spaces not only in the peripheral nerves and plexuses, but partly in the spinal nerve roots, and intravascular spaces in various tissues. Therefore, systemic lymphoma (DLBL) complicated with neurolymphomatosis (NL) and intravascular lymphoma (IVL) was diagnosed. Very early diagnosis and treatment are necessary for the NL patients with poor prognosis.

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Emiko Haruyama, Yuki Ayukawa, Koshiro Kamura, Megumi Mizutamari, Yojiro Ooshima, Akihide Tanimoto .  Morphometric Examination for Development of Reproductive Organs in Male Cynomolgus Monkeys .  TOXICOLOGIC PATHOLOGY40 ( 6 ) 918 - 925   2012.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

We previously reported on a histological classification of cynomolgus monkey testis into six grades (1, immature; 2, prepuberty; 3, onset of puberty; 4, puberty; 5, early adult; 6, adult) based on spermatogenesis development. In this investigation, the accessory reproductive organs from the same animals underwent histomorphometric examination, in addition to being examined histologically and weighed, to evaluate relationships between these parameters and the six grades. Seminiferous tubule diameter increased corresponding to the testicular maturity grade and was notably increased at grade 6. Beginning from grade 3, increases in the areas of the ductus epididymis were noted, and reserved sperm was visible in the lumen. In the prostate, the glandular lumen area per unit area showed an increase beginning from grade 3 but no clear differences between grades 4 and 6; advanced development of epithelial height was observed at grade 6. In the seminal vesicle, development of the epithelial cell layer was markedly increased at grade 6. It was concluded that development of the male accessory reproductive organs began after reserved sperm was observed in the lumen of the ductus epididymis (grade 3) and that these organs were developed notably when the testis reached sexual maturity (grade 6).

DOI： 10.1177/0192623312444620

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永尾 聡子, 前田 ゆかり, 久木田 妙子, 皆倉 愛美, 梅北 善久, 谷本 昭英, 大井 恭代 .  神経内分泌への分化を示す非浸潤性乳管癌の細胞診断 .  日本臨床細胞学会九州連合会雑誌43   51 - 56   2012.8Reviewed

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

目的:神経内分泌への分化を示す非浸潤性乳管癌(Neuroendocrine ductal carcinoma in situ:NE-DCIS)の臨床所見と細胞像を明らかにする。方法:細胞診が行われたNE-DCIS 3例の臨床所見と細胞所見について検討を行った。成績:臨床所見では血性乳頭分泌を認めた(3/3例)。細胞所見は、出血性背景に多数の乳管上皮細胞が出現しており、充実性あるいは結合性に乏しい大小の重積集塊で、発達した血管を伴っていた(3/3例)。核は偏在性で緊満感があり均一であったが(3/3例)、一部に核形不整を認めた(1/3例)。細胞質はライトグリーン好染性で一部細顆粒状を示し、孤立細胞は明瞭な細胞質を有していた(3/3例)。診断は悪性で(3/3例)、組織推定はDCIS(2/3例)、充実腺管癌(1/3例)であった。結論:NE-DCISは細胞学的に特徴的な所見を示し、臨床所見なども考慮すれば、NE-DCISを推定病変として挙げることは可能であると思われた。(著者抄録)

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Emiko Haruyama, Masakazu Suda, Yuki Ayukawa, Koshiro Kamura, Megumi Mizutamari, Yojiro Ooshima, Akihide Tanimoto .  Testicular Development in Cynomolgus Monkeys .  TOXICOLOGIC PATHOLOGY40 ( 6 ) 935 - 942   2012.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

The testes from 136 male cynomolgus monkeys were examined histopathologically in order to investigate the relationship between the development of spermatogenesis and testis weight, age, and body weight. At Grade 1 (immature), Sertoli cells and spermatogonia were the only cell classes in the testis. At Grade 2 (pre-puberty), no elongated spermatids were observed in the testis, although a few round spermatids and small lumen formation were observed. At Grade 3 (onset of puberty), all classes of germ cells were observed in the testis, although seminiferous tubule diameters and numbers of germ cells were small. Slight debris in the epididymis was observed in almost all animals. At Grade 4 (puberty), almost complete spermatogenesis was observed in the seminiferous tubules and it was possible to ascertain the spermatogenesis stage as described by Clermont, although tubule diameters and numbers of germ cells were small. There was less debris in the epididymis than at Grade 3. At Grade 5 (early adult), complete spermatogenesis was observed in the seminiferous tubules. At Grade 6 (adult), complete spermatogenesis in the seminiferous tubules and a moderate or large number of sperm in the epididymis were observed. Moreover, sperm analysis using ejaculated sperm was possible. Logistic regression analysis showed that testis weight is a good indicator of testicular maturity.

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Hiroaki Kawaguchi, Tomonobu Yamada, Naoki Miura, Yoshihiro Takahashi, Tsuyoshi Yoshikawa, Hiroyuki Izumi, Tatsuo Kawarasaki, Noriaki Miyoshi, Akihide Tanimoto .  Reference Values of Hematological and Biochemical Parameters for the World Smallest Microminipigs .  JOURNAL OF VETERINARY MEDICAL SCIENCE74 ( 7 ) 933 - 936   2012.7Reviewed

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC VET SCI  

In this study, we demonstrated growth curves and reference values for hematological and serum biochemical parameters of Microminipigs, the world smallest experimental minipigs. In both male and female animals, the body weights (BWs) at 3 and 6 months of age were &lt;5 kg and &lt;10 kg, respectively, and growth curve revealed almost plateau (approximately 20 kg BW) after 18 months of age. Major hematological and serum biochemical parameters showed no gender differences and the values were very similar to those in Gottingen and Yukatan minipigs. The values obtained in this study can serve as fundamental reference, and thereby facilitate the use of Microminipig in life science research.

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Satoshi Kimura, Akihide Tanimoto, Shohei Shimajiri, Takakazu Sasaguri, Sohsuke Yamada, Ke-Yong Wang, Xin Guo, Yasuyuki Sasaguri .  Unilateral gynecomastia and pseudoangiomatous stromal hyperplasia in neurofibromatosis: case report and review of the literature. .  Pathology, research and practice208 ( 5 ) 318 - 22   2012.5Reviewed International journal

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In this article, we describe unilateral gynecomastia and pseudoangiomatous stromal hyperplasia (PASH) in a case of type-1 neurofibromatosis (NF-1). It is important to distinguish PASH from fibroadenoma clinically, and from true blood capillaries and angiosarcoma histologically. In the present case, giant multinucleated cells lined the pseudovascular spaces, which was markedly different from that of conventional breast PASH. The origin of PASH has been reported to be either the fibroblast or the myofibroblast phenotype and may be affected by endocrine signaling because many cases have been reported in premenopausal women, and cases are often estrogen (ER) and progesterone receptor (PR) positive. However, previous reports have identified PASH in NF-1 in juvenile males only, and the cases were negative for α-SMA, ER and PR. The cause and prognosis of PASH in NF-1 may be distinguished from that of conventional PASH, and mast cells, histiocytes and CD54 may play roles.

DOI： 10.1016/j.prp.2012.03.003

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Takeishi K, Horiuchi M, Kawaguchi H, Deguchi Y, Izumi H, Arimura E, Kuchiiwa S, Tanimoto A, Takeuchi T. .  Acupuncture Improves Sleep Conditions of Minipigs Representing Diurnal Animals through an Anatomically Similar Point to the Acupoint (GV20) Effective for Humans. .  Evid Based Complement Alternat Med.   472982   2012.1Reviewed

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Yamada S, Tanimoto A, Nabeshima A, Tasaki T, Wang KY, Kitada S, Noguchi H, Sasaguri Y. .  Diffuse Large B-Cell Lymphoma Presenting with Neurolymphomatosis and Intravascular Lymphoma: A Unique Autopsy Case with Diverse Neurological Symptoms. .  Diagn Pathol. 7   94   2012.1Reviewed

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Ohi Y, Umekita Y, Sagara Y, Rai Y, Yotsumoto D, Matsukata A, Baba S, Tamada S, Matsuyama Y, Ando M, Sagara Y, Sasaki M, Tsuchimochi S, Tanimoto A, Sagara Y. .  Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer. .  Br J Cancer 2012107   1239 - 1243   2012.1Reviewed

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Hatanaka K, Higashi M, Fujibayashi M, Hori S, Yoshioka T, Umekita Y, Tanimoto A. .  A case of complete hydatidiform mole in a perimenopausal woman with diagnostic usefulness of p57kip2 immunohistochemistry and HER2 fluorescent in situ hybridization. .  Pathol Res Pract.208   118 - 120   2012.1Reviewed

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Guo X, Yamada S, Tanimoto A, Ding Y, Wang KY, Shimajiri S, Murata Y, Kimura S, Tasaki T, Nabeshima A, Watanabe T, Kohno K, Sasaguri Y. .  Overexpression of Peroxiredoxin 4 Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice. .  Antioxid Redox Signal 17   1362 - 1375   2012.1Reviewed

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Haruyama E, Suda M, Ayukawa Y, Kamura K, Mizutamari M, Ooshima Y, Tanimoto A. .  Testicular Development in Cynomolgus Monkeys. .  Toxicol Pathol.40   935 - 942   2012.1Reviewed

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Haruyama E, Ayukawa Y, Kamura K, Mizutamari M, Ooshima Y, Tanimoto A. .  Morphometric Examination for Development of Reproductive Organs in Male Cynomolgus Monkeys. .  Toxicol Pathol. 40   918 - 925   2012.1Reviewed

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Kawaguchi H, Yamada T, Miura N, Takahashi Y, Yoshikawa T, Izumi H, Kawarasaki T, Miyoshi N, Tanimoto A. .  Reference Values of Hematological and Biochemical Parameters for the World Smallest Microminipigs. .  J Vet Med Sci.74   933 - 936   2012.1Reviewed

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Kazuhito Hatanaka, Michiyo Higashi, Mariko Fujibayashi, Shinpei Hori, Takako Yoshioka, Yoshihisa Umekita, Akihide Tanimoto .  A case of complete hydatidiform mole in a perimenopausal woman with diagnostic usefulness of p57(kip2) immunohistochemistry and HER2 fluorescent in situ hybridization .  PATHOLOGY RESEARCH AND PRACTICE208 ( 2 ) 118 - 120   2012Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Gestational trophoblastic disease in perimenopausal women is very rare. A 53-year-old perimenopausal woman complained about amenorrhea lasting over a period of 4 months. Ultrasound showed enlargement of the uterus with a complex echogeneous area in the uterine cavity. Serum human chorionic gonadotropin was 67,611 mIU/ml. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The uterus contained hemorrhagic and fragile tumor with grape-like vesicles in the enlarged endometrial cavity. Microscopic examination revealed hydropically degenerated villi with circumferential hyperplasia of atypical trophoblast and cistern formation. p57(kip2) immnostaining was negative in villous cytotrophoblasts and stromal cells. Moreover, fluorescent in situ hybridization for HER2 was scored as diploid. These findings are consistent with complete hydatidiform mole. The diagnosis of hydatidiform mole must be considered in perimenopausal women, and the combination of p57(kip2) immunostaining and HER2 fluorescent in situ hybridization seems to be a very useful testing strategy for difficult situations regarding the differential diagnosis of completed and partial hydatidiform mole. (C) 2011 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2011.11.005

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Ka-ichiro Takeishi, Masahisa Horiuchi, Hiroaki Kawaguchi, Yoshiki Deguchi, Hiroyuki Izumi, Emi Arimura, Satoshi Kuchiiwa, Akihide Tanimoto, Toru Takeuchi .  Acupuncture Improves Sleep Conditions of Minipigs Representing Diurnal Animals through an Anatomically Similar Point to the Acupoint (GV20) Effective for Humans .  EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE2012   472982 - 472982   2012Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

Acupuncture, an alternative medicine, has been widely applied for people with sleep disturbances; therefore, the effects should be evaluated objectively. Micro-minipigs (MMPigs), the smallest miniature pigs for animal experiments, were used. Acupuncture was performed at two different points: Dafengmen is located on the head and is an anatomically similar point to human-Baihui (GV20), an effective acupoint for sleep disturbances in humans; pig-Baihui is on the back. The procedure was performed as follows: shallow, within 5 mm depth for several seconds; deep, 10-20 mm depth for 20 min. The sleep conditions were evaluated by actigraph, and the amount of catecholamine in pooled urine after acupuncture treatment. MMPigs with deep acupuncture at Dafengmen showed significantly efficient values on actigraph and catecholamine analysis as compared with untreated MMPigs. The effective acupoint for sleep conditions in the porcine model is at an anatomically similar point to humans, rather than the point determined by traditional Chinese medicine.

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Yasuyo Ohi, Yoshihisa Umekita, Takako Yoshioka, Masakazu Souda, Yoshiaki Rai, Yoshiaki Sagara, Yasuaki Sagara, Yoshiatsu Sagara, Akihide Tanimoto .  Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer .  HISTOPATHOLOGY59 ( 4 ) 776 - 780   2011.10Reviewed International journal

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Aims: Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells, and its clinical significance as a prognostic indicator of breast cancer has been reported by several investigators. However, the clinical significance of ALDH1 expression in triple-negative (TN) breast cancer, a high-risk breast cancer lacking the benefit of specific therapy, remains to be solved.
Methods and results: We performed immunohistochemical analyses of 106 TN breast cancers, using paraffin-embedded sections. The basal-like phenotype was also investigated with the use of basal cytokeratin 5/6 and epidermal growth factor receptor. ALDH1 expression in carcinoma cells was found in 59% of cases and was correlated with high histological grade alone (P &lt; 0.006), whereas ALDH1 expression in stromal cells was found in 49% of cases but was not correlated with any clinicopathological parameter. Patients with ALDH1 expression in carcinoma cells had a shorter relapse-free survival (RFS) according to the log-rank test (P = 0.015). According to Cox multivariate analysis, ALDH1 expression in carcinoma cells was an independent prognostic indicator of RFS (P = 0.025). The log-rank test revealed that stromal expression of ALDH1 had no effect on RFS.
Conclusions: ALDH1 expression in carcinoma cells is an independent prognostic factor in TN breast cancer patients.

DOI： 10.1111/j.1365-2559.2011.03884.x

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Yumi Furuno, Tsuyoshi Morishita, Yumiko Toyohira, Sohsuke Yamada, Susumu Ueno, Naoya Morisada, Kazunari Sugita, Katsuhiko Noguchi, Mayuko Sakanashi, Hironori Miyata, Akihide Tanimoto, Yasuyuki Sasaguri, Hiroaki Shimokawa, Yutaka Otsuji, Nobuyuki Yanagihara, Masahito Tamura, Masato Tsutsui .  Crucial vasculoprotective role of the whole nitric oxide synthase system in vascular lesion formation in mice: Involvement of bone marrow-derived cells .  NITRIC OXIDE-BIOLOGY AND CHEMISTRY25 ( 3 ) 350 - 359   2011.10Reviewed International journal

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Although all three nitric oxide (NO) synthases (nNOS, iNOS, and eNOS) are expressed in injured arteries, it remains to be elucidated the role of the NOSs in their entirety in the vascular lesion formation. We addressed this issue in mice deficient in all NOS genes. Vascular injury was induced by permanent ligation of a unilateral carotid artery in wild-type (WT), singly, and triply NOS(-/-) mice. Two weeks after the procedure, constrictive vascular remodeling and neointimal formation were recognized in the ligated arteries. While constrictive remodeling was noted in the nNOS(-/-) and iNOS(-/-) genotypes, it was most accelerated in the nfi/eNOS(-/-) genotype. While neointimal formation was evident in the eNOS(-/-) and nNOS(-/-) genotypes, it was also most aggravated in the n/i/eNOS(-/-) genotype. Those lesions were reversed by long-term treatment with isosorbide dinitrate, a NO donor. Finally, we examined the involvement of bone marrow-derived cells in the vascular lesion formation. Bone marrow from the WT, singly, or triply NOS(-/-) mice was transplanted into the WT mice, and then the carotid ligation was performed. Intriguingly, constrictive remodeling and neointimal formation were both similarly most exacerbated in the case of the n/i/eNOS(-/-) bone marrow transplantation. These results indicate that the complete disruption of all the NOS genes causes markedly accelerated vascular lesion formation caused by blood flow disruption in mice in vivo, demonstrating the crucial vasculoprotective role of the whole endogenous NOS system. Our findings also suggest that the NOS system in bone marrow-derived cells may be involved in this vasculoprotective mechanism. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.niox.2011.06.007

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Yoshihisa Umekita, Masakazu Souda, Kazuhito Hatanaka, Taiji Hamada, Takako Yoshioka, Hiroaki Kawaguchi, Akihide Tanimoto .  Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period .  TOXICOLOGY LETTERS205 ( 1 ) 15 - 25   2011.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Diethlstilbestrol (DES) is a synthetic estrogen prescribed to several millions of pregnant women worldwide. The risk for breast cancer after age 40 in women prenatally exposed to DES has been reported; however, the precise mechanism of susceptibility to breast cancer remains to be resolved. We investigated the global gene expression profile of terminal end buds (TEBs), the target of carcinogen, in rat mammary glands neonatally exposed to a low- or high-dose DES at postnatal days (PND) 35 and 45, equivalent to the peripubertal stage in humans. In all groups, the number of TEBs gradually increased, peaked at PND35 and decreased at PND49. At PND35 and 49, the low-dose DES-treated group (low-DES group) showed the highest number of TEBs. In the low-DES group at PND35, beta-casein, gamma-casein and whey acidic protein (WAP) mRNA expression increased 8.2-fold, 26.1-fold and 13.3-fold, respectively, whereas gamma-casein and WAP mRNA decreased 17.6-fold and 27.7-fold, respectively, at PND49. The most significant network revealed by Ingenuity Pathway Analysis (IPA) software showed the relevance of NF-kappa B in low-DES group. The present findings suggest that the deregulation of mammary gland differentiation and development-related genes could be induced and cause the increased number of terminal duct lobular units (TDLUs) in human mammary glands of DES daughters in a critical period of mammary gland development. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.toxlet.2011.04.031

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Sohsuke Yamada, Yan Ding, Akihide Tanimoto, Ke-Yong Wang, Xin Guo, Zhi Li, Takashi Tasaki, Atsunori Nabesima, Yoshitaka Murata, Shohei Shimajiri, Kimitoshi Kohno, Hidenori Ichijo, Yasuyuki Sasaguri .  Apoptosis Signal-Regulating Kinase 1 Deficiency Accelerates Hyperlipidemia-Induced Atheromatous Plaques via Suppression of Macrophage Apoptosis .  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY31 ( 7 ) 1555 - U172   2011.7Reviewed International journal

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Objective-The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis.
Methods and Results-We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1(-/-)/apoE(-/-)) and analyzed atherosclerosis in ASK1(-/-)/apoE(-/-) mice fed a high-cholesterol diet for 12 weeks. ASK1(-/-)/apoE(-/-) mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE(-/-) mice. Bone marrow transplantation from ASK1(-/-) or wild-type to apoE(-/-) mice confirmed the above observation that the recipient mice of ASK1(-/-) donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors.
Conclusion-These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development. (Arterioscler Thromb Vasc Biol. 2011; 31:1555-1564.)

DOI： 10.1161/ATVBAHA.111.227140

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Masahiro Yokouchi, Mikio Terahara, Satoshi Nagano, Yoshiya Arishima, Michihisa Zemmyo, Takako Yoshioka, Akihide Tanimoto, Setsuro Komiya .  Clinical implications of determination of safe surgical margins by using a combination of CT and 18FDG-positron emission tomography in soft tissue sarcoma .  BMC MUSCULOSKELETAL DISORDERS12   166 - 166   2011.7Reviewed International journal

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Background: To determine safe surgical margins for soft tissue sarcoma, it is essential to perform a general evaluation of the extent of tumor, responses to auxiliary therapy, and other factors preoperatively using multiple types of diagnostic imaging. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is a tool for diagnostic imaging that has recently spread rapidly in clinical use. At present, the roles played by FDG-PET/CT in determination of margins for surgical resection of sarcoma are unclear. The present study was undertaken to explore the roles of FDG-PET/CT in determination of surgical margins for soft tissue sarcoma and to examine whether PET can serve as a standard means for setting the margins of surgical resection during reduced surgery.
Methods: The study involved 7 patients with sarcoma who underwent surgery in our department and in whom evaluation with FDG-PET/CT was possible. Sarcoma was histologically rated as MFH in 6 cases and leiomyosarcoma in 1 case. In all cases, sarcoma was superficial (T1a or T2a). The tumor border was defined by contrast-enhanced MRI, and SUVs were measured at intervals of 1 cm over a 5-cm long area from the tumor border. Mapping of viable tumor cells was carried out on whole-mount sections of resected tissue, and SUVs were compared with histopathological findings.
Results: Preoperative maximum SUVs (SUV-max) of the tumor averaged 11.7 (range: 3.8-22.1). Mean SUV-max was 2.2 (range: 0.3-3.8) at 1 cm from the tumor border, 1.1 (0.85-1.47) at 2 cm, 0.83 (0.65-1.15) at 3 cm, 0.7 (0.42-0.95) at 4 cm, and 0.64 (0.45-0.82) at 5 cm. When resected tissue was mapped, tumor cells were absent in the areas where SUV-max was below 1.0.
Conclusions: Our findings suggest that a safe surgical margin free of viable tumor cells can be ensured if the SUV cut-off level is set at 1.0. FDG-PET/CT is promising as a diagnostic imaging technique for setting of safe minimal margins for surgical resection of soft tissue sarcoma.

DOI： 10.1186/1471-2474-12-166

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Ke-Yong Wang, Akihide Tanimoto, Xin Guo, Sohsuke Yamada, Shohei Shimajiri, Yoshitaka Murata, Yan Ding, Masato Tsutsui, Seiya Kato, Teruo Watanabe, Hiroshi Ohtsu, Ken-Ichi Hirano, Kimitoshi Kohno, Yasuyuki Sasaguri .  Histamine Deficiency Decreases Atherosclerosis and Inflammatory Response in Apolipoprotein E Knockout Mice Independently of Serum Cholesterol Level .  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY31 ( 4 ) 800 - U188   2011.4Reviewed International journal

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Objective-Histamine and histamine receptors are found in atherosclerotic lesions, and their signaling and subsequent proatherogenic or proinflammatory gene expression are involved in atherogenesis. In the present study, we generated apolipoprotein E (apoE) and histamine synthesizing histidine decarboxylase double knockout (DKO) mice on a C57BL/6J (wild-type mice) background to clarify the roles of histamine in atherosclerosis.
Methods and Results-Wild-type, apoE knockout (KO), and DKO mice were fed a high-cholesterol diet to analyze hyperlipidemia-induced atherosclerosis. Compared with wild-type mice, apoE-KO mice showed increased expression of histamine and its receptors, corresponding to increased atherosclerotic lesion areas and expression of inflammatory regulators, such as nuclear factor-kappa B, scavenger receptors, inflammatory cytokines, and matrix metalloproteinases. Histamine deficiency after deletion of histidine decarboxylase reduced atherosclerotic areas and expression of a range of the inflammation regulatory genes, but serum cholesterol levels of DKO mice were higher than those of apoE-KO mice.
Conclusion-These results indicate that histamine is involved in the development of atherosclerosis in apoE-KO mice by regulating gene expression of inflammatory modulators, an action that appears to be independent of serum cholesterol levels. In addition to acute inflammatory response, histamine participates in chronic inflammation, such as hyperlipidemia-induced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:800-807.)

DOI： 10.1161/ATVBAHA.110.215228

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Bin Han, Hiroto Izumi, Yoshihiro Yasuniwa, Masaki Akiyama, Takahiro Yamaguchi, Naohiro Fujimoto, Tetsuro Matsumoto, Bin Wu, Akihide Tanimoto, Yasuyuki Sasaguri, Kimitoshi Kohno .  Human mitochondrial transcription factor A functions in both nuclei and mitochondria and regulates cancer cell growth .  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS408 ( 1 ) 45 - 51   2011.4Reviewed International journal

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Mitochondrial transcription factor A (mtTFA) is one of the high mobility group protein family and is required for both transcription from and maintenance of mitochondrial genomes. However, the roles of mtTFA have not been extensively studied in cancer cells. Here, we firstly reported the nuclear localization of mtTFA. The proportion of nuclear-localized mtTFA varied among different cancer cells. Some mtTFA binds tightly to the nuclear chromatin. DNA microarray and chromatin immunoprecipitation assays showed that mtTFA can regulate the expression of nuclear genes. Overexpression of mtTFA enhanced the growth of cancer cell lines, whereas downregulation of mtTFA inhibited their growth by regulating mtTFA target genes, such as baculoviral IAP repeat-containing 5 (BIRC5; also known as survivin). Knockdown of mtTFA expression induced p21-dependent G1 cell cycle arrest. These results imply that mtTFA functions in both nuclei and mitochondria to promote cell growth. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.03.114

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畑中 一仁, 吉岡 孝子, 梅北 善久, 谷本 昭英 .  診断に苦慮した細気管支肺胞上皮癌の1例 .  診断病理28 ( 2 ) 126 - 129   2011.4

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Publisher：(一社)日本病理学会  

70代、女性。乳癌術後、右下葉に増大傾向のあるmixed-ground glass opacity陰影を認め、区域切除術を施行。組織学的には構造が保たれた肺胞上皮置換性の病変で、異型は弱く、粘液貯留や線毛を有する細胞が混在した複雑な像を認めた。免疫染色より転移は否定的で、粘液非産生性の単一な細胞の肺胞上皮置換性増殖より粘液非産生性細気管支肺胞上皮癌と診断した。粘液や線毛上皮の混在は背景の間質性変化に伴うものと考えられた。近年、末梢小型腺癌を診断する機会が増えているが、本症例のように異型が弱く、背景に間質性変化等が加わった複雑な像の場合には標本全体像の把握が重要である。(著者抄録)

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Yoshihisa Umekita, Yasuyo Ohi, Masakazu Souda, Yoshiaki Rai, Yoshiaki Sagara, Yasuaki Sagara, Shugo Tamada, Akihide Tanimoto .  Maspin expression is frequent and correlates with basal markers in triple-negative breast cancer .  DIAGNOSTIC PATHOLOGY6   36 - 36   2011.4Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Maspin is a unique member of the serine protease inhibitor superfamily and its expression is found in myoepithelial cells of normal mammary glands; therefore, it has been considered to be a myoepithelial marker. We previously reported that maspin was frequently expressed in biologically aggressive breast cancers. In turn, triple-negative (TN) breast cancer is a subtype of tumor with aggressive clinical behavior and shows frequent expression of basal markers. We hypothesized that maspin expression may be frequent and correlate with basal rather than myoepithelial markers in TN breast cancer.
Methods: Paraffin-embedded 135 TN invasive ductal carcinoma tissue samples were immunohistochemically investigated using the Dako Envision+ kit and primary antibodies for maspin, basal (CK5/6, EGFR, CK14) and myoepithelial markers (p63, CD10). The correlation between maspin expression and relapse-free survival (RFS) was investigated by the log-rank test.
Results: The positive rate for maspin was 85.9% and significantly correlated with younger age (P = 0.0015), higher histological grade (P = 0.0013), CK5/6 positivity (P &lt; 0.0001), CK14 positivity (P = 0.0034) and the basal-like subtype defined by CK5/6, EGFR and CK14 positivity (P = 0.013). The positive rates for CK5/6, EGFR, CK14, CD10 and p63 were 59.2%, 48.9%, 34.1%, 17.8% and 12.6%, respectively. There was no significant correlation between maspin expression and RFS.
Conclusions: The positive rate for maspin is the highest among known basal and myoepithelial markers, and strongly correlates with basal markers in TN breast cancer. These results suggested that maspin could be a candidate for a therapeutic target for TN breast cancer.

DOI： 10.1186/1746-1596-6-36

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Yasuyo Ohi, Yoshihisa Umekita, Yoshiaki Rai, Yasuaki Sagara, Shinichi Baba, Shugo Tamada, Yoshiaki Sagara, Taeko Kukita, Takako Yoshioka, Kazuhito Hatanaka, Yoshiatsu Sagara, Akihide Tanimoto .  Mucocele-like lesions of the breast: a long-term follow-up study .  DIAGNOSTIC PATHOLOGY6   29 - 29   2011.4Reviewed International journal

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Mucocele-like lesions (MLL) of the breast were originally described as benign lesions composed of multiple cysts lined by uniform flat to cuboidal epithelium with extravasated mucin, but subsequent reports described the coexistence of columnar cell lesions (CCL), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). Several reports have investigated whether core biopsy can diagnose MLL reliably; however, there is only one report with a long-term follow-up after excision of MLL. We report here 15 surgically excised MLL with a long-term follow-up.
Findings: Fifteen lesions diagnosed as MLL from 13 patients who had undergone excisional biopsy between January 2001 and December 2006 were retrieved and followed-up for 24-99 months (median 63.8). Two lesions were accompanied with CCL, 5 with ADH and 3 with low grade DCIS. Four lesions (2 ADH, 2 DCIS) were additionally resected and their histology revealed 2 ADH, one DCIS and one MLL with CCL. Of 4 lesions (3 ADH, one DCIS) without additional resection, one lesion (ADH) relapsed accompanied with DCIS at 37 months after excision.
Conclusions: MLL were frequently accompanied with CCL, ADH or low grade DCIS. Complete resection may be recommended in case of MLL with ADH or DCIS because of intralesional heterogeneity and the probabilities of relapse.

DOI： 10.1186/1746-1596-6-29

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Takako Yoshioka, Yoshihisa Umekita, Yasuyo Ohi, Masakazu Souda, Yoshiatsu Sagara, Yasuaki Sagara, Yoshiaki Sagara, Yoshiaki Rai, Akihide Tanimoto .  Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study .  HISTOPATHOLOGY58 ( 4 ) 608 - 616   2011.3Reviewed International journal

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Aims:
Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells. The aim was to determine the prognostic significance of ALDH1 expression in a long-term follow-up study.
Methods and results:
Immunohistochemical analyses were performed on 257 invasive ductal carcinomas (IDCs), 109 matched lymph node metastases and 190 ductal carcinomas in situ (DCISs), using paraffin-embedded sections. ALDH1 expression was found in 26% of IDCs, and correlated with larger tumour size (P = 0.007), high histological grade (P &lt; 0.001), HER2 overexpression (P &lt; 0.001) and negative hormone receptor status (P &lt; 0.001). ALDH1 expression was observed in 14% of DCISs but was not correlated with any clinicopathological parameter. The IDC patients were followed up for 7-190 months (median: 120 months), and groups with ALDH1 expression had shorter relapse-free survival (P = 0.0013) and overall survival (OS) (P = 0.0005) by log-rank test. By Cox&apos;s multivariate analysis, it had a weak effect on OS (P = 0.047), and its most significant effect on OS was observed in node-positive groups (P = 0.013). No significant differences in OS stratified by ALDH1 expression status in lymph node metastases were noted.
Conclusions:
ALDH1 expression in primary cancer is an independent prognostic factor in node-positive breast cancer patients.

DOI： 10.1111/j.1365-2559.2011.03781.x

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Hiroaki Kawaguchi, Noriaki Miyoshi, Naoki Miura, Makoto Fujiki, Masahisa Horiuchi, Yasukatsu Izumi, Hiroaki Miyajima, Ryoichi Nagata, Kazuhiro Misumi, Toru Takeuchi, Akihide Tanimoto, Hiroki Yoshida .  Microminipig, a Non-rodent Experimental Animal Optimized for Life Science Research: Novel Atherosclerosis Model Induced by High Fat and Cholesterol Diet .  JOURNAL OF PHARMACOLOGICAL SCIENCES115 ( 2 ) 115 - 121   2011.2Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

Atherosclerotic lesions were observed in male and ovariectomized female Microminipig (MMP) fed a high fat and cholesterol diet with sodium cholate (HFCD/SC) for 3 months. HFCD/SC induced hypercholesterolemia accompanied by an increase in serum total cholesterol (T-Cho), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and cholesterol ester (CE). Unlike the mouse or rabbit, a dominant LDL-C fraction in the intact M MP, similar to that in humans, was observed by serum lipoprotein analysis. HFCD/SC increased body weight gain. At the end of the experiment, computed tomography scans of conscious animals showed that HFCD/SC had decreased liver attenuation values (Hounsfield unit) and increased subcutaneous and abdominal fat, suggesting the induction of fatty liver and obesity. HFCD/SC induced atherosclerotic lesions in systemic arteries, including the external and internal iliac arteries, abdominal aorta, coronary artery, and cerebral arterial circle. Atherosclerosis and pathological findings induced by HFCD/SC in MMP were similar to those in humans. The MMP is a potentially suitable tool for investigating human atherosclerosis.

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Terahara M, Nagano S, Arishima Y, Zemmyo M, Yokouchi M, Yoshioka T, Tanimoto A, Komiya S. .  Exploration with 18F-FDG PET/CT of new ways of determination of safe surgical margins for soft tissue sarcoma. .  BMC Musculoskeletal Disorders12   166   2011.1Reviewed

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Umekita Y, Souda M, Hatanaka K, Hamda T, Yoshioka T, Kawaguchi H, Tanimoto A. .  Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period. .  Toxicol Lett. 205   15 - 25   2011.1Reviewed

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Furuno Y, Morishita T, Toyohira Y, Yamada S, Ueno S, Morisada N, Sugita K, Tanimoto A, Sasaguri Y, Shimokawa H, Otsuji Y, Yanagihara N, Tamura M, Tsutsui M. .  Crucial Vasculoprotective Role of the Whole Nitric Oxide Synthases System in Vascular Lesion Formation in Mice: Involvement of Bone Marrow-Derived Cells. .  Nitric Oxide, Biol Chem.25   350 - 359   2011.1Reviewed

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Yamada S, Ding Y, Tanimoto A, Wang KY, Guo X, Zhi Li, Murata Y, Shimajiri S, Kohno K, Ichijo H, Sasaguri Y. .  Apoptosis signal-regulating kinase 1 deficiency is an atherogenic factor in atheromatous plaques via suppressed macrophage apoptosis. .  Arterioscler Thromb Vasc Biol. 31   1555 - 1564   2011Reviewed

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Wang KY, Tanimoto A, Guo X, Yamada S, Shimajiri S, Murata Y, Ding Y, Tsutsui M, Kato S, Watanabe T, Ohtsu H, Hirano K, Kohno K, Sasaguri Y. .  Histamine deficiency decreases atherosclerosis and inflammatory response in apoE-KO mice independently on serum cholesterol level. .  Arterioscler Thromb Vasc Biol.31   800 - 807   2011Reviewed

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Yamada S, Tanimoto A, Wang KY, Ding Y, Guo X, Shimajiri S, Sasano H, Sasaguri Y. .  Non-functional adrenocortical adenoma: A unique case of combination with myelolipoma and endothelial cysts. .  Pathol Res Pract.207   192 - 196   2011Reviewed

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Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Sagara Y, SagaraY, Rai Y, Tanimoto A. .  Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study. .  Histopathology 201158   608 - 616   2011Reviewed

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Hayashi H, Narita R, Hiura M, Abe S, Tabaru A, Tanimoto A, Sasaguri Y, Harada M. .  A case of adult autoimmune hepatitis with histological features of giant cell hepatitis. .  Intern Med. 50   315 - 319   2011Reviewed

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Ohi Y, Umekita Y, Rai Y, Sagara Y, Baba S, Tamada S, Sagara Y, Kukita T, Yoshioka T, Hatanaka K, Sagara Y, Tanimoto A. .  Mucocele-like lesions of the breast: a long-term follow-up study. .  Diagn Pathol. 20116   29   2011Reviewed

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Han B, Izumi H, Yasuniwa Y, Akiyama M, Yamaguchi T, Fujimoto N, Matsumoto T, Wu B, Tanimoto A, Sasaguri Y, Kohno K. .  Human mitochondrial transcription factor A functions in both nuclei and mitochondria and regulates cancer cell growth. .  Biochem Biophys Res Commun.408   45 - 51   2011Reviewed

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Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, Sagara Y, Sagara Y, Tanimoto A. .  Aldehyde Dehydrogenase 1 Expression Predicts Poor Prognosis in Triple-Negative Breast Cancer. .  Histopathology59 ( 4 ) 776 - 780   2011Reviewed

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Umekita Y, Ohi Y, Dr, Souda M, Rai Y, Sagara Y, Sagara Y, Tamada S, Tanimoto A. .  Maspin is a better marker for basal-like subtype in triple-negative breast cancer. .  Diagn Pathol. 6   36   2011Reviewed

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Hiroki Hayashi, Ryoichi Narita, Masaaki Hiura, Shintaro Abe, Akinari Tabaru, Akihide Tanimoto, Yasuyuki Sasaguri, Masaru Harada .  A Case of Adult Autoimmune Hepatitis with Histological Features of Giant Cell Hepatitis .  INTERNAL MEDICINE50 ( 4 ) 315 - 319   2011Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Giant cell hepatitis is rare in adult patients. This form of hepatitis shows fast progression to cirrhosis. A 65-year-old woman was admitted to our hospital with jaundice. She was negative for hepatitis virus markers and positive for antinuclear antibodies. We diagnosed her as autoimmune hepatitis. Liver biopsy findings revealed typical features of interface hepatitis and giant cell hepatitis. Giant cells were positive for keratin 8/18, but not for keratin 19, keratin 7 or Ki-67. These results suggest that giant cell formation is associated with the fusion of matured hepatocytes rather than the active proliferation of immature cells.

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Terahara M, Nagano S, Arishima Y, Zemmyo M, Yokouchi M, Yoshioka T, Tanimoto A, Komiya S .  Exploration with 18F-FDG PET/CT of new ways of determination of safe surgical margins for soft tissue sarcoma. .  BMC Musculoskeletal Disorders12   166   2011Reviewed

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Kawaguchi Hiroaki, Miyoshi Noriaki, Miura Naoki, Horiuchi Masahisa, Ono Tomoji, Murakoshi Michiaki, Nishino Hoyoku, Nagata Ryoichi, Sahara Hisashi, Tanimoto Akihide, Yamada Kazuhiko, Yoshida Hiroki .  Microminipig: research models to break through cardiovascular disease .  JOURNAL OF PHARMACOLOGICAL SCIENCES115   49P   2011Reviewed

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Sohsuke Yamada, Akihide Tanimoto, Ke-Yong Wang, Yan Ding, Xin Guo, Shohei Shimajiri, Hironobu Sasano, Yasuyuki Sasaguri .  Non-functional adrenocortical adenoma: A unique case of combination with myelolipoma and endothelial cysts .  PATHOLOGY RESEARCH AND PRACTICE207 ( 3 ) 192 - 196   2011Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

A case of non-functioning adrenocortical adenoma combined with myelolipoma and endothelial cysts is reported. A 72-year-old Japanese female was noticed to have right renal and left adrenal tumors by an abdominal CT scan. At surgery, the mildly enlarged left adrenal gland contained a well-demarcated tumor. Macroscopically, it was yellowish to dark red or grayish in color, and was characterized by geographic appearance on the cut surface. Histopathological examination revealed a solid proliferation of clear or compact cells and a normal rim of adrenal gland, coexisting with vascular multiple cysts and myelolipomas. The cysts were filled with clotted blood, fibrinous material, or thrombi, and were partially lined with flattened endothelial cells with focal papillary hyperplasia, which were immunohistochemically positive for CD31 and CD34. These cystic walls were often thickened with hyalinized fibrosis and calcification, and were connected to myelolipomatous elements. To our knowledge, this is the first case report of adrenocortical adenoma associated with myelolipoma and endothelial cysts. It is probable that the extensive degeneration in adenoma might induce myelolipomatous metaplasia and cystic vascular formation. (C) 2010 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2010.07.008

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Naoya Morisada, Masayoshi Nomura, Hisae Nishii, Yumi Furuno, Mayuko Sakanashi, Ken Sabanai, Yumiko Toyohira, Susumu Ueno, Seiji Watanabe, Masahito Tamura, Tetsuro Matsumoto, Akihide Tanimoto, Yasuyuki Sasaguri, Hiroaki Shimokawa, Koichi Kusuhara, Nobuyuki Yanagihara, Akira Shirahata, Masato Tsutsui .  Complete Disruption of All Nitric Oxide Synthase Genes Causes Markedly Accelerated Renal Lesion Formation Following Unilateral Ureteral Obstruction in Mice In Vivo .  JOURNAL OF PHARMACOLOGICAL SCIENCES114 ( 4 ) 379 - 389   2010.12Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

The role of nitric oxide (NO) derived from all three NO synthases (NOSs) in renal lesion formation remains to be fully elucidated We addressed this point in mice lacking all NOSs Renal injury was induced by unilateral ureteral obstruction (UUO) UUO caused significant renal lesion formation (tubular apoptosis, interstitial fibrosis, and glomerulosclerosis) in wild-type, singly, and triply NOS-/- mice However, the extents of renal lesion formation were markedly and most accelerated in the triply NOS-/- genotype UUO also elicited the infiltration of inflammatory macrophages, up-regulation of transforming growth factor (TGF)-beta 1, and induction of epithelial mesenchymal transition (EMT) in all of the genotypes, however, the extents were again largest by far in the triply NOS-/- genotype Importantly, long-term treatment with the angiotensin II type 1 (AT(1))-receptor blocker olmesartan significantly prevented the exacerbation of those renal structural changes after UUO in the triply NOS-/- genotype, along with amelioration of the macrophage infiltration, TGF-beta 1 levels, and EMT These results provide the first evidence that the complete disruption of all NOS genes results in markedly accelerated renal lesion formation in response to UUO in mice in vivo through the AT(1)-receptor pathway, demonstrating the critical renoprotective role of all NOSs-derived NO against pathological renal remodeling

DOI： 10.1254/jphs.10143FP

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Hiroto Izumi, Tetsuro Wakasugi, Shohei Shimajiri, Akihide Tanimoto, Yasuyuki Sasaguri, Eiji Kashiwagi, Yoshihiro Yasuniwa, Masaki Akiyama, Bin Han, Ying Wu, Takeshi Uchiumi, Tokuzo Arao, Kazuto Nishio, Ryuta Yamazaki, Kimitoshi Kohno .  Role of ZNF143 in tumor growth through transcriptional regulation of DNA replication and cell-cycle-associated genes .  CANCER SCIENCE101 ( 12 ) 2538 - 2545   2010.12Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

The cell cycle is strictly regulated by numerous mechanisms to ensure cell division. The transcriptional regulation of cell-cycle-related genes is poorly understood, with the exception of the E2F family that governs the cell cycle. Here, we show that a transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-associated genes and is highly expressed in multiple solid tumors. RNA-interference (RNAi)-mediated knockdown of ZNF143 showed that expression of 152 genes was downregulated in human prostate cancer PC3 cells. Among these ZNF143 targets, 41 genes (27%) were associated with cell cycle and DNA replication including cell division cycle 6 homolog (CDC6), polo-like kinase 1 (PLK1) and minichromosome maintenance complex component (MCM) DNA replication proteins. Furthermore, RNAi of ZNF143 induced apoptosis following G2/M cell cycle arrest. Cell growth of 10 lung cancer cell lines was significantly correlated with cellular expression of ZNF143. Our data suggest that ZNF143 might be a master regulator of the cell cycle. Our findings also indicate that ZNF143 is a member of the growing list of non-oncogenes that are promising cancer drug targets. (Cancer Sci 2010; 101: 2538-2545).

DOI： 10.1111/j.1349-7006.2010.01725.x

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Kiyoko Shibata, Yasuko Yatera, Yumi Furuno, Ken Sabanai, Naoya Morisada, Sei Nakata, Tsuyoshi Morishita, Fumio Yamazaki, Akihide Tanimoto, Yasuyuki Sasaguri, Hiromi Tasaki, Yasuhide Nakashima, Hiroaki Shimokawa, Nobuyuki Yanagihara, Yutaka Otsuji, Masato Tsutsui .  Spontaneous Development of Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthases .  CIRCULATION JOURNAL74 ( 12 ) 2681 - 2692   2010.12Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 NOS genes.
Methods and Results: Morphological, echocardiographic, and hemodynamic analyses were performed in wildtype (WT), singly nNOS(-/-), iNOS-1-, eNOS(-/-), and triply n/i/eNOS(-/-) mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS(-/-) mice and to a lesser extent in eNOS(-/-) mice, but not in nNOS(-/-) or iNOS(-/-) mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic -dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS(-/-) mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT(1)) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS(-/-) mice.
Conclusions: These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT(1) receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis. (Cur J 2010; 74: 2681-2692)

DOI： 10.1253/circj.CJ-10-0277

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Yuriz Bakhtiar, Kazunori Arita, Hirofumi Hirano, Mika Habu, Shingo Fujio, Shinichi Kitajima, Akihide Tanimoto .  Prolactin-Producing Pituitary Adenoma With Abundant Spherical Amyloid Deposition Masquerading as Extensive Calcification -Case Report- .  NEUROLOGIA MEDICO-CHIRURGICA50 ( 11 ) 1023 - 1026   2010.11Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN NEUROSURGICAL SOC  

A 53-year-old male presented with a case of prolactin-producing pituitary adenoma with abundant spherical amylo id depositions masquerading as extensive calcification and manifesting as visual disturbance Computed tomography revealed a large high density mass suggesting calcified tumor in the intra- and supra seller regions Magnetic resonance imaging revealed a heterogeneously enhanced large pituitary tumor reaching lateral ventricle Blood prolactin level was elevated to 5971 ng/ml Cabergoline treatment for 3 months provided considerable shrinkage of the tumor but failed to improve the visual symptoms Transcranial surgery revealed that the tumor was fibrous and included abundant grayish translucent spherical granules with diameter of 0 5-1 5 mm Immunohistochemically, the tumor was strongly positive for prolactin Congo red stain and polarized light showed that these spherical bodies were amyloid depositions No calcification was noted

DOI： 10.2176/nmc.50.1023

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Yan Ding, Sohsuke Yamada, Ke-Yong Wang, Shohei Shimajiri, Xin Guo, Akihide Tanimoto, Yoshitaka Murata, Shuji Kitajima, Teruo Watanabe, Hiroto Izumi, Kimitoshi Kohno, Yasuyuki Sasaguri .  Overexpression of Peroxiredoxin 4 Protects Against High-Dose Streptozotocin-Induced Diabetes by Suppressing Oxidative Stress and Cytokines in Transgenic Mice .  ANTIOXIDANTS & REDOX SIGNALING13 ( 10 ) 1477 - 1490   2010.11Reviewed International journal

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Peroxiredoxin 4 (PRDX4) is one of a newly discovered family of antioxidative proteins. We generated human PRDX4 (hPRDX4) transgenic (Tg) mice, displaying a high level of hPRDX4 expression in the pancreatic islets, and then focused on the functions of PRDX4 in a type 1 diabetes mellitus (T1DM) model using a single high dose of streptozotocin (SHDS). After SHDS-injection, Tg mice showed significantly less hyperglycemia and hypoinsulinemia and a much faster response on glucose tolerance test than wild-type (WT) mice. Morphologic and immunohistochemical observation revealed that the pancreatic islet areas of Tg mice were larger along with less CD3-positive lymphocyte infiltration compared with WT mice. Upon comparison between these two mouse models, beta-cell apoptosis was also repressed, and reversely, beta-cell proliferation was enhanced in Tg mice. Real-time RT-PCR demonstrated that the expression of many inflammatory-related molecules and their receptors and transcription factors were significantly downregulated in Tg mice. These data indicate that PRDX4 can protect pancreatic islet beta-cells against injury caused by SHDS-induced insulitis, which strongly suggests that oxidative stress plays an essential role in SHDS-induced diabetes. This study, for the first time, implicates that PRDX4 has a pivotal protective function against diabetes progression in this T1DM model. Antioxid. Redox Signal. 13, 1477-1490.

DOI： 10.1089/ars.2010.3137

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Michihisa Zenmyo, Akihide Tanimoto, Harutoshi Sakakima, Masahiro Yokouchi, Satoshi Nagano, Takuya Yamamoto, Yasuhiro Ishido, Setsuro Komiya, Kosei Ijiri .  Gadd45 beta expression in chondrosarcoma: A pilot study for diagnostic and biological implications in histological grading .  DIAGNOSTIC PATHOLOGY5   69 - 69   2010.10Reviewed International journal

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Background: Although the diagnosis of chondrosarcoma, especially the distinction between enchondroma and low-grade chondrosarcoma or low-grade chondrosarcoma and high-grade chondrosarcoma, is pathologically difficult, differential diagnosis is very important because the treatment strategies for these diseases are completely different. The grading system is crucial in predicting biologic behavior and prognosis, however, exact pathological grading is difficult using only routine examinations because the criteria of the grading system are not necessarily definitive. Growth arrest and DNA damage-inducible protein 45 beta (GADD45 beta) is an essential molecule for chondrocytes during terminal differentiation. In the present study, we investigated the immunohistochemical expression of GADD45 beta in enchondroma, and chondrosarcoma of histological grades I, II, and III, to clarify the diagnostic significance of GADD45 beta in pathological grading of chondrosarcoma.
Methods: Twenty samples (enchondroma = 6, chondrosarcoma grade I = 7, grade II = 6, grade III = 1) were used for immunohistochemical analysis to investigate the expression of GADD45 beta. Quantitative analysis was performed to compare the number of GADD45 beta positive cells and pathological grading.
Results: Over 70% of the cells in enchondromas expressed GADD45 beta. On the other hand, the expression of GADD45 beta decreased significantly according to the histological grade of chondrosarcoma (grade I: 45%; grade II: 13.8%; and grade III: 3.8%).
Conclusions: The association of GADD45 beta expression and pathological grading of chondrosarcoma in the present study suggests that the immunohistochemical study of GADD45 beta may be a specific diagnostic parameter for chondrosarcoma cell differentiation.

DOI： 10.1186/1746-1596-5-69

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Michihisa Zenmyo, Yasuhiro Ishido, Mikio Terahara, Takuya Yamamoto, Akihide Tanimoto, Setsuro Komiya, Kosei Ijiri .  Intramedullary Subependymoma of the Cervical Spinal Cord: A Case Report with lmmunohistochemical Study .  INTERNATIONAL JOURNAL OF NEUROSCIENCE120 ( 10 ) 676 - 679   2010.10Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Spinal subependymomas, which have a relatively benign nature, are very rare tumors. It is difficult to distinguish spinal subependymomas from other intramedullary spinal tumors based on neuroradiological findings. A case of cervical intramedullary subependymoma in a 63-year-old female is reported. The diffused enlargement of the spinal cord at C2 level involved the lesion with isointensity on a T1-weighted MRI and relatively high intensity on a T2-weighted MRI. Enhancement in the small part of the tumor was observed on a T1-weighted MRI with gadolinium administration. The tumor occupied the left side of the spinal cord, and was totally removed through a laminoplasty of C2. Immunohistochemistry was useful for pathological diagnosis. The clinical feature of this patient is described with the review of literatures.

DOI： 10.3109/00207454.2010.509894

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Noriaki Miyoshi, Masahisa Horiuchi, Yoshinori Inokuchi, Yoko Miyamoto, Naoki Miura, Satatoshi Tokunaga, Makoto Fujiki, Yasukatsu Izumi, Hiroaki Miyajima, Ryoichi Nagata, Kazuhiro Misumi, Toru Takeuchi, Akihide Tanimoto, Nobuhiro Yasuda, Hiroki Yoshida, Hiroaki Kawaguchi .  Novel Microminipig Model of Atherosclerosis by High Fat and High Cholesterol Diet, Established in Japan .  IN VIVO24 ( 5 ) 671 - 680   2010.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Novel atherosclerotic lesions were induced in the Microminipig (MMP, registered with the Japanese Ministry of Agriculture, Forestry and Fisheries as a novel variety of swine), the smallest pig available for experimental use, by feeding a high fat (12%) and high cholesterol (5%) diet (HFCD) with sodium cholate (SC, 0.7%) (HFCD/SC) for three months. Three MMPs were used: a male fed with normal diet (M-ND), and a male and an ovariectomized female fed with HFCD/SC (M-HFCD/SC and Fx-HFCD/SC). HFCD/SC induced hypercholesterolemia accompanied by an increase in serum total cholesterol (T-Cho), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and cholesterol ester (CE) from the first week. Serum levels of T-Cho, LDL-C and CE reached a maximum in two to three weeks, and HDL-C gradually increased during the experimental period (duration). Serum lipoprotein analysis showed a dominant LDL-C fraction, as seen in humans, in all three MMPs. Body weight gain in the MMPs fed with HFCD/SC was greater than in the animal fed with M-ND. At the end of the experiment, computed tomography scans of conscious animals showed increases in subcutaneous and abdominal fat in those fed with HFCD/SC, suggesting the induction of obesity. Atherosclerotic lesions in systemic arteries (including external and internal iliac arteries, abdominal aorta, coronary artery, cerebral arterial circle), fatty changes, and foamy cell infiltration in the liver and spleen were histopathologically observed in the MMPs fed with HFCD/SC. Atherosclerosis and the pathological findings induced by HFCD/SC in MMPs were similar to the pathological changes associated with human atherosclerosis, suggesting that the MMP has the potential to be a suitable animal model for human atherosclerosis.

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Yasuko Yatera, Kiyoko Shibata, Yumi Furuno, Ken Sabanai, Naoya Morisada, Sei Nakata, Tsuyoshi Morishita, Yumiko Toyohira, Ke-Yong Wang, Akihide Tanimoto, Yasuyuki Sasaguri, Hiromi Tasaki, Yasuhide Nakashima, Hiroaki Shimokawa, Nobuyuki Yanagihara, Yutaka Otsuji, Masato Tsutsui .  Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet .  CARDIOVASCULAR RESEARCH87 ( 4 ) 675 - 682   2010.9Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The precise role of the nitric oxide synthase (NOS) system in lipid metabolism remains to be elucidated. We addressed this point in mice that we have recently developed and that lack all three NOS isoforms.
Wild-type (WT), singly, doubly, and triply NOS(-/-) mice were fed either a regular or high-cholesterol diet for 3-5 months. The high-cholesterol diet significantly increased serum low-density lipoprotein (LDL) cholesterol levels in all the genotypes when compared with the regular diet. Importantly, when compared with the WT genotype, the serum LDL cholesterol levels in the high-cholesterol diet were significantly and markedly elevated only in the triply NOS(-/-) genotype, but not in any singly or doubly NOS(-/-) genotypes, and this was associated with remarkable atherosclerosis and sudden cardiac death, which occurred mainly in the 4-5 months after the high-cholesterol diet. Finally, hepatic LDL receptor expression was markedly reduced only in the triply NOS(-/-) genotype, accounting for the diet-induced dyslipidaemia in the genotype.
These results provide the first direct evidence that complete disruption of all NOS genes causes severe dyslipidaemia, atherosclerosis, and sudden cardiac death in response to a high-fat diet in mice in vivo through the down-regulation of the hepatic LDL receptor, demonstrating the critical role of the whole endogenous NOS system in maintaining lipid homeostasis.

DOI： 10.1093/cvr/cvq092

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Noriaki Miyoshi, Masahisa Horiuchi, Yoshinori Inokuchi, Yoko Miyamoto, Naoki Miura, Satatoshi Tokunaga, Makoto Fujiki, Yasukatsu Izumi, Hiroaki Miyajima, Ryoichi Nagata, Kazuhiro Misumi, Toru Takeuchi, Akihide Tanimoto, Nobuhiro Yasuda, Hiroki Yoshida, Hiroaki Kawaguchi .  Novel Microminipig Model of Atherosclerosis by High Fat and High Cholesterol Diet, Established in Japan .  IN VIVO24 ( 5 ) 671 - 680   2010.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Novel atherosclerotic lesions were induced in the Microminipig (MMP, registered with the Japanese Ministry of Agriculture, Forestry and Fisheries as a novel variety of swine), the smallest pig available for experimental use, by feeding a high fat (12%) and high cholesterol (5%) diet (HFCD) with sodium cholate (SC, 0.7%) (HFCD/SC) for three months. Three MMPs were used: a male fed with normal diet (M-ND), and a male and an ovariectomized female fed with HFCD/SC (M-HFCD/SC and Fx-HFCD/SC). HFCD/SC induced hypercholesterolemia accompanied by an increase in serum total cholesterol (T-Cho), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and cholesterol ester (CE) from the first week. Serum levels of T-Cho, LDL-C and CE reached a maximum in two to three weeks, and HDL-C gradually increased during the experimental period (duration). Serum lipoprotein analysis showed a dominant LDL-C fraction, as seen in humans, in all three MMPs. Body weight gain in the MMPs fed with HFCD/SC was greater than in the animal fed with M-ND. At the end of the experiment, computed tomography scans of conscious animals showed increases in subcutaneous and abdominal fat in those fed with HFCD/SC, suggesting the induction of obesity. Atherosclerotic lesions in systemic arteries (including external and internal iliac arteries, abdominal aorta, coronary artery, cerebral arterial circle), fatty changes, and foamy cell infiltration in the liver and spleen were histopathologically observed in the MMPs fed with HFCD/SC. Atherosclerosis and the pathological findings induced by HFCD/SC in MMPs were similar to the pathological changes associated with human atherosclerosis, suggesting that the MMP has the potential to be a suitable animal model for human atherosclerosis.

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Ke-Yong Wang, Akihide Tanimoto, Sohsuke Yamada, Xin Guo, Yan Ding, Teruo Watanabe, Takeshi Watanabe, Kimitoshi Kohno, Ken-Ichi Hirano, Hideo Tsukada, Yasuyuki Sasaguri .  Histamine Regulation in Glucose and Lipid Metabolism via Histamine Receptors Model for Nonalcoholic Steatohepatitis in Mice .  AMERICAN JOURNAL OF PATHOLOGY177 ( 2 ) 713 - 723   2010.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-D-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH. (Am J Pathol 2010, 177:713-723; DOI: 10.2353/ajpath.2010.091198)

DOI： 10.2353/ajpath.2010.091198

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Yusuke Matsuura, Mitsuyasu Kitajima, Toru Hachisuga, Akihide Tanimoto, Naohumi Okura, Ikuo Kihara .  Malignant mixed mullerian tumor with malignant neuroectodermal components (teratoid carcinosarcoma) of the ovary: Report of a case with clinicopathologic findings .  JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH36 ( 4 ) 907 - 911   2010.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Malignant mixed mullerian tumor (MMMT) or carcinosarcoma of the female genital tract is a rare neoplasm. Malignant ovarian tumor composed of mullerian epithelial tumor and malignant germ cell tumor is also rare, with most cases composed of endometrioid adenocarcinoma and yolk sac tumor. Ovarian MMMT with malignant neuroectodermal components resembling immature teratoma is extremely rare. We report a case of teratoid carcinosarcoma of the ovary occurring in a 40-year-old female. The resected tumor measuring over 20 cm in diameter consisted of cystic and solid components and was very fragile. Microscopic examination showed a heterogenous mixed tumor composed of malignant epithelial, malignant mesodermal and malignant neuroectodermal components. The cells of ganglioneuroblastoma-like area were positive for neural markers (Synaptophysin, S-100 protein, neuron-specific enolase). There was no tumor immunoreactivity to alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin, and inhibin. In spite of aggressive combination chemotherapy and three times of laparotomy, the patient died of disease 3 years 10 months after the initial treatment. This quite rare ovarian tumor closely resembled nasopharyngeal tumors described as &apos;teratoid carcinosarcoma&apos; is biologically aggressive. We report the fourth case of ovarian teratoid carcinosarcoma. Further cases need to be accumulated to make diagnosis and to determine a successful treatment modality.

DOI： 10.1111/j.1447-0756.2010.01238.x

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王 克よう, 谷本 昭英, 笹栗 靖之 .  細胞外マトリックスと動脈硬化 .  産業医科大学雑誌32 ( 2 ) 195 - 203   2010.6

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Publisher：産業医科大学  

動脈壁の細胞外マトリックスは、主に血管平滑筋細胞から作られる。動脈硬化病変においては、とくにI、III、IV、V、VIII型コラーゲンとエラスチンの高発現が確認されている。細胞外マトリックス分解に中心的役割を果たす酵素としてマトリックスメタロプロテアーゼ(matrix metalloproteinase;MMP)が知られており、動脈硬化の発症と進展、動脈瘤の発生と破裂、粥腫の不安定性などにMMPは関連している。MMP1、2、3、7、9、12、MT1-MMPなど多くのMMPが動脈脈壁に発現しており、主たるMMPの産生細胞は血管平滑筋細胞と動脈硬化病変に浸潤したマクロファージである。本総説では動脈硬化病変と細胞外マトリックスおよびその分解酵素でありMMPの関連について詳述する。(著者抄録)

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Kazuhito Hatanaka, Akihide Tanimoto, Yoshihisa Umekita, Takako Yoshioka, Takuro Kanekura .  Unusual anogenital apocrine tumor resembling mammary-like gland adenoma in male perineum: a case report .  DIAGNOSTIC PATHOLOGY5   42 - 42   2010.6Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

A rare case of an apocrine tumor in the male perineal region is reported. A dermal cystic lesion developed in the region between the anus and scrotum of a 74-year-old Japanese male. The cystic lesion, measuring 3.5 x 5.0 cm in size, was lined by columnar or flattened epithelium with occasional apocrine features and supported by a basal myoepithelium lining. A mural nodule, measuring 1 x 1.5 cm in size, protruded into the cystic space and consisted of a solid proliferation of tubular glands with prominent apocrine secretion and basal myoepithelial cells. Immunohistochemical examination showed that the luminal cells were partially positive for gross cystic disease fluid protein 15 and human milk fat globulin 1, and the basal myoepithelial cells were positive for alpha-smooth muscle actin and S-100 protein. Estrogen and progesterone hormone receptors were focally and weakly positive for luminal epithelium. Although no mammary-like glands were present in the dermis around the tumor, this unusual apocrine tumor has been suggested to be derived from male anogenital mammary-like glands and mimic a mammary-like gland adenoma in the male perineum.

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Takako Yoshioka, Mizue Harada, Yoshihisa Umekita, Shuhei Taguchi, Michiyo Higashi, Daisuke Nakamura, Shinsuke Suzuki, Akihide Tanimoto .  Necrotizing sialometaplasia of the parotid gland associated with angiocentric T-cell lymphoma: A case report and review of the Literature .  PATHOLOGY INTERNATIONAL60 ( 4 ) 326 - 329   2010.4Reviewed International journal

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

A very rare case of necrotizing sialometaplasia of the parotid gland associated with angiocentric T-cell lymphoma was described. A 66-year-old male had left neck and pharyngeal masses and biopsy specimen showed a monotonous proliferation of atypical lymphoid cells with massive necrosis in the parotid gland. Angiocentric pattern or vascular invasion by the lymphoid cells was observed and the involved parotid gland exhibited squamous metaplasia of the ducts and acini; necrotizing sialometaplasia. Immunohistochemical analysis revealed a cytotoxic T-cell phenotype of the lymphoid cells (CD3+, CD4-, CD5+, CD8+, CD56-, Granzyme B+, TIA-1+, Perforin-) but in situ hybridization showed no relation to Epstein-Barr virus. Although necrotizing sialometaplasia is relatively rare in the parotid gland, angiocentric T-cell lymphoma should be considered for a causative condition of necrotizing sialometaplasia.

DOI： 10.1111/j.1440-1827.2010.02518.x

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王 克よう, 谷本 昭英, 笹栗 靖之 .  動脈硬化病変におけるヒスタミンの役割 .  産業医科大学雑誌32 ( 1 ) 63 - 71   2010.3

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ヒスタミンは、ヒスチジン脱炭酸酵素によってL-ヒスチジンから合成され、炎症、アレルギー、胃酸分泌、神経伝達といった生体反応を調節する生体アミンである。動脈硬化病変では、マクロファージ由来の泡沫細胞から産生されたヒスタミンは、血管平滑筋、血管内皮、炎症細胞に特異的ヒスタミン受容体を介して作用し、炎症反応に関わる多くの分子の発現を調節している。動脈硬化病変の形成と進展には、ヒスタミンネットワークによる慢性炎症反応の制御システムが関与している。(著者抄録)

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Morisada N, Nomura M, Nishii H, Furuno Y, Sakanashi M, Sabanai K, Toyohira Y, Ueno S, Watanabe S, Tamura M, Matsumoto T, Tanimoto A, Sasaguri Y, Shimokawa H, Kusuhara K, Yanagihara N, Shirahata A, Tsutsui M. .  Complete Disruption of All Nitric Oxide Synthase Genes Causes Markedly Accelerated Renal Lesion Formation Following Unilateral Ureteral Obstruction in Mice In Vivo. .  J Pharmacol Sci.114   379 - 389   2010Reviewed

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Yoshioka T, Harada M, Umekita Y, Taguchi S, Higashi M, Nakamura D, Suzuki S, Tanimoto A. .  Necrotizing sialometaplasia of the parotid gland associated with angiocentric T-cell lymphoma: a case report and review of the literature. .  Pathol Int.60   326 - 329   2010Reviewed

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Hatanaka K, Tanimoto A, Umekita Y, Yoshioka T, Kanekura T. .  Unusual anogenital apocrine tumor resembling mammary-like gland adenoma in male perineum: a case report. .  Diagn Pathol.5   42   2010Reviewed

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Matsuura Y, Kitajima M, Hachisuga T, Tanimoto A, Okura N, Kihara I. .  Malignant mixed mullerian tumor with malignant neuroectodermal components (teratoid carcinosarcoma) of the ovary: Report of a case with clinicopathologic findings. .  J Obstet Gynaecol Res.36   907 - 911   2010Reviewed

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Zenmyo M, Tanimoto A, Sakakima H, Yokouchi M, Nagano S, Yamamoto T, Ishido Y, Komiya S, Ijiri K. .  Gadd45beta expression in chondrosarcoma: A pilot study for diagnostic and biological implications in histological grading. .  Diagn Pathol.13   69   2010Reviewed

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Zenmyo M, Ishido Y, Terahara M, Yamamoto T, Tanimoto A, Komiya S, Ijiri K. .  Intramedullary subependymoma of the cervical spinal cord: a case report with immunohistochemical study. .  Int J Neurosci.120   676 - 679   2010Reviewed

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Bakhtiar Y, Arita K, Hirano H, Habu M, Fujio S, Kitajima S, Tanimoto A. 2010, 50: 1023-1026 .  Prolactin-producing pituitary adenoma with abundant spherical amyloid deposition masquerading as extensive calcification. .  Neurol Med Chir (Tokyo). 50   1023 - 1026   2010Reviewed

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Yatera Y, Shibata K, Furuno Y, Sabanai K, Morisada N, Nakata S, Morishita T, Toyohira Y, Wang KY, Tanimoto A, Sasaguri Y, Tasaki H, Nakashima Y, Shimokawa H, Yanagihara N, Otsuji Y, Tsutsui M. .  Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet. .  Cardiovasc Res.87   675 - 682   2010Reviewed

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Ding Y, Yamada S, Wang KY, Shimajiri S, Guo X, Tanimoto A, Murata Y, Kitajima S, Watanabe T, Izumi H, Kohno K, Sasaguri Y. .  Overexpression of Peroxiredoxin 4 Protects Against High-Dose Streptozotocin-Induced Diabetes by Suppressing Oxidative Stress and Cytokines in Transgenic mice. .  Antioxid Redox Signal13   1477 - 1490   2010Reviewed

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Wang KY*, Tanimoto A* (*equal contribution), Yamada S, Guo X, Ding Y, Watanabe T, Watanabe T, Kohno K, Hirano KI, Tsukada H, Sasaguri Y. .  Histamine Regulation in Glucose and Lipid Metabolism via Histamine Receptors. Model for Nonalcoholic Steatohepatitis in Mice. .  Am J Pathol. 2010177   713 - 723   2010Reviewed

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Izumi H, Wakasugi T, Shimajiri S, Tanimoto A, Sasaguri Y, Kashiwagi E, Yasuniwa Y, Akiyama M, Han B, Wu Y, Uchiumi T, Arao T, Nishio K, Yamazaki R, Kohno K. .  Role of ZNF143 in tumor growth through transcriptional regulation of DNAreplication and cell-cycle-associated genes. .  Cancer Sci.101   2538 - 2545   2010Reviewed

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Miyoshi N, Horiuchi M, Inokuchi Y, Miyamoto Y, Miura N, Tokunaga S, Fujiki M, Izumi Y, Miyajima H, Nagata R, Misumi K, Takeuchi T, Tanimoto A, Yasuda N, Yoshida H, Kawaguchi H. .  Novel microminipig model of atherosclerosis by high fat and high cholesterol diet, established in Japan. .  In Vivo.24   671 - 680   2010Reviewed

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Shibata K, Yatera Y, Furuno Y, Sabanai K, Morisada N, Nakata S, Morishita T, Yamazaki F, Tanimoto A, Sasaguri Y, Tasaki H, Nakashima Y, Shimokawa H, Yanagihara N, Otsuji Y, Tsutsui M. .  Spontaneous Development of Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthases. .  Circ J.74   2681 - 2692   2010Reviewed

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Ke-Yong Wang, Akihide Tanimoto, Yasuyuki Sasaguri .  Extracellular matrix and atherosclerosis .  Journal of UOEH32 ( 2 ) 195 - 203   2010Reviewed

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：University of Occupational and Environmental Health  

Many kinds of extracellular matrixes (ECMs) are mainly produced by smooth muscle cells (SMC) in both normal arterial walls and atherosclerotic lesions. In particular, type I, III, IV, V, and VIII collagens and elastin are highly expressed in atherosclerotic lesions. The matrix metalloproteinases (MMPs) constitute multigene family enzymes and play a central role in the degradation of ECM components. The expression of MMPs is related to atherosclerotic formation. The MMPs produced by SMC and macrophages are MMP-1, 2, 3, 7, 9 and 12 in the arterial wall, and have their highest expression in atherosclerotic lesions. This review focuses on recent work on matrix metalloproteinases and extracellular matrixes in relation to atherosclerosis.

DOI： 10.7888/juoeh.32.195

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Ke-Yong Wang, Akihide Tanimoto, Yasuyuki Sasaguri .  Role of histamine in atherosclerotic lesions .  Journal of UOEH32 ( 1 ) 63 - 71   2010Reviewed

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：University of Occupational and Environmental Health  

Histamine is synthesized from L-histidine by histidine decarboxylase and is involved in a variety of physiologic responses, such as inflammation, type I allergy, gastric acid secretion and neurotransmission. In the arteriosclerotic lesions, histamine produced by macrophage-derived foam cells acts on smooth muscle cells, endocrine cells and inflammation cells through the specific histamine receptors and regulates the expression of many molecules concerned with inflammatory reaction. A regulatory system of chronic inflammatory reaction by the histamine network is involved in the formation and development of arteriosclerosis.

DOI： 10.7888/juoeh.32.63

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王 克よう, 谷本 昭英, 稲永 隆, 山田 壮亮, 島尻 正平, 丁 妍, 郭 きん, 笹栗 靖之 .  大動脈弁狭窄症による慢性心不全患者にみられた肺毛細血管腫症の1剖検例(Pulmonary Capillary Hemangiomatosis In Chronic Cardiac Failure due to Aortic Stenosis) .  産業医科大学雑誌31 ( 4 ) 339 - 344   2009.12Reviewed

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我々は大動脈弁狭窄症を伴った肺毛細血管腫症の1剖検例を経験したので報告する。症例は86歳日本人女性、大動脈弁狭窄症による慢性心不全にて血液透析を施行中に、突然死となった。剖検すると、大動脈弁の高度な狭窄と、両心室壁の肥厚を伴った高度な心肥大とが認められた。肺の病理組織学的所見では、ヘモジデリンを貪食した肺胞内マクロファージの集簇を伴って、肥厚した肺胞壁における毛細血管のびまん性増生が認められ、肺毛細血管腫症に一致する像であった。以上より当症例は、大動脈弁狭窄症により長期間慢性的に持続した肺うっ血が、肺毛細血管腫症を引き起こしたものと考えられた。(著者抄録)

DOI： 10.7888/juoeh.31.339

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大井 恭代, 雷 哲明, 久木田 妙子, 相良 安昭, 相良 吉昭, 馬場 信一, 玉田 修吾, 松山 義人, 佐々木 道朗, 土持 進作, 安藤 充嶽, 相良 吉厚, 吉田 愛知, 梅北 善久, 谷本 昭英 .  非触知乳癌の臨床病理学的特徴 .  乳癌の臨床24 ( 6 ) 762 - 763   2009.12Reviewed

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Language：Japanese   Publisher：(株)篠原出版新社  

2003年5月〜2008年12月に根治手術を施行した非触知乳癌330例(全乳癌の12.6%)を対象に臨床病理学的特徴を検討した。MMG石灰化症例120例の確定診断は、生検組織診が77例、穿刺吸引細胞診が43例で、comedo typeでは穿刺吸引細胞診が有用であった。また、ステレオガイド下切除生検から低侵襲のマンモトーム吸引式針生検への移行がみられ、症例数は増加傾向であった。MMG/US mass症例127例は、非浸潤癌あるいは浸潤径の小さな浸潤癌が92例で、穿刺吸引細胞診は122例に施行され、不適率は4.1%、91.5%を悪性もしくは悪性疑いと診断しえた。鑑別困難例が7.7%あり、すべて低異型度癌であった。US massのみの症例86例の病理学的特徴は、MMG/US massとほぼ同様であった。乳頭分泌を発現契機とする症例43例は、23例がneuroendocrine differentiationを示し、同時期の非浸潤性乳管癌全体と比較して有意に高い傾向であった。pT2以上の症例は、3例が乳頭腺管癌、2例が浸潤性小葉癌であった。浸潤性小葉癌は穿刺吸引細胞診においてごく少数の小型異型細胞を認めるのみであった。非触知乳癌は画像所見や症状により病理学的特徴を有しており、それらを考慮することで、診断効率・精度の向上が期待できると思われた。

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Sohsuke Yamada, Akihide Tanimoto, Ke-Yong Wang, Shohei Shimajiri, Yasuyuki Sasaguri .  Stromal luteoma and nodular hyperthecosis of the bilateral ovaries associated with atypical endometrial hyperplasia of the uterus .  PATHOLOGY INTERNATIONAL59 ( 11 ) 831 - 833   2009.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

DOI： 10.1111/j.1440-1827.2009.02454.x

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Sohsuke Yamada, Akihide Tanimoto, Yasumasa Matsuki, Yuji Hisada, Yasuyuki Sasaguri .  Sclerosing encapsulating peritonitis (abdominal cocoon) associated with liver cirrhosis and diffuse large B-cell lymphoma: Autopsy case .  PATHOLOGY INTERNATIONAL59 ( 9 ) 681 - 686   2009.9Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

A case of sclerosing encapsulating peritonitis (SEP) associated with liver cirrhosis (LC) and complicated by diffuse large B-cell lymphoma (DLBCL) is reported herein. A 49-year-old Japanese man had undergone peritoneo-venous shunt against refractory ascites due to hepatitis C virus-positive uncompensated LC for 2 years. After he received a diagnosis of DLBCL of the left neck lymph node 3 months before his death, palliative care was given because of his poor general condition. He developed severe abdominal distention and pain over 1 week and was found to have marked ascites and whole bowel lumped together on abdominal CT. At autopsy, the peritoneum was covered with a thick white membrane and the bowel could not be distinguished, which was macroscopically characterized by a cocoon-like appearance. Histology indicated a proliferation of diffusely thickened or hyalinized fibrocollagenous tissue in the entire peritoneum with a slight chronic inflammatory infiltrate and without remarkable change of mucosa. A diagnosis of SEP, also known as abdominal cocoon, was established based on these features. Additionally, in the abdominal cavity, a large amount of serous ascites and multiple peritoneal nodules or masses involved by DLBCL were recognized. To the authors' knowledge this is the first case report of SEP associated with LC and complicated by the invasion of DLBCL in the abdominal cavity.

DOI： 10.1111/j.1440-1827.2009.02427.x

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林 海輝, 成田 竜一, 日浦 政明, 阿部 慎太郎, 田原 章成, 原田 大, 谷本 昭英, 笹栗 靖之 .  Giant cell hepatitisの組織像を呈した自己免疫性肝炎の1例 .  臨牀と研究86 ( 7 ) 945 - 946   2009.7

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石原 善三郎, 大西 英生, 戸羽 直樹, 中村 利孝, 青木 隆敏, 谷本 昭英 .  脛骨骨幹端から骨端に進展したBrodie骨膿瘍の1例 .  整形・災害外科52 ( 7 ) 923 - 927   2009.6

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Publisher：金原出版(株)  

17歳男。2年前に誘因なく右足関節痛が出現し、前医でのX線で骨嚢胞性疾患を指摘されたが、疼痛が消失したため放置していた。今回、再び疼痛が出現し、MRIで内部がT1強調像で低信号、T2強調像で高信号を示す嚢胞性病変を認め、特に病変部に4層構造(病巣中心のT1強調像での低信号域、病巣内壁のT1強調像でのリング状高信号域、病巣外壁のT2強調像でのリング状低信号域、病巣外壁周辺のT1強調像での低信号域)を認めた。また、CTの矢状断像で骨幹端部から骨端軟骨下骨まで進展した病巣を認め、横断像で病巣部のfistulaを認めた。Brodie骨腫瘍と診断し、病巣の掻爬および洗浄術を施行し、術後はセフェム系抗生剤を3ヵ月間経口投与した。経過は良好で、術後2年2ヵ月経過した現在、再発は認めていない。

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Masaki Shiota, Hiroto Izumi, Akihide Tanimoto, Mayu Takahashi, Naoya Miyamoto, Eiji Kashiwagi, Akihiko Kidani, Gen Hirano, Daisuke Masubuchi, Yasushi Fukunaka, Yoshihiro Yasuniwa, Seiji Naito, Shigeru Nishizawa, Yasuyuki Sasaguri, Kimitoshi Kohno .  Programmed Cell Death Protein 4 Down-regulates Y-Box Binding Protein-1 Expression via a Direct Interaction with Twist1 to Suppress Cancer Cell Growth .  CANCER RESEARCH69 ( 7 ) 3148 - 3156   2009.4Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Programmed cell death protein 4 (PDCD4) has recently been shown to be involved in both transcription and translation, and to regulate cell growth. However, the mechanisms underlying PDCD4 function are not well understood. In this study, we show that PDCD4 interacts directly with the transcription factor Twist1 and leads to reduced cell growth through the down-regulation of the Twist1 target gene Y-box binding protein-1 (YB-1). PDCD4 interacts with the DNA binding domain of Twist1, inhibiting its DNA binding ability and YB-1 expression. Immunohistochemical analysis showed that an inverse correlation between nuclear PDCD4 and YB-1 expression levels was observed in 37 clinical prostate cancer specimens. Growth suppression by PDCD4 expression was completely recovered by either Twist1 or YB-1 expression. Moreover, PDCD4-overexpressing cells are sensitive to cisplatin and paclitaxel but not to etoposide or 5-fluorouracil. In summary, PDCD4 negatively regulates YB-1 expression via its interaction with Twist1 and is involved in cancer cell growth and chemoresistance. [Cancer Res 2009;69(7):3148-56]

DOI： 10.1158/0008-5472.CAN-08-2334

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山田 壮亮, 谷本 昭英, 島尻 正平, 笹栗 靖之 .  皮膚腫瘍papillary eccrine adenomaの1症例 .  診断病理26 ( 1 ) 58 - 61   2009.1

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Publisher：(一社)日本病理学会  

79歳男性の皮膚に発生したpapillary eccrine adenoma(PEA)の1例を経験したので報告する。右大腿部皮膚に軽い掻痒感を伴う腫瘤を自覚し、切除術を施行された。肉眼的に、径16×10×8mmで、黄白色調の境界明瞭な真皮内腫瘍であった。組織学的に、腫瘍はほぼ対称性の真皮中層から下層の病変で、拡張した腺管や嚢胞により構成されており、好酸性無構造物質の貯留を伴っていた。管腔の多くは異型のない二層性上皮で裏打ちされており、腔内へ乳頭状に突出する像や篩状様構造を呈していた。鑑別としてtubular apocrine adenoma(TAA)とaggressive digital papillary adenocarcinoma(ADPAca)が挙げられたが、前者は明らかな断頭分泌像を認めないことより、後者は細胞異型、構造異型の乏しいことより、PEAと診断した。(著者抄録)

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Shiota M, Izumi H, Tanimoto A, Takahashi M, Miyamoto N, Kashiwagi E, Kidani A, Hirano G, Masubuchi D, Fukunaka Y, Yasuniwa Y, Naito S, Nishizawa S, Sasaguri Y, Kohno K. .  Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth. .  Cancer Res. 69   3148 - 3156   2009Reviewed

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Yamada S, Tanimoto A, Matsuki Y, Hisada Y, Sasaguri Y. .  Sclerosing encapsulating peritonitis (abdominal cocoon) associated with liver cirrhosis and diffuse large B-cell lymphoma: autopsy case. .  Pathol Int.59   681 - 686   2009Reviewed

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Yamada S, Tanimoto A, Wang KY, Shimajiri S, Sasaguri Y. .  Stromal luteoma and nodular hyperthecosis of the bilateral ovaries associated with atypical endometrial hyperplasia of the uterus. .  Pathol Int.59   831 - 833   2009Reviewed

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Wang KY, Tanimoto A, Inenaga T, Yamada S, Shimajiri S, Ding Y, Guo X, Sasaguri Y. .  Pulmonary capillary hemangiomatosis in chronic cardiac failure due to aortic stenosis. .  J UOEH.31   339 - 344   2009Reviewed

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小原 光祥, 岡 ハル子, 佐藤 斉, 藤原 仁, 岩井 幸子, 松山 篤二, 島尻 正平, 久岡 正典, 谷本 昭英, 濱田 哲夫 .  乳腺髄様癌の4症例 .  日本臨床細胞学会九州連合会雑誌39   81 - 85   2008.7

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Publisher：日本臨床細胞学会-九州連合会  

いずれも乳房腫瘤を主訴とし、症例1(75歳)は定型的乳房切除術、症例2(31歳)は非定型的乳房切除術、症例3(40歳)と症例4(48歳)は乳房温存術(円状部分切除)を施行され、全例が4人の病理医により髄様癌と診断された。これら4例についてRadolfiらの3群亜型分類による再評価を行い、亜型分類とそれぞれの穿刺吸引細胞所見及び予後を比較検討した。Radolfiらの亜分類によるTMC(typical medullary carcinoma)に特徴的な細胞像は未分化な腫瘍細胞としての核・細胞質所見であると考えられた。

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Ken Sabanai, Masato Tsutsui, Akinori Sakai, Hideyuki Hirasawa, Shinya Tanaka, Eiichiro Nakamura, Akihide Tanimoto, Yasuyuki Sasaguri, Masako Ito, Hiroaki Shimokawa, Toshitaka Nakamura, Nobuyuki Yanagihara .  Genetic disruption of all NO synthase isoforms enhances BMD and bone turnover in mice in vivo: Involvement of the renin-angiotensin system .  JOURNAL OF BONE AND MINERAL RESEARCH23 ( 5 ) 633 - 643   2008.5Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BONE & MINERAL RES  

Introduction: NO is synthesized by three different NO synthase (NOS) isoforms, including neuronal (nNOS), inducible (iNOS) and endothelial NOS (eNOS). The roles of NO in bone metabolism have been extensively investigated in pharmacological studies and in studies with NOS isoform-deficient mice. However, because of the nonspecificity of agents and compensation among the NOS isoforms, the ultimate roles of endogenous NO are still poorly understood. To address this point, we successfully generated mice in which all three NOS genes are completely disrupted. In this study, we examined whether bone metabolism is abnormal in those mice.
Materials and Methods: Experiments were performed in 12-wk-old male wildtype, singly nNOS(-/-), iNOS(-/-), and eNOS(-/-) and triply n/i/eNOS(-/-) mice. BMD was assessed by DXA. The kinetics of osteoblastic bone formation and those of osteoclastic bone resorption were evaluated by measurements of morphological and biochemical markers.
Results: BMD was significantly higher only in the triply NOS-/- mice but not in any singly NOS-/- mice compared with the wildtype mice. Markers of osteoblastic bone formation, including bone formation rate, mineral apposition rate, and serum alkaline phosphatase concentration, were also significantly larger only in the triply NOS-/- mice compared with wildtype mice. Furthermore, markers of osteoclastic bone resorption, including osteoclast number, osteoclast surface, and urinary deoxypyridinoline excretion, were again significantly greater only in the triply NOS-/- mice. Importantly, the renin-angiotensin system in bone was significantly activated in the triply NOS-/- mice, and long-term oral treatment with an angiotensin II type I (AT,) receptor blocker normalized this pathological bone remodeling in those mice.
Conclusions: These results provide the first direct evidence that genetic disruption of the whole NOS system enhances BMD and bone turnover in mice in vivo through the AT, receptor pathway, showing the critical role of the endogenous NO/NOS system in maintaining bone homeostasis.

DOI： 10.1359/JBMR.080107

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Sohsuke Yamada, Ke-Yong Wang, Akihide Tanimoto, Jianglin Fan, Shohei Shimajiri, Shuji Kitajima, Masatoshi Morimoto, Masato Tsutsui, Teruo Watanabe, Kosei Yasumoto, Yasuyuki Sasaguri .  Matrix metalloproteinase 12 accelerates the initiation of atherosclerosis and stimulates the progression of fatty streaks to fibrous plaques in transgenic rabbits .  AMERICAN JOURNAL OF PATHOLOGY172 ( 5 ) 1419 - 1429   2008.5Reviewed International journal

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Whether fatty streaks are directly followed by fibrous plaque formation in atherosclerosis remains controversial. Disruption of the basement membrane and elastic layers is thought to be essential for this process. Matrix metalloproteinase 12 (MMP-12) can degrade a broad spectrum of substrates, but the role of MMP-12 in the early stage of atherosclerosis is unclear. To investigate MMP-12 function in the initiation and progression of atherosclerosis, we investigated macrophage migration and elastolysis in relation to fatty streaks in human MMP-12 transgenic (hMMP-12 Tg) rabbits. Fatty streaks in hMMP-12 Tg rabbits fed a 1% cholesterol diet for 6 weeks (cholesterol-induced model of atherosclerosis) were more pronounced and were associated with more significant degradation of the internal elastic layer compared with wild-type (WT) animals. Numbers of infiltrating macrophages and smooth muscle cells in the lesions were increased in hMMP-12 Tg compared with WT animals. In both cuff- and ligation-induced models of atherosclerosis, smooth muscle cell-predominant atherosclerotic lesions were elevated with significant elastolysis of the internal elastic lamina in Tg compared with WT animals; "microelastolytic sites" were recognized before formation of the neointima in the cuff model only. These results indicate that MMP-12 may be critical to the initiation and progression of atherosclerosis via degradation of the elastic layers and/or basement membrane. Therefore, a specific MMP-12 inhibitor might prove useful for the treatment of progressive atherosclerosis.

DOI： 10.2353/ajpath.2008.070604

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Sei Nakata, Masato Tsutsui, Hiroaki Shimokawa, Osamu Suda, Tsuyoshi Morishita, Kiyoko Shibata, Yasuko Yatera, Ken Sabanai, Akihide Tanimoto, Machiko Nagasaki, Hiromi Tasaki, Yasuyuki Sasaguri, Yasuhide Nakashima, Yutaka Otsuji, Nobuyuki Yanagihara .  Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms .  CIRCULATION117 ( 17 ) 2211 - 2223   2008.4Reviewed International journal

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Background - The roles of nitric oxide (NO) in the cardiovascular system have been investigated extensively in pharmacological studies with NO synthase (NOS) inhibitors and in studies with NOS isoform - deficient mice. However, because of the nonspecificity of the NOS inhibitors and the compensatory interactions among NOS isoforms (nNOS, iNOS, and eNOS), the ultimate roles of endogenous NO derived from the entire NOS system are still poorly understood. In this study, we examined this point in mice deficient in all 3 NOS isoforms (triply n/i/eNOS(-/-) mice) that we have recently developed.
Methods and Results - The triply n/i/eNOS(-/-) mice, but not singly eNOS(-/-) mice, exhibited markedly reduced survival, possibly due to spontaneous myocardial infarction accompanied by severe coronary arteriosclerotic lesions. Furthermore, the triply n/i/eNOS(-/-) mice manifested phenotypes that resembled metabolic syndrome in humans, including visceral obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance. Importantly, activation of the renin-angiotensin system was noted in the triply n/i/eNOS(-/-) mice, and long-term oral treatment with an angiotensin II type 1 receptor blocker significantly suppressed coronary arteriosclerotic lesion formation and the occurrence of spontaneous myocardial infarction and improved the prognosis of those mice, along with ameliorating the metabolic abnormalities.
Conclusions - These results provide the first direct evidence that genetic disruption of the whole NOS system causes spontaneous myocardial infarction associated with multiple cardiovascular risk factors of metabolic origin in mice in vivo through the angiotensin II type 1 receptor pathway, demonstrating the critical role of the endogenous NOS system in maintaining cardiovascular and metabolic homeostasis.

DOI： 10.1161/CIRCULATIONAHA.107.742692

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山田 壮亮, 谷本 昭英, 島尻 正平, 笹栗 靖之 .  腎のmucinous tubular and spindle cell carcinomaの1症例 .  診断病理25 ( 2 ) 121 - 124   2008.4

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65歳女性の左腎上極に発生したmucinous tubular and spindle cell carcinoma(MTSC)の1例を経験したので報告する。生来健康であったが、健診時に偶然左腎腫瘍を指摘され、悪性を完全に否定できないため、左腎摘出術を施行された。腫瘍は径3.5×3×3cmの大きさで腎皮質に限局する境界明瞭な白色調の病変であり、内部に出血・壊死を認めなかった。組織学的に、腫瘍は主に管状に増殖し、間質には泡状変化の目立つムチンの沈着を伴っていた。一部では、紡錘形細胞の錯綜性増殖も見られたが、いずれにおいても、腫瘍細胞は異型の弱い小型細胞であった。鑑別としてpapillary renal cell carcinoma(papillary RCC)が挙げられたが、細胞異型が弱いこと、ムチンの沈着が目立つことなどより、MTSCと診断した。(著者抄録)

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山田 壮亮, 谷本 昭英, 島尻 正平, 笹栗 靖之 .  Neurolymphomatosisを合併したdiffuse large B cell lymphomaの1症例 .  福岡大学医学紀要35 ( 1 ) 71 - 72   2008.3

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Akihide Tanimoto, Yoshitaka Murata, Ke-Yong Wang, Masato Tsutsui, Kimitoshi Kohno, Yasuyuki Sasaguri .  Monocyte chemoattractant protein-1 expression is enhanced by granulocyte-macrophage colony-stimulating factor via jak2-stat5 signaling and inhibited by atorvastatin in human monocytic U937 cells .  JOURNAL OF BIOLOGICAL CHEMISTRY283 ( 8 ) 4643 - 4651   2008.2Reviewed International journal

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The proinflammatory cytokine granulocyte-macrophage colonystimulating factor (GM-CSF) is expressed in inflammatory and atherosclerotic lesions. GM-CSF is known to enhance monocytic expression of monocyte chemoattractant protein-1 (MCP-1). However, the molecular mechanism(s) by which GMCSF up-regulates the MCP-1 expression remains to be clarified. Thus, in this study, we examined our hypothesis that GM-CSF up-regulates the MCP-1 expression via Jak2-Stat5 signaling pathway. In human monocytic cell line U937, GM-CSF increased MCP-1 expression in protein and mRNA levels. Furthermore, analysis of the GM-CSF promoter element revealed that the STAT5 (signal transducer and activator of transcription5) transcription factor binding site, located between-152 and -144 upstream of the transcription start site, as well as Janus kinase-2-mediated Stat5 activation were necessary for the GM-CSF-induced transcriptional up-regulation of the MCP-1 gene. This GM-CSF-induced MCP-1 expression, measured as both protein and mRNA levels, was down-regulated by atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. However, this decrease in MCP-1 expression was not at the transcriptional level of MCP-1 gene but rather at the level of the stability of MCP-1 mRNA. These results indicate that GM-CSF regulates MCP-1 expression via Janus kinase-2-Stat5 pathway and by a novel regulatory mechanism of statins to reduce inflammatory reactions by down-regulating the expression of monocytic MCP-1, which promotes atherogenesis.

DOI： 10.1074/jbc.M708853200

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Fumihiko Kamezaki, Hiromi Tasaki, Kazuhito Yamashita, Masato Tsutsui, Shinichiro Koide, Sei Nakata, Akihide Tanimoto, Masahiro Okazaki, Yasuyuki Sasaguri, Tetsuo Adachi, Yutaka Otsuji .  Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats .  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE177 ( 2 ) 219 - 226   2008.1Reviewed International journal

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Rationale: Pulmonary hypertension (PH) is a life-threatening disease, characterized by vascular remodeling and vasoconstriction. Evidence suggests that oxidative stress may contribute to the pathogenesis and/or development of PH.
Objectives: In the present study, we examined whether intratracheal gene transfer of human extracellular superoxide dismutase (EC-SOD) could ameliorate monocrotaline (MCT)-induced PH in rats.
Methods: MCT-injected rats were intratracheally administered vehicle (MCT group) or an adenovirus encoding beta-galactosidase (Ad beta gal group) or human EC-SOD (AdEC-SOD group).
Measurements and Main Results: After intratracheal gene transfer, EC-SOD was successfully expressed in lung tissue, bronchoalveolar lavage fluid, and plasma. Twenty-eight days after MCT injection, right ventricular systolic pressure and the weight ratio of the right ventricle to the left ventricle plus septum were significantly lower in the AdEC-SOD group (42.50 +/- 1.46 mm Hg and 0.453 +/- 0.029, respectively) than in the MCT group (59.89 +/- 1.61 mm Hg and 0.636 +/- 0.022, respectively) or the Ad beta gal group (61.50 +/- 2.61 mm Hg and 0.653 +/- 0.038, respectively). Moreover, vascular remodeling and proliferation of vascular smooth muscle cells in pulmonary arteries were markedly suppressed in the AdEC-SOD group. Importantly, 8-isoprostane in lung tissue was also significantly reduced in the AdEC-SOD group.
Conclusions: EC-SOD overexpression to the lung ameliorated MCT-induced PH in rats. We suggest that EC-SOD may act as an antioxidant in PH and that increased oxidative stress may be important in the pathogenesis of MCT-induced PH.

DOI： 10.1164/rccm.200702-264OC

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Wu L, Tanimoto A, Murata Y, Sasaguri T, Fan J, Sasaguri Y, Watanabe T .  Matrix metalloproteinase-12 gene expression in human vascular smooth muscle cells. .  Genes to Cells.8 ( 3 ) 225 - 234   2008Reviewed

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DOI： 10.1046/j.1365-2443.2003.00628.x

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Masaji Hashimoto, Akihide Tanimoto, Tomoharu Yoshiya, Syuichiro Matoba, Toshihito Sawada, Goro Watanabe, Kunihiko Seki, Hiroshi Hashimoto .  Mesenchymal tumor of the pancreas: Report of a case .  SURGERY TODAY37 ( 12 ) 1117 - 1119   2007.12Reviewed

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Mesenchymal tumors of the pancreas are rare and difficult to classify. We report a case of a solitary mesenchymal tumor in the body of the pancreas. The tumor showed immunocytochemical reactivity for anti-vimentin, anti-alpha-smooth muscle actin, and anti-CD34; however, it was negative immunohistochemically for antibodies to cytokeratins, as well as for the following antibodies: anti-desmin, anti-S-100, anti-chromogranin A, anti-CD117 (c-Kit), anti-CD99, and anti-bcl-2. This tumor could not be classified as a specific type of mesenchymal tumor immunocytochemically.

DOI： 10.1007/s00595-007-3531-7

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渡辺 次郎, 佐藤 圭, 松本 聡美, 中島 章, 大蔵 尚文, 谷本 昭英 .  Placental site trophoblastic tumorとの鑑別が困難であった子宮動静脈瘻を伴った胎盤遺残と思われる1例 .  診断病理24 ( 4 ) 445 - 447   2007.10

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今回、Placental site trophoblastic tumor(以下PSTT)との鑑別に苦慮した、動静脈瘻を伴う胎盤遺残と思われる1例を経験した。本症例は当初、高度の筋層浸潤、静脈侵襲を伴う中間型トロホブラスト主体の病変であることからPSTTを疑った。しかしトロホブラストの局在が散在性であり、腫瘍としては腫瘤形成性に乏しい点から最終的には胎盤遺残と判断した。(著者抄録)

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Akihide Tanimoto, Ke-Yong Wang, Yoshitaka Murata, Satoshi Kimura, Masako Nomaguchi, Sei Nakata, Masato Tsutsui, Yasuyuki Sasaguri .  Histamine upregulates the expression of inducible nitric oxide synthase in human intimal smooth muscle cells via histamine H1 receptor and NF-kappa B signaling pathway .  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY27 ( 7 ) 1556 - 1561   2007.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective - Histamine increases endothelial nitric oxide ( NO) production as an endothelium- dependent vasodilator, which acts as a vasoconstrictor in atherosclerotic coronary arteries. To investigate the relation between histamine and NO production in intimal smooth muscle cells ( SMCs), we studied the effect of histamine on inducible NO synthase ( iNOS) expression in the SMCs.
Methods and Results - In cultured human intimal SMCs, histamine increased NO production, iNOS expression, and NF-kappa B nuclear translocation, which were inhibited by histamine H1 blocker and NF-kappa B inhibitor. Luciferase assay using -8.3 kb upstream of human iNOS promoter region and electrophoretic mobility shift assay suggested that a NF-kappa B motif located at -3922 to -3914 would be necessary for histamine- inducible promoter activity. In addition, H1 blocker, NF-kappa B inhibitor, and dominant negative I kappa B alpha or I kappa B kinase beta downregulated the histamine- induced iNOS promoter activity. In the human aorta, histamine content was estimated to be 310 +/- 66 pmol/ mg protein in the atherosclerotic intima, while that was to be 43 +/- 22 pmol/ mg protein in the media ( P &lt; 0.001).
Conclusions - Histamine stimulates intimal SMCs to increase iNOS expression via H1 receptors and NF-kappa B signaling pathway. Histamine could be one of NO- regulating factors, by inducing iNOS expression in intimal SMCs, and may be related to atherogenesis.

DOI： 10.1161/ATVBAHA.106.139089

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山田 壮亮, 谷本 昭英, 松木 康真, 島尻 正平, 笹栗 靖之 .  Pancreatic hamartomaの1症例 .  診断病理24 ( 3 ) 335 - 338   2007.7

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71歳女性の膵体尾部に発生した過誤腫の1例を経験したので報告する。2年前、上行結腸癌にて切除術を施行され、経過観察中の腹部CTにて膵尾部嚢胞性腫瘍が認められた。悪性を疑われ、膵体尾部脾合併切除術を施行された。腫瘍は径5×4×3cmの大きさで膵体尾部に限局する境界明瞭な白色調の病変であり、内部に出血と嚢胞性変化を伴っていた。組織学的に、充実性成分から嚢胞性成分への細胞密度の移行は緩やかであり、後者では上皮の裏打ちを認めなかった。充実性部分では、紡錘形から類円形の腫瘍細胞が無秩序に増殖しており、一部では硝子化した厚みのある線維性間質を伴っていた。鑑別として孤在性線維性腫瘍と胃腸間質性腫瘍が考えられたが、ラ氏島形成がなく、腺房細胞と介在導管上皮細胞の配置および構成割合に異常の認められる腺房組織を内在していたことより過誤腫と診断した。(著者抄録)

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Shinichiro Koide, Masahiro Okazaki, Masahito Tamura, Kiyoshi Ozumi, Hiroyuki Takatsu, Fumihiko Kamezaki, Akihide Tanimoto, Hiromi Tasaki, Yasuyuki Sasaguri, Yasuhide Nakashima, Yutaka Otsuji .  PTEN reduces cuff-induced neointima formation and proinflammatory cytokines .  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY292 ( 6 ) H2824 - H2831   2007.6Reviewed International journal

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An inflammatory response followed by vascular injury plays an important role in neointima formation and development of atherosclerotic lesions, which are in part mediated by proinflammatory cytokines. Using a Cuff injury model, we examined the effects of adenovirus-mediated overexpression of phosphatase and tensin homology deleted on chromosome 10 (PTEN) on neointima formation and the proinflammatory response. A cuff was placed around the femoral artery. and adenovirus expressing human PTEN type 1 (AdPTEN) or Escherichia coli P-galactosidase (AdLacZ) was injected between the cuff and the adventitia. After 14 days, the arteries were examined histopathologically and by Western blotting. The significant reduction of neointima formation by AdPTEN compared with AdLacZ was accompanied by reduced cell proliferation and increased adventitial cell apoptosis. AdPTEN also reduced expression of phosphorylated I kappa B-alpha., but not nonphosphorylated I kappa B-alpha. Western blotting revealed that AdPTEN reduced the cuff injury-induced expression levels of monocyte chemoattractant protein-1, TNF-alpha, and IL-1 beta and their expression in all layers of the arterial wall. In contrast, cuff-induced macrophage invasion, which was also inhibited by AdPTEN, was detected only at the intimal Surface and in the adventitia. In cultured vascular smooth muscle cells, PTEN directly inhibited ANG II-induced monocyte chemoattractant protein-1 expression as quantified by real-time PCR and Western blotting. Our results suggest that overexpression of PTEN reduces neointima formation, possibly in part through inhibition of the inflammatory response by macrophage invasion and proinflammatory cytokine expression.

DOI： 10.1152/ajpheart.01221.2006

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堤 謙二, 宇田川 晴司, 木ノ下 義宏, 上野 正紀, 峯 真司, 江原 一尚, 谷本 昭英, 鶴丸 昌彦 .  リンパ節微小転移からみた早期胃癌における色素法によるセンチネルリンパ節/リンパ流域の検討 .  日本臨床外科学会雑誌68 ( 3 ) 540 - 546   2007.3

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色素法によるセンチネルリンパ節(sentinel node;SN)を指標としたリンパ節転移診断の問題点を微小転移の観点から検討した.早期胃癌57例を対象に,色素法によるSNおよびセンチネルリンパ流(Sentinel lymphatic basin,SB)同定率,SNおよびSBを指標とした微小転移を含む転移検出感度,正診率を検討した.微小転移は癌細胞1個をtumor cell microinvolvement,cluster形成をtumor clusterと定義した.M癌では2.9%(1/34),SM癌では60.9%(14/23)に微小転移を認めた.微小転移を指標としたSN同定率は100%,感度60.0%,正診率89.5%と感度が低く,一方SB単位で検討すると感度は86.7%,正診率96.5%と良好であった.早期胃癌におけるリンパ節微小転移頻度は高く,SNを指標とした場合の偽陰性症例の頻度を考慮すると,現状ではSNを指標とするよりもSBを指標とした方がより安全性の高い縮小手術が可能であると考えられた.(著者抄録)

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Sei Nakata, Masato Tsutsui, Hiroaki Shimokawa, Takahiro Yamashita, Akihide Tanimoto, Hiromi Tasaki, Kiyoshi Ozumi, Ken Sabanai, Tsuyoshi Morishita, Osamu Suda, Hideyasu Hirano, Yasuyuki Sasaguri, Yasuhide Nakashima, Nobuyuki Yanagihara .  Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappa B pathway .  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY27 ( 1 ) 92 - 98   2007.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective - Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are known to enhance vascular expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS). In this study, we examined whether statins also upregulate vascular expression of neuronal NOS (nNOS).
Methods and Results - In cultured rat aortic smooth muscle cells, treatment with atorvastatin significantly increased nNOS expression, associated with activation of Akt and NF-kappa B. Inhibition of Akt by dominant-negative Akt suppressed atorvastatin-induced nNOS expression as well as Akt and NF-kappa B activation. Inhibition of NF-kappa B by dominant-negative I kappa B also attenuated atorvastatin-induced nNOS expression and NF-kappa B activation, but not Akt activation. We further examined whether atorvastatin also enhances nNOS expression in isolated mouse aorta, and if so, how much nNOS-derived NO accounts for atorvastatin-induced NOx production. In isolated aortas of wild-type mice, atorvastatin significantly increased all three NOS isoform expression and NOx production. In isolated aortas of doubly i/eNOS(-/-), n/eNOS(-/-), and n/iNOS(-/-) mice, which express only nNOS, iNOS, and eNOS, respectively, atorvastatin- induced NOx production was approximately 25%, 25%, and 50% to that of wild-type mice, respectively, suggesting that nNOS accounts for 25% of the atorvastatin-mediated NOx production.
Conclusions - These results indicate that atorvastatin upregulates vascular nNOS through Akt/NF-kappa B pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.

DOI： 10.1161/01.ATV.0000251615.61858.33

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山田 壮亮, 谷本 昭英, 笹栗 毅和, 松木 康真, 島尻 正平, 笹栗 靖之 .  子宮頸部に見られたendocervicosisの1症例 .  診断病理24 ( 1 ) 102 - 105   2007.1

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47歳女性の子宮頸部に発生し、腟腔を占拠するendocervicosisの1例を経験したので報告する。約2年前より徐々に増大する下腹部膨隆が出現、卵巣嚢腫と診断され経過観察されていた。1ヵ月前より悪臭の強い帯下を認めたが精査出来ず、単純子宮全摘出術が施行された。病変は子宮腟部・後唇から突出する12×9×7cmの柔らかい腫瘤であり、腟腔を占拠していた。割面では粘液の貯留した多房状嚢胞性病変であった。腫瘤は大小の嚢胞性腺管により構成されており、異型のない内頸部型の粘液性円柱上皮が一層性に並んでいた。鑑別としてminimal deviation adenocarcinoma(adenoma malignum)とdeep nabothian cystが考えられたが、正常頸管腺との連続性がないこと、腺管の嚢胞性変化が見られること、および細胞異型が乏しいことなどよりendocervicosisと診断した。(著者抄録)

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Akihide Tanimoto, Yasuyuki Sasaguri, Hiroshi Ohtsu .  Histamine network in atherosclerosis .  TRENDS IN CARDIOVASCULAR MEDICINE16 ( 8 ) 280 - 284   2006.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE LONDON  

Histamine is a low-molecular-weight amine, synthesized from L-histidine by histidine decarboxylase. It has been suggested that the histamine is produced in the atherosclerotic lesion although the activity of histamine has not been clarified completely. To avoid the pharmacologic problems, genetically engineered mice are useful. We recently observed the histidine decarboxylase-gene knockout mice ameliorates' atherosclerotic region, compared with that of the wild-type control mice. The source of histamine in atherosclerotic lesion should be clarified in details; however, it could be macrophage, endothelial cells, and mast cells. All four types of histamine receptors (H1-H4) have the possibilities to be involved in the atherosclerotic regions. Because H1 and H2 receptors are discovered previously, the activities through those receptors are investigated relatively well, but as the other two types of receptors have been cloned recently, their involvement in atherosclerotic lesion should be investigated further.

DOI： 10.1016/j.tcm.2006.06.001

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山田 壮亮, 谷本 昭英, 松木 康真, 笹栗 靖之 .  マンソン孤虫症Sparganosisの1症例 .  診断病理23 ( 4 ) 296 - 298   2006.10

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Publisher：(一社)日本病理学会  

70歳女性の右乳房皮下に認められたマンソン孤虫症の1例を経験したので報告する。偶然右乳房B領域に硬結を指摘され、局麻下に腫瘤切除術を施行された。腫瘤性病変の主体は蛇行する虫体であり、周囲には肉芽腫の形成と好酸球の浸潤が認められた。虫体には、外側を覆う好酸性の外被、その内層に縦列する紡錘形の外被細胞、および疎な内部組織が認められた。内部組織には腸管などの分化した器官は見られなかったが、同心円状の石灰小体が分布していた。以上より、マンソン裂頭条虫の幼虫であるPlerocercoid(擬充尾虫)がヒトを第二中間宿主として寄生し迷入・迷走した皮膚爬行症creeping diaseseと考え、マンソン孤虫症Sparganosisと診断した。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J03623&link_issn=&doc_id=20061107260012&doc_link_id=%2Fcd9jjodp%2F2006%2F002304%2F012%2F0296-0298%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcd9jjodp%2F2006%2F002304%2F012%2F0296-0298%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

山田 壮亮, 松木 康真, 谷本 昭英, 笹栗 毅和, 中野 盛夫, 笹栗 靖之 .  Aggressive digital papillary adenocarcinomaの1症例 .  診断病理23 ( 3 ) 193 - 195   2006.7

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Publisher：(一社)日本病理学会  

79歳男性の右拇指腹側に発生したaggressive digital papillary adenocarcinoma(以下ADPAca)の1例を経験したので報告する.右拇指腹側に,約3ヵ月の間に徐々に増大する径20〜30mm大の皮下腫瘤を認め,切開掻爬された.腫瘍は境界明瞭で,分葉状に充実性発育しており,内部に管状・低乳頭状構造を伴っていた.腫瘍細胞は円形から紡錘形で,核の大小不同,核分裂像の認められる異型上皮細胞であり,免疫組織化学的にAE1/AE3,EMAおよびS-100に陽性を呈した.Chondroid syringomaとの鑑別が考えられたが,細胞異型と特徴的な増殖様式よりADPAcaと診断した(著者抄録)

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Y Kohno, Y Matsuki, A Tanimoto, H Izumi, T Uchiumi, K Kohno, S Shimajiri, Y Sasaguri .  Expression of Y-box-binding protein dbpC/contrin, a potentially new cancer/testis antigen .  BRITISH JOURNAL OF CANCER94 ( 5 ) 710 - 716   2006.3Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Y- box- binding proteins are members of the human cold- shock domain protein superfamily, which includes dbpA, dbpB/ YB- 1, and dbpC/ contrin. dbpC/ contrin is a germ cell- specific Y- box- binding protein and is suggested to function as a nuclear transcription factor and RNA- binding protein in the cytoplasm. Whereas ubiquitous dbpB/ YB- 1 expression has been well studied in various types of human carcinomas as a prognostic or predictive marker, the dbpC/ contrin expression in human tumour cells has not been reported. In this report, we provide the first evidence showing that dbpC was highly expressed in human testicular seminoma and ovarian dysgerminomas, and in carcinomas in other tissues and that its expression in normal tissues is nearly restricted to germ cells and placental trophoblasts. These results indicate that dbpC/ contrin would be a potentially novel cancer/ testis antigen.

DOI： 10.1038/sj.bjc.6602987

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堤 謙二, 宇田川 晴司, 木ノ下 義宏, 上野 正紀, 峯 真司, 江原 一尚, 谷本 昭英, 鶴丸 昌彦 .  早期胃癌に対する幽門輪温存手術の適応からみた幽門上リンパ節微小転移の臨床的意義 .  日本臨床外科学会雑誌67 ( 2 ) 281 - 287   2006.2

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Publisher：日本臨床外科学会  

早期胃癌における幽門上リンパ節(以下No. 5)への癌微小転移状況から,迷走神経幽門枝/右胃動脈を温存した幽門保存胃切除術(PPG)の適応拡大の可能性について検討した.D2郭清を行った中下部早期胃癌267例を対象にCytokeratin(CAM5.2)染色,HE染色によるNo. 5転移状況を検討.癌細胞が1個のtumor cell micro involvement(MI)が6例,cluster形成したmicro metastasis(MM)が2例,HE染色での転移は1例.M癌ではMIが1例.SM1癌では転移を認めず,SM2癌ではMIが5例,MMが2例,HE染色で1例,SM2癌は全体の9.3%(8/86)に転移を認めた.さらにSM2の小彎病変では16.7%(5/30),非小彎病変5.4%(3/56),組織型は全例,中・低分化型で,中低分化型・小彎病変の19.2%(5/26)に転移を認めた.微小転移の臨床的意義はいまだ解明されていないが,SM2癌でのPPG適応の際には慎重を期す必要がある

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Yoshida T, Izumi H, Uchiumi T, Sasaguri Y, Tanimoto A, Matsumoto T, Naito S, Kohno K .  Expression and cellular localization of dbpC/Contrin in germ cell tumor cell lines. .  Biochimica et biophysica acta1759 ( 1-2 ) 80 - 88   2006.1

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DOI： 10.1016/j.bbaexp.2006.02.005

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T Yoshida, H Izumi, T Uchiumi, Y Sasaguri, A TaniMoto, T Matsumoto, S Naito, K Kohno .  Expression and cellular localization. of dbpC/Contrin in germ cell tumor cell lines .  BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION1759 ( 1-2 ) 80 - 88   2006.1

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Publisher：ELSEVIER SCIENCE BV  

The transcriptional regulation of the germ cell-specific cold-shock domain protein dbpC/Contrin was investigated, and the promoter region between -272 and -253 relative to the transcription start site was shown to be critical for the manifestation of cell-type specific transcription. In vivo footprint analysis demonstrated that the E-box located between -272 and -253 is protected in the dbpC/Contrin-positive germ cell tumor cell lines NEC8 and TERA1, but not in the dbpC/Contrin-negative bladder cancer cell line T24 or ovarian cancer cell line A2780. The promoter activity of the dbpC/Contrin gene was transactivated by co-transfection with c-Myc and the N-Myc expression plasmid. Western blotting analysis clearly showed that N-Myc is highly expressed in both NEC8 and TERA1 cells, and that c-Myc is expressed in both T24 and A2780 cells. These data demonstrate that cell-type specific dbpC/Contrin expression in germ cells is regulated by N-Myc. In addition, dbpC/Contrin is localized mainly in the cytoplasm of NEC8 and TERA1 cells, but is translocated to the nucleus when its C-terminal region is partially deleted. Our findings also suggest that dbpC/Contrin can be used as a molecular tool for the detection of germ cell tumors. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbaexp.2006.02.005

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T Morishita, M Tsutsui, H Shimokawa, K Sabanai, H Tasaki, O Suda, S Nakata, A Tanimoto, KY Wang, Y Ueta, Y Sasaguri, Y Nakashima, N Yanagihara .  Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms .  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA102 ( 30 ) 10616 - 10621   2005.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Nitric oxide (NO) is produced in almost all tissues and organs, exerting a variety of biological actions under physiological and pathological conditions. NO is synthesized by three different isoforms of NO synthase (NOS), including neuronal, inducible, and endothelial NOSs. Because there are substantial compensatory interactions among the NOS isoforms, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. Here, we have successfully developed mice in which all three NOS genes are completely deleted by crossbreeding singly NOS-/- mice. NOS expression and activities were totally absent in the triply NOS-/- mice before and after treatment with lipopolysaccharide. Although the triply NOS-/- mice were viable and appeared normal, their survival and fertility rates were markedly reduced as compared with the wild-type mice. Furthermore, these mice exhibited marked hypotonic polyuria, polydipsia, and renal unresponsiveness to an antidiuretic hormone, vasopressin, all of which are characteristics consistent with nephrogenic diabetes insipidus. In the kidney of the triply NOS-/- mice, vasopressin-induced cAMP production and membranous aquaporin-2 water channel expression were reduced associated with tubuloglomerular lesion formation. These results provide evidence that the NOS system plays a critical role in maintaining homeostasis, especially in the kidney.

DOI： 10.1073/pnas.0502236102

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中村 雄介, 澤田 寿仁, 的場 周一郎, 横山 剛, 志田 勝義, 谷本 昭英 .  小腸capillary hemangiomaに対して腹腔鏡補助下切除術を施行した1例 .  外科67 ( 7 ) 851 - 855   2005.7

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Publisher：(株)南江堂  

56歳男性.患者は貧血および血便を主訴に,精査加療目的で著者らの施設へ入院となった.入院時,正球性色素性貧血を認め,下部消化管内視鏡にてBauhin弁から約20cm口側の回腸に隆起性病変を発見し,腹腔鏡補助下小腸部分切除術を施行した.病理組織学的にcapillary hemangiomaと診断され,術後は経過良好であった

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Y Sasaguri, KY Wang, A Tanimoto, M Tsutsui, H Ueno, Y Murata, Y Kohno, S Yamada, H Ohtsu .  Role of histamine produced by bone marrow-derived vascular cells in pathogenesis of atherosclerosis .  CIRCULATION RESEARCH96 ( 9 ) 974 - 981   2005.5Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

To clarify the role of histamine-producing cells and its origin in atherosclerosis, we investigated histidine decarboxylase (HDC; histamine-producing enzyme) expression in murine arteries with vascular injuries after the animal had received transplanted bone marrow (BM) from green fluorescent protein (GFP)-transgenic mice. The neointima in the ligated carotid arteries contained BM-derived HDC+ cells that expressed macrophage (Mac-3) or smooth muscle cell antigen (&alpha;-SMA). In contrast, the HDC+ BM-derived cells, which were positive for Mac-3, were mainly located in the adventitia in the cuff replacement model. In apolipoprotein E-knockout mice on a high cholesterol diet, BM-derived cells expressing Mac-3 in the atheromatous plaques were also positive for HDC. In comparison with wild-type mice, HDC-/- mice showed reduced neointimal thickening and a decreased intima-to-media ratio after ligation and cuff replacement. These results indicate that histamine produced from BM-derived progenitor cells, which could transdifferentiate into SMC- or macrophage-like cells, are important for the formation of neointima and atheromatous plaques.

DOI： 10.1161/01.RES.0000166325.00383.ed

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Y Murata, A Tanimoto, KY Wang, M Tsutsui, Y Sasaguri, F De Corte, H Matsushita .  Granulocyte macrophage-colony stimulating factor increases the expression of histamine and histamine receptors in monocytes/macrophages in relation to arteriosclerosis .  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY25 ( 2 ) 430 - 435   2005.2Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective - To study the effect of granulocyte macrophage - colony-stimulating factor (GM-CSF) on histamine metabolism in arteriosclerosis, the expression of histidine decarboxylase (HDC; histamine-producing enzyme), histamine receptors 1 and 2 (HH1R and HH2R), and GM-CSF was investigated in human and mouse arteriosclerotic carotid arteries. Furthermore, the molecular mechanisms of GM-CSF - induced HDC and HH1R expression in monocytic U937 cells were investigated.
Methods and Results - Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC-expressing macrophages. Gene expression of HDC, HH1R, HH2R, and GM-CSF was also detected in the lesions. In U937 cells, GM-CSF enhanced histamine secretion and gene expression of HDC and HH1R. A promoter assay showed that GM-CSF enhanced gene transcription of HDC and HH1R but not HH2R.
Conclusion - The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion, and that GM-CSF induces HDC and HH1R expression in monocytes. Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells.

DOI： 10.1161/01.ATV.0000148705.13411.65

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Shigeo Hara, Yutaka Yamaguchi, Shigeko Hara, Akihide Tanimoto, Kunihiko Seki, Hiroshi Matsushita, Shinji Tomikawa, Keihachiro Kuzuhara .  Long-term course of post-transplant mesangial IgA deposition: Clinicopathologic study of nine cases .  Clinical Transplantation, Supplement19 ( 14 ) 32 - 40   2005

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We conducted the present study to elucidate the fate of post-transplant mesangial IgA deposit under the long-term observation. Out of a total of 45 cases with post-transplant mesangial IgA deposition, nine cases with more than 4 yr of follow-up term were enrolled in this study, and clinicopathologic characteristics were described. The study included three men and six women with a mean age of 34.2 yr. The average observation time from the detection of mesangial IgA deposition was 6.1 yr. Three cases were categorized as recurrent IgA nephropathy, while six cases were classified into latent mesangial IgA deposition. One case with hypertension developed end-stage renal disease. The significant improvement in microscopic hematuria was observed in one recurrent IgA nephropathy case. Microscopic findings included mild mesangial stalk thickening in all but one case. IgA deposition demonstrated a significant decrease in three latent mesangial IgA deposition cases. No apparent reduction in dense deposit quantity was observed on electron microscopy. There was no association between clinicopathologic findings and the regimen of anti-immunosuppressive agents. This study showed the improvement of the disease activity did occur in both recurrent IgA nephropathy and latent mesangial IgA deposition. Further investigation of latent mesangial IgA deposition may present the important clue to the pathogenesis of IgA nephropathy. Copyright © Blackwell Munksgaard 2005.

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S Hara, Y Yamaguchi, S Hara, A Tanimoto, K Seki, H Matsushita, S Tomikawa, K Kuzuhara .  Long-term course of post-transplant mesangial IgA deposition: clinicopathologic study of nine cases .  CLINICAL TRANSPLANTATION19   32 - 40   2005

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Publisher：WILEY-BLACKWELL  

We conducted the present study to elucidate the fate of posttransplant mesangial IgA deposit under the long-term observation. Out of a total of 45 cases with post-transplant mesangial IgA deposition nine cases with more than 4 yr of follow-up term were enrolled in this study, and clinicopathologic characteristics were described. The study included three men and six women with a mean age of 34.2 yr. The average observation time from the detection of mesangial IgA deposition was 6.1 yr. Three cases were categorized as recurrent IgA nephropathy, while six cases were classified into latent mesangial IgA deposition. One case with hypertension developed end-stage renal disease. The significant improvement in microscopic hematuria was observed in one recurrent IgA nephropathy case. Microscopic findings included mild mesangial stalk thickening in all but one case. IgA deposition demonstrated a significant decrease in three latent mesangial IgA deposition cases. No apparent reduction in dense deposit quantity was observed on electron microscopy. There was no association between clinicopathologic findings and the regimen of anti-immunosuppressive agents. This study showed the improvement of the disease activity did occur in both recurrent IgA nephropathy and latent mesangial IgA deposition. Further investigation of latent mesangial IgA deposition may present the important clue to the pathogenesis of IgA nephropathy.

DOI： 10.1111/j.1399-0012.2005.00402.x

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久保 孝利, 能勢 卓, 谷本 昭英, 笹栗 靖之, 森 陽, 伊東 晃 .  ウサギ関節軟骨の細胞外マトリックスおよびマトリックスメタロプロテアーゼ産生におよぼす加齢の影響 .  Connective Tissue36 ( 4 ) 197 - 205   2004.12

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Publisher：日本結合組織学会  

ウサギ関節軟骨細胞を用い軟骨マトリックス合成の指標としてプロテオグリカン生合成,また分解の指標としてマトリックスメタロプロテアーゼ(MMPs)産生におよぼす加齢の影響を軟骨組織の組織学的変化とともに検討した.加齢によりウサギ関節組織では軟骨細胞数の減少とともにマトリックス合成能の減少によるマトリックス維持能の低下を認めた.また,軟骨細胞への炎症性メディエーターであるIL-1結合能の増加が起こり,IL-1によるMMPs産生をはじめとするマトリックス分解系の亢進が誘発されやすくなることが示唆された.したがって,これらが総合的に加齢による変形性関節症をはじめとする関節疾患の発症頻度増大の原因となる可能性が示唆された

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Ono C, Ashida T, Sugiyama T, Fujii J, Homma S, Tanimoto A .  [Rupture of a thoracic aortic aneurysm in a patient with hypertension, myocardial infarction, hyperlipidemia and operation for abdominal aortic aneurysm rupture after follow-up for 28 years]. .  Nihon Ronen Igakkai Zasshi41 ( 6 ) 670 - 674   2004.11Reviewed

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A Japanese man who died at age 86 had been followed since the age of 58, when he presented with hypertension of 150/95 mmHg. The patient remained socially active until he died suddenly of a ruptured thoracic aortic aneurysm, although he experienced angina pectoris in August 1974, and myocardial infarction was identified on electrocardiography in October 1974. He underwent operation for rectal cancer in 1987, and an abdominal aortic aneurysm 38mm in diameter was identified at that time. The patient underwent an operation for rupture of the abdominal aortic aneurysm in 1991. A thoracic aneurysm of 40 mm diameter was identified in 1995, and this expanded to 53 mm by 1997. Autopsy revealed a thoracic aortic aneurysm in the arch (8 x 5 x 5 cm) and descending aorta (7 x 7 x 8 cm). A large volume (2,080 ml) of bloody pleural fluid was present

DOI： 10.3143/geriatrics.41.670

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Takashi Kato, Yoshifumi Ubara, Naoki Sawa, Tetsuo Tagami, Hideyuki Katori, Fumi Takemoto, Akihide Tanimoto, Kenmei Takaichi .  A case of rheumatoid arthritis exhibiting accelerating rheumatoid pleurisy during low-dose weekly methotrexate therapy .  Modern Rheumatology14 ( 5 ) 414 - 418   2004.11Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)  

A 75-year-old Japanese man suffering from rheumatoid arthritis (RA) had received methotrexate (MTX) treatment for 9 years and developed bilateral pleural thickening with exudative pleural effusions despite remission of the polyarthritis. A diagnosis of rheumatoid pleurisy, made by exclusion, was supported by the elevated rheumatoid factor level of the pleural fluid. The pleurisy developed concomitantly with MTX-induced leukocytopenia, and discontinuation of the MTX treatment partially improved the CRP level. These findings indicate a causal relation between the rheumatoid pleurisy and MTX and suggest that MTX therapy may be ineffective in the treatment of rheumatoid pleurisy. Treatment with 10 mg of prednisolone and 100 mg of cyclosporine A daily resulted in rapid resolution of the pleurisy. Although MTX-induced rheumatoid pleurisy is a rare condition, MTX therapy should be considered carefully in RA patients with concomitant rheumatoid pleurisy. © Japan College of Rheumatology and Springer-Verlag Tokyo 2004.

DOI： 10.1007/s10165-004-0337-y

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小野 周子, 芦田 映直, 杉山 卓郎, 藤井 潤, 本間 栄, 谷本 昭英 .  高血圧,陳旧性心筋梗塞,高脂血症で28年間経過観察中に腹部大動脈瘤破裂術後11年で胸部大動脈瘤破裂にて死亡した86歳男性の1剖検例 .  日本老年医学会雑誌41 ( 6 ) 670 - 674   2004.11

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Publisher：(一社)日本老年医学会  

58歳男(初診時).労作時胸痛を主訴とした.50歳時に高血圧を発症したが無治療であった.心電図でV1-2に陰性T波,V3にq波を認め,心筋梗塞と診断し,患者の希望でプロプラノロール,イソソルビド硝酸塩を投与し自宅療養となった.以後発作は無かった.71歳時に直腸癌手術を施行し人工肛門を造設した.腹部大動脈瘤径38mmを腹部エコーで認めたが,β遮断薬による血圧コントロールで対処した.75歳時に腹痛と腹部膨満感が出現し,イレウスにて緊急手術を行ったところ,空腸腸間膜内に血腫を認め,イレウスの先進部と考えた.血腫の原因として,腹部大動脈瘤切迫破裂が考えられ,降圧療法後,腹部大動脈瘤に対して人工血管Y字グラフト置換術を施行した.77歳時に高脂血症に対してプラバスタチンを,高血圧に対してマニジピンを開始した.79歳時にCTで胸部大動脈瘤径40mmを認め,83歳時に62mmまで増大したが,患者の希望で手術は行わず,降圧薬内服による治療を開始した.86歳時に腹部大動脈瘤破裂で死亡した

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Y Kohno, A Tanimoto, C Cirathaworn, S Shimajiri, A Tawara, Y Sasaguri .  GM-CSF activates RhoA, integrin and MMP expression in human monocytic cells .  PATHOLOGY INTERNATIONAL54 ( 9 ) 693 - 702   2004.9Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

Monocyte migration is one of the key events occurring in the early stage of atherosclerosis. This process includes monocytic adhesion to and penetration through the arterial intima. In such an environment, many factors stimulate the monocytes to enhance integrin activation and extracellular matrix degradation. To investigate the coordinative operation of these two events in relation to monocyte migration, we paid particular attention to the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on monocytes in terms of RhoA activation and matrix metalloproteinase (MMP) expression. RhoA and integrin clustering were activated by GM-CSF, monocyte chemoattractant protein-1 (MCP-1) and platelet-derived growth factor-BB (PDGF-BB) in human monocytic cell lines. Furthermore, enhancement of migration was observed with stimulation by MCP-1 and PDGF-BB. Granulocyte-macrophage colony-stimulating factor did not enhance the migration, even though it activated RhoA and integrin. However, GM-CSF is known to stimulate monocytes to express MCP-1, suggesting the presence of an indirect mechanism for GM-CSF-mediated migratory activity. In contrast, only GM-CSF enhanced the expression of MMP-1 and MMP-9. These results provide evidence that GM-CSF has multiple functions enhancing monocytic migration via RhoA and integrin activation, and via MMP expression.

DOI： 10.1111/j.1440-1827.2004.01682.x

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奥田 逸子, 星原 芳雄, 宇田川 晴司, 小久保 守, 谷本 昭英 .  【Barrett食道癌 表在癌の境界・深達度診断】Barrett食道癌の境界を読む 範囲と深達度 X線の立場から .  胃と腸39 ( 9 ) 1223 - 1232   2004.8

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S Kimura, KY Wang, A Tanimoto, Y Murata, Y Nakashima, Y Sasaguri .  Acute inflammatory reactions caused by histamine via monocytes/macrophages chronically participate in the initiation and progression of atherosclerosis .  PATHOLOGY INTERNATIONAL54 ( 7 ) 465 - 474   2004.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

Previously we demonstrated that histidine decarboxylase (HDC), which produces histamine from L-histidine, was detected in monocytes/macrophages located in human atherosclerotic lesions. As monocytic migration is a key event of atherogenesis, we investigated whether histamine induces monocytic expression of monocyte chemoattractant protein (MCP)-1 and its receptors CCR2-A and -B, and also endothelial expression of ICAM-1 and VCAM-1. Furthermore, we studied the effect of interleukin (IL)-4, which inhibits the HDC expression, on the expression of MCP-1 and CCR2. Histamine stimulated monocytes, but not macrophages, to express MCP-1 and CCR2-A and -B. The expression of MCP-1 was inhibited by histamine H2 blocker. In contrast, IL-4 enhanced CCR2 expression but not MCP-1. Histamine stimulated endothelial cells to express ICAM-1 and VCAM-1. These results indicate that histamine and IL-4, which are both synthesized in the arterial intima, chronically participates in the pathogenesis of atherosclerosis via the enhanced expression of monocytic MCP-1, CCR2 and endothelial adhesion molecules.

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A Tanimoto, Y Matsuki, T Tomita, T Sasaguri, S Shimajiri, Y Sasaguri .  Histidine decarboxylase expression in pancreatic endocrine cells and related tumors .  PATHOLOGY INTERNATIONAL54 ( 6 ) 408 - 412   2004.6Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

Histidine decarboxylase (HDC) is an enzyme for decarboxylating L-histidine to histamine and is expressed in various types of cells including neuroendocrine tumors. Recent findings have demonstrated a high percentage of HDC immunoreactivity in many neuroendocrine tumors, including carcinoid tumors, small cell carcinomas of the lung, pheochromocytomas, and medullary carcinomas of the thyroid. HDC immunostaining was applied to pancreatic islet cells and related tumors to explore possible expression of HDC as a wide spectrum marker for neuroendocrine differentiation. A total of 24 cases (22 pancreatic endocrine neoplasms, one small cell carcinoma of the pancreas, and one mixed exocrine-endocrine carcinoma) along with normal pancreatic tissue were immunostained with the anti-HDC antibody. In a normal pancreas, a double immunostaining revealed possible colocalization of HDC with glucagon- or insulin-positive cells in the islets. Seventeen of 22 pancreatic endocrine neoplasms (77%) were found to be positive for HDC, and no distinct relation to hormonal activity was observed. One small cell carcinoma was strongly positive to HDC. One non-functional tumor with mixed exocrine and endocrine components showed a diffuse positive immunostaining for HDC, and some neoplastic glucagon- or somatostatin (SRIF)-positive cells coexpressed HDC. In conclusion, we demonstrated that the majority of pancreatic endocrine tumors expressed HDC, and we suggest that HDC is a wider new marker for neuroendocrine differentiation.

DOI： 10.1111/j.1440-1827.2004.01641.x

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H Ikota, A Tanimoto, H Komatsu, Y Ozawa, H Matsushita .  Ureteral leiomyoma causing hydronephrosis in Type 1 multiple endocrine neoplasia .  PATHOLOGY INTERNATIONAL54 ( 6 ) 457 - 459   2004.6Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

A rare case of leiomyoma of the ureter in a patient with type 1 multiple endocrine neoplasia (MEN) is reported. The case is of a Japanese man in his forties who had a past history of parathyroid gland hyperplasia, pancreatic islet cell tumors, and bilateral adrenocortical nodular hyperplasia. The leiomyoma, measuring 15 x 13 x 12 mm, was located in the right upper ureter, obstructing the lumen and causing hydronephrosis. Three small leiomyomas were also detected in the lower portion. Furthermore, histological examination revealed three tiny leiomyomatous nodules embedded in the muscular layer. It has been reported that type 1 MEN is often complicated by multiple leiomyoma in many organs, including the esophagus, stomach, lung, uterus, and skin. However, it is believed that this is the first report of leiomyomatosis of the ureter occurring in a patient with type 1 MEN. It should be recognized that multiple ureteral leiomyomas may develop in patients of type 1 MEN and can potentially result in hydronephrosis. The multiple development of leiomyoma suggests a causal relationship to MEN1 gene alteration.

DOI： 10.1111/j.1440-1827.2004.01642.x

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山本 信彦, 星原 芳雄, 志田 勝義, 布袋屋 修, 飯塚 敏郎, 田中 達朗, 橋本 光代, 山本 敬, 乳原 善文, 谷本 昭英 .  内視鏡的切除にて診断された回腸毛細血管腫の1例 .  Gastroenterological Endoscopy46 ( 4 ) 949 - 954   2004.4

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Publisher：(一社)日本消化器内視鏡学会  

57歳女.ネフローゼ症候群と診断されており,腎不全にて血液透析が開始されていた.貧血に対してエリスロポエチン投与が行われたが徐々に進行し,当センター紹介入院となった.下部消化管内視鏡検査で回盲弁より10cmほど口側に径7mm大の隆起性病変があり,持続性に小量の出血が認められた.可動性があり内視鏡的切除可能と判断し,高周波ポリペクトミーを施行した.病理組織学的診断は毛細血管腫であった.切除後は貧血の改善がみられ,切除7ヵ月後に施行した内視鏡検査では,切除部位に瘢痕が認められるのみで,特に病変の遺残再発は認められなかった

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T Sasaguri, A Tanimoto, S Kimura, Y Kohno, M Hirasawa, Y Matsuki, K Abe, H Hashimoto, T Hamada, Y Sasaguri .  Primary leiomyosarcoma of the vertebra: Case report and review of the literature .  PATHOLOGY INTERNATIONAL54 ( 1 ) 73 - 76   2004.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

A case of primary leiomyosarcoma of a thoracic vertebra associated with a compression fracture in a 75-year-old woman was preoperatively thought to be granulation tissue. Surgical decompression was performed and the histological and immunohistochemical studies established the diagnosis of leiomyosarcoma. Based on the clinical and radiological examinations, metastases were ruled out. Primary leiomyosarcoma of the vertebra is extremely rare and in that site it is considered to have a relatively poor prognosis.

DOI： 10.1111/j.1440-1827.2004.01582.x

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Sasaguri Y, Tanimoto A .  Role of macrophage-derived histamine in atherosclerosis-- chronic participation in the inflammatory response --. .  Journal of atherosclerosis and thrombosis11 ( 3 ) 122 - 130   2004Reviewed

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The atherosclerotic intimal lesion contains endothelial cells, smooth muscle cells, monocytes/macrophages and T lymphocytes, which constitute a histamine-cytokine network that participates in chronic inflammatory responses. Monocytes/macrophages and T lymphocytes express the histamine-producing enzyme histidine decarboxylase (HDC), and specific histamine receptors (HHR), which are switched from HH2R to HHR1 during macrophage differentiation. Endothelial and smooth muscle cells also express HHR in response to histamine. The effects of histamine on these cells include a regulation of atherosclerosis-related events such as cell proliferation, expression of matrix metalloproteinase, adhesion molecules and cytokines. Furthermore, recent studies have indicated that histamine and the activation of its specific receptors modulate the Th1/Th2 balance in inflammatory lesions through the regulation of cytokine production from inflammatory cells. The histamine-cytokine network in the atherosclerotic intima could regulate inflammatory and immune responses, including Th1/Th2 balance, and contribute to atherogenesis.

DOI： 10.5551/jat.11.122

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H Xu, A Tanimoto, Y Murata, S Kimura, KY Wang, Y Sasaguri .  Difference in responsiveness of human esophageal squamous cell carcinoma lines to epidermal growth factor for MMP-7 expression .  INTERNATIONAL JOURNAL OF ONCOLOGY23 ( 2 ) 469 - 476   2003.8Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Expression of MMP-7 in human esophageal squamous cell carcinoma lines (TE-9 and -10) was investigated. Under normal culture conditions, immunocytochemical staining and enzymography demonstrated the production of MMP-7 in their cytoplasm and its gelatinolytic activity in the medium of TE-9 and -10 cell cultures. When EGF was added to the cultures, Western blotting, and RT-PCR analysis showed a dose-dependent increase in the amount of MMP-7 synthesized in the TE-9 cells, whereas in TE-10 cells, EGF failed to stimulate MMP-7 production. For luciferase reporter analysis of MMP-7 transcription, pMMP7LucWI (1132-bp) and pMMP7LucWII (334-bp) were cloned in the luciferase pGL3-basic vector. The promoter activity was enhanced from 1.5- to 2-fold by the addition of EGF to TE-9 cells transfected with pMMP7LucWI or WII, even though the response was low as compared with that of 12-O-tetradecanoyl-phorbol-13-acetate (TPA); and in TE-10 cells, only TPA enhanced the promoter activity of MMP-7. Luciferase promoter analysis using a pMMP7WII mutant series revealed that the AP-1 site was essential for transcription of the MMP-7 gene in TE-9 cells, and Tcf-I was also an important site, and that to a lesser degree, Tcf-II and PEA3s participated in the transcription of the MMP-7 gene in these cells. Unlike the results with TE-9 cells, in TE-10 cells, EGF failed to stimulate transcription of the MMP-7 gene; and up-regulation of the promoter activity by TPA was dependent on the AP-1 site and to lesser degree, on Tcf-I and Tcf-II. These results suggest that EGF plays also an important role in MMP-7 production of TE-9 cells and that there is a difference not only in EGF-intracellular signaling system but also in regulation mechanisms of MMP-7 transcription by beta-catenin-Tcf and/or PEA3 system between these 2 carcinoma lines.

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K Aita, A Tanimoto, Y Fujimoto, S Momomura, F Takemoto, S Hara, H Matsushita .  Sarcomatoid collecting duct carcinoma arising in the hemodialysis-associated acquired cystic kidney: An autopsy report .  PATHOLOGY INTERNATIONAL53 ( 7 ) 463 - 467   2003.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

A case of sarcomatoid collecting duct carcinoma (CDC) arising in a long-term hemodialysis-associated acquired cystic kidney was reported. A 71-year-old woman with a 21-year history of hemodialysis showed a peritoneal metastatic carcinoma (carcinomatous peritonitis) with an unknown primary site. An autopsy revealed a sarcomatoid collecting duct carcinoma of the right kidney with multicyst formation. In addition to the carcinomatous peritonitis, the tumor metastasized to the lymph nodes and bilateral lung. The primary tumor was composed of both carcinomatous and sarcomatous components, suggesting a high-grade transformation. Carcinomatous tumor cells were positive for epithelial membranous antigen (EMA), cytokeratin, and reactive to soybean agglutinin and peanut agglutinin, whereas the sarcomatous cells were positive for vimentin as well as EMA. Thus, the immunohistochemical and lectin-histochemical analysis confirmed that the tumor originated in the medullary collecting duct. Although CDC is not common in acquired cystic kidney disease patients, attention should be given to the occurrence of high-grade carcinoma of rare histological variant, as well as conventional renal cell carcinoma.

DOI： 10.1046/j.1440-1827.2003.01502.x

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自見 政一郎, 佛坂 正幸, 松本 伸二, 藤井 圭, 柴田 恵介, 谷本 昭英, 武田 成彰 .  術前に診断しえた瘻孔形成を伴う回腸原発T細胞性悪性リンパ腫の1例 .  日本消化器外科学会雑誌36 ( 4 ) 289 - 293   2003.4

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Publisher：(一社)日本消化器外科学会  

症例は64歳男性で,便秘・右下腹部痛を主訴に,近医の注腸検査で回盲部腫瘍を指摘され,紹介入院となった.小腸造影透視では回腸末端に潰瘍性病変を認め,回腸末端と上行結腸の間には約6cmの瘻孔がみられた.ガリウムシンチでは右下腹部に集積を認め,大腸内視鏡検査では回腸末端に一部潰瘍形成を伴う全周性腫瘤を認めた.生検にてT細胞性悪性リンパ腫と診断し,右半結腸切除術を施行した.切除標本にて回腸末端に潰瘍性病変を認め,潰瘍性病変と上行結腸の間には瘻孔が確認された.病理組織学的に異型細胞は消化管壁内に限局し,免疫組織染色にてLCAおよびUCHL-I陽性,CD2,CD3,CD4,CD5,CD7陽性を示し,回腸原発T細胞性悪性リンパ腫stage Iと確診した.術後,CHOP療法を4クール行い,術後2年8ヵ月経過した現在,再発はみられない

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LH Wu, A Tanimoto, Y Murata, T Sasaguri, JL Fan, Y Sasaguri, T Watanabe .  Matrix metalloproteinase-12 gene expression in human vascular smooth muscle cells .  GENES TO CELLS8 ( 3 ) 225 - 234   2003.3

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Publisher：BLACKWELL PUBLISHING LTD  

Background: Matrix metalloproteinases (MMPs) play an important role in smooth muscle cell (SMC) migration and proliferation during vascular remodelling. To investigate the expression of MMP-12 by SMCs, we examined the protein secretion and mRNA expression of MMP-12 by cultured medial SMCs and intimal SMCs derived from human aortic atherosclerotic lesions. To further elucidate the molecular mechanism for MMP-12 expression in SMCs, we determined the sequence requirements for MMP-12 gene transcriptional activity.
Results: Cultured medial SMCs and intimal SMCs showed substantial MMP-12 expression at both the protein and mRNA levels. A series of 5'-deletion and site-directed mutants of the human MMP-12 promoter demonstrated that an AP-1 site spanning -81 to -75 bp was critical for the MMP-12 promoter activity in SMCs. An electrophoretic mobility shift assay confirmed the AP-1 binding activity in SMCs and showed that the protein bound to the AP-1 site consisted predominantly of c-Jun, JunD and Fra-1. Two structurally different inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY294002, inhibited MMP-12 transcriptional activity and AP-1 binding.
Conclusion: These results indicated the expression of MMP-12 in vascular SMCs and showed that the MMP-12 gene expression was dependent on the AP-1 binding activity. Phosphatidylinositol 3-kinase signalling may be involved in MMP-12 transcriptional activation through AP-1 binding activity.

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Y Matsuki, A Tanimoto, T Hamada, Y Sasaguri .  Histidine decarboxylase expression as a new sensitive and specific marker for small cell lung carcinoma .  MODERN PATHOLOGY16 ( 1 ) 72 - 78   2003.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Histidine decarboxylase is one of the enzymes of the amine precursor uptake and decarboxylation. system and is known to be distributed in mast cells and enterochromaffin-like cells. With the hypothesis that histidine decarboxylase expression is a marker for neuroendocrine differentiation, we studied the immunoreactivity of histidine decarboxylase in neuroendocrine cells and tumors of the thyroid gland, adrenal medulla, lung, and gastrointestinal tract. Formalin-fixed paraffin sections were subjected to immunohistochemistry using and histidine decarboxylase antibody, and the sensitivity and specificity were compared with those of conventional neuroendocrine markers (CD56, chromogranin A, synaptophysin, and neuron-specific enolase). Enterochromaffin or enterochromaffin-like cells, adrenal chromaffin cells, and thyroid C-cells were positive for histidine decarboxylase, and related tumors (carcinoid tumor, pheochromocytoma, medullary carcinoma) showed a high percentage of positive staining. Furthermore, we used the antibody to distinguish small cell lung carcinoma from non-neuroendocrine lung carcinoma and also to detect neuroendocrine differentiation in large-cell neuroendocrine carcinoma and gastrointestinal small-cell carcinoma. The anti-histidine decarboxylase antibody stained most small cell lung carcinoma (18 of 23, sensitivity 0.78), and was rarely reactive with non-neuroendocrine lung tumors (2 of 44; specificity, 0.95). These values were close to those obtained from CD56 staining (sensitivity/specificity, 0.87/0.98). Histidine decarboxylase was also positive for 6 of 12 large cell neuroendocrine carcinomas and 4 of 7 gastrointestinal small cell carcinomas. In conclusion, we demonstrated that histidine decarboxylase is useful to distinguish between small cell lung carcinoma and non-neuroendocrine carcinoma and to demonstrate neuroendocrine differentiation.

DOI： 10.1097/01.MP.0000044485.14910.3A

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Sasaguri Y, Tanimoto A .  Multi-functional roles of granulocyte macrophage-colony stimulating factor in atherosclerosis. .  Journal of Japanese Colleage of Angiology43   585 - 594   2003Reviewed

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R Padmanabhan, A Tanimoto, Y Sasaguri .  Transactivation of human cdc2 promoter by adenovirus E1A .  ADENOVIRUSES: MODEL AND VECTORS IN VIRUS-HOST INTERACTIONS272   365 - 397   2003Invited Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG BERLIN  

Expression of the adenovirus oncoprotein E1A 12S induces the heterotrimeric transcription factor, NF-Y. NF-Y binds to the two CCAAT motifs upstream of the transcriptional start site of the human cdc2 promoter and is required for activation of the promoter by El A 12S in cycling cells. The observations that a number of eukaryotic cell cycle regulatory genes also contain the CCAAT motifs and NF-Y binds to them support the notion that E1A 12S could play an important role in deregulated expression of these genes through activation of NF-Y gene in cycling cells.

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笹栗 靖之, 谷本 昭英 .  【動脈硬化と細胞外マトリックス】動脈硬化における細胞外マトリックスとマトリックスメタロプロテアーゼの役割(Atherosclerosis and Extracellular Matrix Extracellular Matrix and Matrix Metalloproteinases in Atherosclerosis) .  Connective Tissue34 ( 4 ) 327 - 336   2002.12Reviewed

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Language：English   Publisher：日本結合組織学会  

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T Morishita, M Tsutsui, H Shimokawa, M Horiuchi, A Tanimoto, O Suda, H Tasaki, PL Huang, Y Sasaguri, N Yanagihara, Y Nakashima .  Vasculoprotective roles of neuronal nitric oxide synthase .  FASEB JOURNAL16 ( 12 ) 1994 - +   2002.10Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

Nitric oxide (NO) has multiple important actions that contribute to the maintenance of vascular homeostasis. NO is synthesized by three different isoforms of NO synthase (NOS), all of which have been reported to be expressed in human atherosclerotic vascular lesions. Although the regulatory roles of endothelial NOS (eNOS) and inducible NOS (iNOS) on the development of atherosclerosis have been described, little is known about the role of neuronal NOS (nNOS). Here, we show that nNOS also exerts important vasculoprotective effects in vivo. In a carotid artery ligation model, nNOS gene-deficient (nNOS-KO) mice exhibited accelerated neointimal formation and constrictive vascular remodeling caused by blood flow disruption. In a rat balloon injury model, the selective inhibition of nNOS activity potently enhanced vasoconstrictor responses to a variety of calcium-mobilizing stimuli, suppressed tissue cGMP concentrations, a marker of vascular NO production, and exacerbated neointimal formation. In both models, nNOS was absent before injury and was up-regulated only after the injury, and was predominantly expressed in the neointima and medial smooth muscle cells. These results provide the first direct evidence that nNOS plays important roles in suppressing arteriosclerotic vascular lesion formation in vivo.

DOI： 10.1096/fj.02-0155fje

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K Imada, T Sato, K Hashizume, A Tanimoto, Y Sasaguri, A Ito .  An antiprogesterone, onapristone, enhances the gene expression of promatrix metalloproteinase 3/prostromelysin-1 in the uterine cervix of pregnant rabbit .  BIOLOGICAL & PHARMACEUTICAL BULLETIN25 ( 9 ) 1223 - 1227   2002.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Using a progesterone receptor antagonist, onapristone/ZK 98.299, we examined the in-vivo effects of progesterone on the function of uterine cervix during pregnancy. Onapristone was intravenously administered to pregnant rabbits on day 20 post coitum. After 24 h, the antiprogesterone increased the wet weight of the uterine cervix and decreased the DNA concentration in the cervix. In-situ hybridization also indicated that antiprogesterone augmented the expression of matrix metalloproteinase (MMP)-3/stromelysin-1 mRNA in the uterine cervix. These changes are very similar to those observed and reported thus far in ripened and dilated uterine cervix. These results suggest that during pregnancy, progesterone closely participates in the maintenance of the function of uterine cervix by preventing the production of MMPs and thereby destruction of extracellular matrix, and thus add support to the theory that antiprogesterone has the potential to accelerate for the uterine cervical ripening and dilatation.

DOI： 10.1248/bpb.25.1223

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O Suda, M Tsutsui, T Morishita, A Tanimoto, M Horiuchi, H Tasaki, PL Huang, Y Sasaguri, N Yanagihara, Y Nakashima .  Long-term treatment with N-omega-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice .  CIRCULATION106 ( 13 ) 1729 - 1735   2002.9Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background-N-omega-nitro-L-arginine methyl ester (L-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects Of L-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice).
Methods and Results-Wild-type and eNOS-KO mice received L-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with L-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with L-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation Of L-arginine. Vascular NO and cGMP levels were not significantly reduced by L-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with L-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin 11 type I receptor antagonist) along with the suppression of vascular lesion formation.
Conclusions-These results provide the first direct evidence that the long-term vascular effects Of L-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects Of L-NAME in vivo.

DOI： 10.1161/01.CIR.0000029749.16101.44

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A Tanimoto, T Hamada, T Yamamoto, S Kimura, Y Matsuki, Y Sasaguri .  MALT lymphoma with extreme plasma cell differentiation of the rectum .  AMERICAN JOURNAL OF GASTROENTEROLOGY97 ( 7 ) 1860 - 1862   2002.7Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0002-9270(02)04235-1

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R Narita, T Oto, Y Mimura, M Ono, S Abe, A Tabaru, Yoshikawa, I, A Tanimoto, M Otsuki .  Biliary obstruction caused by intrabiliary transplantation from hepatocellular carcinoma .  JOURNAL OF GASTROENTEROLOGY37 ( 1 ) 55 - 58   2002.1Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG TOKYO  

A rare autopsy case of hepatocellular carcinoma (HCC) presenting as extrahepatic bile duct obstruction is reported. A 54-year-old man who had been treated at another hospital for obstructive jaundice was referred to our hospital and admitted on March 1, 1998, because of progressive jaundice. On hospital day 94, he died of bleeding esophageal varices. At autopsy, a bile duct tumor, measuring 3.0 X 3.5 cm and adhering to the wall of the left hepatic duct, occluded the common hepatic duct at the hilus. A tumor measuring 2.0 X 2.0 cm was found in the parenchyma of the left liver lobe. The parenchymal tumor was not continuous with the extrahepatic bile duct tumor. Histologically, the bile duct tumor and the parenchymal tumor of the left lobe were diagnosed as HCC. The bile duct tumor was attached to the mucosa of the bile duct with a thin stalk. No invasive growth into the submucosa was observed. The tumor may have been an intrabiliary transplantation from the HCC in the left lobe via the bile duct.

DOI： 10.1007/s535-002-8134-0

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K Yoshimura, A Tanimoto, T Abe, M Ogawa, T Yutsudo, M Kashimura, S Yoshida .  Shiga toxin 1 and 2 induce apoptosis in the amniotic cell line WISH .  JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION9 ( 1 ) 22 - 26   2002.1Reviewed International journal

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Objective: The aim of this study was to evaluate the toxicity of Shiga toxin (Stx) 1 and 2 on amniotic cells in vitro.
Methods: WISH cells, which were derived from human amniotic cells, and Vero cells were cultivated with or without Stxs. After 24 hours of culture, cell viability was measured by Cell Counting Kit-8, and extracted DNA was electrophoresed on a 1% agarose gel. The morphologic changes were observed by Papanicolaou staining, and the apoptotic index (percentage of apoptotic nuclei per total nuclei) was calculated. Quantification of apoptotic cells was also measured by an enzyme-linked immunosorbent assay.
Results: The viability of WISH cells decreased in proportion to the concentrations of Stxs. Cellular ladder formation was observed by DNA electrophoresis of Stx-treated WISH cells, and the typical morphologic changes were observed by Papanicolaon staining. The proportion of apoptotic cells increased in response to Stxs.
Conclusions: Stxs injured WISH cells directly and induced apoptosis in vitro. WISH cells were as sensitive as Vero cells to Stxs and cell death occurred by apoptosis. (J Soc Gynecol Investig 2002;9:22-6) Copyright (C) 2002 by the Society for Gynecologic Investigation.

DOI： 10.1016/S1071-5576(01)00143-5

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A Tanimoto, Y Murata, M Nomaguchi, S Kimura, N Arima, H Xu, T Hamada, Y Sasaguri .  Histamine increases the expression of LOX-1 via H2 receptor in human monocytic THP-1 cells .  FEBS LETTERS508 ( 3 ) 345 - 349   2001.11Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a member of the scavenger receptor family, and is known to be expressed in monocytes/macrophaaes. We investigated the effect of histamine on the expression of LOX-1 in cells of the human monocytic leukemia cell line THP-1. Histamine as well as forskolin and dibutyryl cyclic AMP (Bt(2)-cAMP) stimulated the THP-1 monocytes to express the LOX-1 gene at the transcription level. This histamine effect on LOX-1 gene expression, via the histamine H2 receptor-mediated cAMP signal transduction pathway, was reduced after differentiation of the cells into macrophages, even though forskolin and Bt(2)-cAMP still enhanced the gene expression. The alteration of the responsiveness of LOX-1 expression to histamine was related to suppressed expression of the H2 receptor in THP-1 macrophages. The switch of the predominant class of histamine receptors between H1 and H2 would modulate the effects of histamine on LOX-1 gene expression in monocytes and macrophages, and therefore, would play a certain role in the inflammatory aspects of atherogenesis. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0014-5793(01)03073-3

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S Higuchi, A Tanimoto, N Arima, H Xu, Y Murata, T Hamada, K Makishima, Y Sasaguri .  Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophages in relation to atherosclerosis .  FEBS LETTERS505 ( 2 ) 217 - 222   2001.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We investigated the localization of histidine decarboxylase (HDC), which is the rate-limiting enzyme that generates histamine from histidine, in human aorta/coronary artery. RT-PCR and immunohistochemical staining revealed that the HDC gene was expressed in monocytes/macrophages and T cells in the arterial intima but not in smooth muscle cells in either the arterial intima or the media. A luciferase promoter assay with U937 and Jurkat cells demonstrated that interleukin-4 (IL-4) inhibited the expression of the HDC gene. In contrast, among a scavenger receptor family, IL-4 as well as histamine upregulated U937 cells to express the LOX-1 gene but not the SR-A gene, which genes encode receptors that scavenge oxidized lipids. These findings suggest that histamine synthesized in the arterial wall participates in the initiation and progression of atherosclerosis and that IL-4 can act as an important inhibitory and/or stimulatory factor in the function of monocytes/macrophages modulated by histamine in relation to the process of atherosclerosis. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0014-5793(01)02823-X

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LH Wu, A Tanimoto, Y Murata, JL Fan, Y Sasaguri, T Watanabe .  Induction of human matrix metalloproteinase-12 gene transcriptional activity by GM-CSF requires the AP-1 binding site in human U937 monocytic cells .  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS285 ( 2 ) 300 - 307   2001.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Matrix metalloproteinase-12 (MMP-12) is critical for the migration of monocytes/macrophages into inflammatory sites through the basement membranes. We previously reported that MMP-12 expression was initially induced by granulocyte macrophage colony-stimulating factor (GM-CSF) in human peripheral blood monocytes and U937 monocytic cells. To further elucidate the molecular mechanism for the regulation of MMP-12 expression by GM-CSF in monocytes, we determined the sequence requirements for the MMP-12 gene transcriptional response of U937 monocytic cells to GM-CSF by using luciferase reporter and electrophoretic mobility shift assays. A series of 5 ' -deletion and site-directed mutation of the human MMP-12 promoter demonstrated that an AP-1 site spanning the -81 to -75-bp region is critical for the induction of MMP-12 promoter activity by GM-CSF. The electrophoretic mobility shift assay revealed that AP-1 binding activity was increased by GM-CSF treatment and that the AP-1 complex induced by GM-CSF consisted of multiple Jun and Fos isoforms. These results indicate that MMP-12 expression in U937 monocytes was initially induced by GM-CSF through the AP-1 binding activity. (C) 2001 Academic Press.

DOI： 10.1006/bbrc.2001.5161

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A Tanimoto, N Arima, R Hayashi, T Hamada, Y Matsuki, Y Sasaguri .  Teratoid carcinosarcoma of the ovary with prominent neuroectodermal differentiation .  PATHOLOGY INTERNATIONAL51 ( 10 ) 829 - 832   2001Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

We present what we believe to be only the second report of ovarian teratoid carcinosarcoma. The patient, a 59-year-old woman, was admitted to hospital complaining of a pelvic mass and of abdominal fullness. Advanced ovarian cancer was diagnosed, and a tumorectomy was done. The tumor occupied the pelvis, and metastasis was found in the liver and spleen. The solid tumor was composed of chondrosarcoma, squamous cell carcinoma, adenocarcinoma and malignant neuroectodermal components, which contained ganglioneuroblastoma-like and medulloepithelioma-like areas. Immunohistochemically, the neuroectodermal cells were positive for both neural and epithelial markers. This ovarian tumor consisted of frankly malignant components, with prominent neuroectodermal elements mixed with epithelial and mesenchymal elements in an organoid fashion; a quite rare tumor.

DOI： 10.1046/j.1440-1827.2001.01275.x

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N Arima, A Tanimoto, T Hamada, Y Sasaguri, E Sasaki, T Shimokobe .  MALT lymphoma arising in giant diverticulum of ascending colon .  AMERICAN JOURNAL OF GASTROENTEROLOGY95 ( 12 ) 3673 - 3674   2000.12Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0002-9270(00)02207-3

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N Arima, A Tanimoto, R Hayashi, T Hamada, Y Sasaguri .  Ovarian yolk sac tumor with virilization during pregnancy: Immunohistochemical demonstration of Leydig cells as functioning stroma .  PATHOLOGY INTERNATIONAL50 ( 6 ) 520 - 525   2000.6Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE ASIA  

A case is reported of yolk sac tumor occurring in the left ovary and complicated by pregnancy. The 22-year-old patient presented at 28 weeks gestation with virilization and elevated serum levels of testosterone and alpha-fetoprotein. The tumor showed the typical features of yolk sac tumor with a mixture of islands of Leydig cells. The accumulations of Leydig cells were well demarcated from the cellular components of the yolk sac tumor and were distributed throughout the tumor, although with predominant localization at the periphery. By immunohistochemistry the Leydig cells were intensely positive for vimentin and negative for cytokeratins, allowing clear distinction from the cell components of the yolk sac tumor, which were positive for cytokeratins and negative for vimentin. Testosterone was also identified in the cytoplasm of the Leydig cells. After tumor resection the testosterone and alpha-fetoprotein levels declined simultaneously; this, together with the immunohistochemical demonstration of testosterone, indicates that the Leydig cells were responsible for the endocrine manifestations. Furthermore, antibodies against inhibin alpha-subunit and calretinin could be used to detect the Leydig cells. The present case, a combination of yolk sac tumor and Leydig cells acting as a functioning stroma and causing virilization during pregnancy, is very rare.

DOI： 10.1046/j.1440-1827.2000.01073.x

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KY Wang, N Arima, S Higuchi, S Shimajiri, A Tanimoto, Y Murata, T Hamada, Y Sasaguri .  Switch of histamine receptor expression from H2 to H1 during differentiation of monocytes into macrophages .  FEBS LETTERS473 ( 3 ) 345 - 348   2000.5Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

It is known that histamine suppresses gene expression and synthesis of tumor necrosis factor alpha (TNF-alpha) induced by lipopolysaccharide (LPS) in human peripheral blood mononuclear monocytes (HPM) or alveolar macrophages via histamine H2 receptors. We investigated the effect of histamine and differentiation in macrophages an the expression and secretion of TNF-alpha TNF-alpha-converting enzyme (TACE), and histamine H1 and H2 receptors by use of a leukemia cell line, U937, and HPM. Differentiation of U937 and HPM cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced the H1 receptor expression and rather suppressed the H2 receptor, resulting in up-regulation of the histamine-induced expression and secretion of TNF-alpha, modulated via TACE. Therefore, histamine failed to inhibit up-regulated expression of TNF-alpha induced by LPS in macrophages. The switch from H2 to H1 receptors during differentiation in the monocyte/macrophage lineage could participate in the pathogenic processes of atherosclerosis and inflammatory reactions in the arterial wall. (C) 2000 Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(00)01560-X

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K Yoshimura, J Fujii, A Tanimoto, T Yutsudo, M Kashimura, SI Yoshida .  Effects of Shiga toxin 2 on lethality, fetuses, delivery, and puerperal behavior in pregnant mice .  INFECTION AND IMMUNITY68 ( 4 ) 2254 - 2258   2000.4Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Shiga toxin 2 (Stx2) is produced by enterohemorrhagic Escherichia coli (EHEC) and is known as the major virulence factor of EHEC, The aim of this study was to evaluate the effects of Stx2 on (i) maternal lethality, (ii) fetuses, (iii) delivery period, and (iv) maternal behavior after delivery. Timed pregnant ICR mice were injected intravenously with Stx2 on day 5 of pregnancy (early stage) or on day 15 (late stage). In early-stage experiments, the number of normal fetuses of mice injected with Stx2 was significantly lower than that of control mice. In late-stage experiments, mothers injected with Stx2 delivered normal numbers of neonates, but could not take care of them. The lethal doses of Stx2 were not different for pregnant and nonpregnant female mice at either stage. We conclude that Stx2 is toxic to the fetus in early pregnancy and affects maternal puerperal behavior in late pregnancy.

DOI： 10.1128/IAI.68.4.2254-2258.2000

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CY Kao, A Tanimoto, N Arima, Y Sasaguri, R Padmanabhan .  Transactivation of the human cdc2 promoter by adenovirus E1A - E1A induces the expression and assembly of a heteromeric complex consisting of the CCAAT box binding factor, CBF/NF-Y, and a 110-kDa DNA-binding protein .  JOURNAL OF BIOLOGICAL CHEMISTRY274 ( 33 ) 23043 - 23051   1999.8Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Cyclin-dependent kinases (CDKs) play an important role in the eukaryotic cell cycle progression. Cdc2 (CDK1) is expressed in late G(1)/S phase and required for G(2) to M phase transition in higher eukaryotes, The oncoproteins, SV40 large T antigen and adenovirus E1A, induce a 110-kDa protein which specifically recognizes the two inverted CCAAT motifs of the cdc2 promoter in cycling cells and plays an essential role in transactivation of the human cdc2 promoter. Since these CCAAT motifs also conform to the consensus binding sites for the ubiquitous heterotrimeric transcription factor, CBF/NF-Y, the role of CBF/NF-Y in the transactivation of the cdc2 promoter was examined in this study. Our results indicate that CBF/NF-Y and the 110-kDa protein interact with the CCAAT box motif to form a heteromeric complex. However, mutagenesis of the pentanucleotide CCAAT motif or in the presence of urea greater than 2.5 M, no heteromeric complex was formed. In contrast, the 110-kDa protein could still bind the mutant CCAAT motif or with the wild type motif in the presence of 2.5 M urea. Furthermore, E1A.12S induced the gene expression of all three subunits of CBF/NF-Y. Coexpression of E1A and a dominant negative mutant NF-YA subunit significantly reduced the E1A-mediated transactivation of the cdc2 promoter in a dose-dependent manner. These results support the conclusion that E1A protein mediates optimal transactivation of the human cdc2 promoter by inducing the expression and assembly of a heteromeric complex consisting of the 110-kDa protein and the CBF/NF-Y which interacts with the two CCAAT motifs of the cdc2 promoter.

DOI： 10.1074/jbc.274.33.23043

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S Shimajiri, N Arima, A Tanimoto, Y Murata, T Hamada, KY Wang, Y Sasaguri .  Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene .  FEBS LETTERS455 ( 1-2 ) 70 - 74   1999.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

One characteristic elements in re promoter of the matrix metalloproteinase 9 (MMP-9) gene is the d(CA) repeat. To investigate whether this element regulates the transcription of the MMP-9 gene and its enzymatic activities, we sequenced the promoter region isolated from esophageal carcinoma cell lines. TE9 cells with low MMP-9 enzymatic activity had the number of d(CA) repeats shortened from 21 to 14 or 18, TE8, TE10 and TE11 cells with high MMP-9 activities had 21 or 23 d(CA) repeats, Luciferase assays using MMP-9 promoter containing 18, 14 or 0 d(CA) repeats showed transcriptional activities which were 50, 50 or 5%, respectively, of the level achieved with promoter containing 21 d(CA) repeats, Sequence analysis of the promoter of 223 Japanese subjects revealed that most had two alleles with 20, 21 or 22 d(CA) repeats, whereas six had one or two alleles with 14, 18 or 19 d(CA) repeats, We postulate that length alteration of the d(CA) repeat causes phenotypic: differences among carcinoma cells and that microsatellite instability may contribute to the polymorphism of d(CA) repeat length, (C) 1999 Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(99)00863-7

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T Sasaguri, A Tanimoto, N Arima, T Hamada, H Hashimoto, T Sasaguri .  Myoepithelioma of soft tissue .  PATHOLOGY INTERNATIONAL49 ( 6 ) 571 - 576   1999.6Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE ASIA  

A myoepithelioma occurred in the subcutaneous tissue of the right shoulder of a 28-year-old man. The well-demarcated nodular tumor (3.0 x 2.8 cm) was located in the subcutaneous tissue with no adhesion to the deltoid muscle. The tumor was composed of a fascicular proliferation of spindle cells with variable amounts of stroma and showed areas of Sheets of epithelioid cells, In most areas, the tumor cells had uniform nuclei, but pleomorphic epithelioid cells were focally present. Mitotic activity was three per 10 high-power fields. No ductular structure was found throughout the tumor. Immunohistochemical and ultrastructural studies confirmed the myoepithelial origin of the tumor cells. The occurrence of myoepithelioma in the subcutaneous tissue has been rarely reported. Even though the tumor showed no aggressive behavior on the 2-year followup, it is still too early to comment definitely on the behavior of myoepithelioma of the subcutaneous tissue. This case provides further information about soft tissue myoepithelioma.

DOI： 10.1046/j.1440-1827.1999.00912.x

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A Tanimoto, T Hamada, K Higashi, Y Sasaguri .  Distribution of cadmium and metallothionein in CdCl2-exposed rat kidney: Relationship with apoptosis and regeneration .  PATHOLOGY INTERNATIONAL49 ( 2 ) 125 - 132   1999.2Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Male Sprague-Dawley rats were injected subcutaneously with 0.6 mg cadmium/kg bodyweight per day for 6 weeks. In each week of exposure, rats were killed and the localization of cadmium and metallothionein in the kidney was studied by histochemical and immunohistochemical methods. Although cadmium was localized throughout the proximal tubules during exposure, apoptosis and subsequent regeneration were observed mainly in the straight portion of the proximal tubules after 4 weeks of exposure. The distribution of tubular injury may thus not necessarily coincide with that of cadmium. Expression of metallothionein was also detected in the cytoplasm and nuclei of the convoluted and the straight portion of the proximal tubules, but the latter became positive in accordance with apoptosis and regeneration. These results suggest a close relationship between metallothionein distribution and tubular cell regeneration.

DOI： 10.1046/j.1440-1827.1999.00833.x

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T Hamada, A Tanimoto, T Sasaguri, N Arima, S Shimajiri, R Nakano, Y Sasaguri .  Apoptosis of human kidney 293 cells is promoted by polymerized Cd-metallothionein .  METALLOTHIONEIN IV   489 - 495   1999

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Publisher：BIRKHAUSER VERLAG AG  

Exposure to 12.5 to 37.5 mu M CdCl2 induced apoptosis in transformed human kidney cells (293 cells) as confirmed by characteristic ultrastructural features, a ladder on gel electrophoresis of extracted DNA, and fragmentation of nucleosomes as detected by enzyme linked immunosorbent assay (ELISA). Higher concentrations of Cd were less effective in inducing apoptosis. Furthermore, addition of the protein extract from the serum-free medium used for Cd-exposure promoted apoptosis exhibiting the same features as that after Cd-exposure. The apotosis induced by the protein was dose-dependent. The molecular weight of the protein (Cd-protein) was shown to be 40 kDa by gel filtration. Two-dimensional electrophoresis revealed the Cd-protein as a single spot with a molecular weight of 6 kDa and pI of 4.5. Competitive ELISA showed that the Cd-protein reacted with anti-metallothionein antibody. The present findings suggest that apoptosis is induced not only by Cd itself but also by poly merited metallothionein (MT) molecules released from cells into the medium.

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Ying Yan, Ken Higashi, Akihide Tanimoto, Yukiyo Fukamachl, Hideaki Itoh, Tetsuya Abe, Taneaki Higashi .  Remarkable difference in the incidence of liver tumors by N- nitrosodimethylamine in carcinogen-resistant DRH rat and its parental strain Donryu rat .  Journal of UOEH20 ( 4 ) 307 - 314   1998.12Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：University of Occupational and Environmental Health  

The carcinogen-resistant inbred DRH rat strain was developed from the carcinogen-sensitive Donryu rat and showed a remarkably lower incidence of liver tumors than the latter after administration of either 3'-methyl-4- dimethylaminoazobenzene (3'-Me-DAB) or 2-acetylaminofluorene (2-AAF). In the present study, we examined the tolerance of DRH rat to another type of hepatocarcinogen, that is, N-nitrosodimethylamine (DMN). Male DRH and Donryu rats, 3 weeks of age, were given a single i.p. injection of 10 mg/kg body weight DMN and were sacrificed I year later. Five of 11 Donryu rats (45%) had macroscopically detectable tumors: 9 liver tumors in 4 rats and 1 urinary bladder tumor in the other rat. On the contrary, no tumors were detectable in the livers or other organs of 10 DRH rats under the same conditions. These results and other circumstantial evidence indicate that the different susceptibility of chemical carcinogenesis between DRH and Donryu rats is independent of individual pathways of metabolic activation of carcinogens.

DOI： 10.7888/juoeh.20.307

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Yan Ying, 東 監, 谷本 昭英, 深町 幸代, 伊藤 英明, 安部 哲哉, 東 胤昭 .  N-ニトロソジメチルアミンによる肝癌の発生における発癌耐性DRHラットとその親株呑竜ラットとの間での顕著な差異 .  産業医科大学雑誌20 ( 4 ) 307 - 314   1998.12

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Publisher：産業医科大学  

近交系の発癌耐性ラット(DRH)は,発癌感受性である呑竜ラットから単離・樹立され,3'-メチル-DABやアセチルアミノフルオレン等による肝癌の発生は著しく抑制されている.上記の肝化学発癌物質とは代謝的活性化の全く異なるN-ニトロソジメチルアミンを用いて両ラットで発癌実験を行った.N-ニトロソジメチルアミンを離乳直後の雄ラットの腹腔内に1回(10mg/kg)投与し,1年後での発癌状態を調べた.11匹の呑竜ラットで5匹に肉眼的に検出できる腫瘍が認められた.4匹の呑竜ラットで9肝癌と,他の1匹では膀胱癌が存在し,病理組織学的にも確認した.これに反し,10匹のDRHラットでは肝及び他の臓器で肉眼的に識別できるような腫瘍は皆無であった

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A Tanimoto, H Chen, CY Kao, E Moran, Y Sasaguri, R Padmanabhan .  Transactivation of the human cdc2 promoter by adenovirus E1A in cycling cells is mediated by induction of a 110-kDa CCAAT-box-binding factor .  ONCOGENE17 ( 24 ) 3103 - 3114   1998.12Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

Cyclin-dependent protein kinases (Cdks) are key regulatory proteins of the eukaryotic cell cycle. Cdc2 is expressed in late G1/S phase and functions in the G2 to M phase transition. Adenovirus E1A proteins are known to induce the expression of p34(cdc)2 and DNA synthesis in normal quiescent cells. In this study, mutational analysis of the human cdc2 promoter revealed that transactivation of the promoter by the E1A proteins in cycling cells is mediated through the two CCAAT box binding motifs. A 110-kDa protein (CBF/cdc2) was identified in nuclear extracts from monkey kidney (CV-1) cells stably expressing E1A as well as from adenovirus-transformed human 293 cells, Further, we show that this E1A-inducible CBF/cdc2 is related to the CBF which was shown to activate the heat shock protein 70 promoter. Analyses of the functional domain(s) of E1A required for the induction of the CBF and transactivation of the cdc2 promoter in these conditions revealed that E1A mutants which were defective in binding the pRB family of proteins or the cellular p300 protein were still active in assays measuring the induction of the CBF and transactivation of the cdc2 promoter, albeit with reduced efficiencies. But the E1A mutant which lost both functional domains was inactive in these assays. These results suggest that E1A has redundant functional domains for the induction of the 110-kDa CBF and activation of human cdc2 gene expression.

DOI： 10.1038/sj.onc.1202236

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A Tanimoto, CY Kao, CC Chang, Y Sasaguri, R Padmanabhan .  Deregulation of cdc2 gene expression correlates with overexpression of a 110 kDa CCAAT box binding factor in transformed cells .  CARCINOGENESIS19 ( 10 ) 1735 - 1741   1998.10Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Eukaryotic cell cycle progression is regulated by an orderly and sequential activation of several cyclin-dependent kinases, which phosphorylate key substrates during this process. p34(cdc2), the catalytic subunit of cdc2 kinase, is expressed at the late G(1)/S boundary and is required for the G(2)--&gt;M phase transition. Transactivation of the human cdc2 promoter by the DNA tumor virus-encoded oncogenic protein SV40 large T antigen is mediated by induction of a novel 110 kDa CCAAT box binding factor (CBF/cdc2), To investigate whether induction of CBF/cdc2 is an intrinsic property of the viral oncoprotein or is a common event during transformation of normal cells, expression of CBF/cdc2 was analyzed in many human tumor cell lines and in rodent cells spontaneously transformed or stably expressing various oncogenes, Our results showed that CBF/cdc2 was overexpressed in all transformed cells examined, including human 293, MCF-7, HeLa and HepG2 cells. Moreover, expression of CBF/cdc2 was elevated in spontaneously transformed rat liver epithelial cells (C4T), but not detectable in the non-tumorigenic parental (RLE) cells. The elevated levels of CBF/cdc2 expression in C4T cells correlated well with increased cdc2 mRNA and p34(cdc2) levels. CBF/cdc2 was also overexpressed in a rat liver epithelial cell line (WB) stably transfected with various oncogenes, v-myc, v-Ha-ras and mutated rat neu and v-src, Using an electrophoretic mobility shift assay, specific binding of CBF/cdc2 to the CCAAT box motifs of the human cdc2, cycA and cdc25C promoters was detected, suggesting that transcription of these cell cycle regulatory genes are coordinately activated by CBF/cdc2.

DOI： 10.1093/carcin/19.10.1735

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T Hamada, A Tanimoto, N Arima, Y Ide, T Sasaguri, S Shimajiri, Y Sasaguri .  Altered membrane skeleton of red blood cells participates in cadmium-induced anemia .  BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL45 ( 4 ) 841 - 847   1998.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS AUST  

Poikilocytosis of red blood cells (RBCs) was observed to be associated with anemia in rats given subcutaneous injections of cadmium (Cd). Phase-contrast light and scanning electron microscopic examinations revealed that acanthocytes appeared in the early stages of administration, and that the number of RBC fragments increased later. Ultrastructural analysis of RBC ghosts by negative staining demonstrated that the normal lattice structure of the membrane skeleton was abolished. The osmotic fragility curve of the Cd-exposed RBCs disclosed that most of the cells were less fragile than control RBCs. These data indicate that the RBC membrane skeleton is initially altered by Cd-exposure, followed by deformation of the cell, thus promoting intrasplenic hemolysis, and resulting in anemia.

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Nishigaki, I, A Tanimoto, Y Sasaguri, K Yagi .  Glycated protein-iron chelate increases lipid peroxide level in cultured aortic endothelial and smooth muscle cells .  BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL45 ( 3 ) 519 - 526   1998.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS AUST  

Formation of an iron chelate of glycated protein was demonstrated by the appearance of an absorption peak at approximately 270 nm after mixing glycated bovine serum albumin with FeCl3. This peak disappeared and a new peak appeared at approximately 420 nm to form an isosbestic point at approximately 340 nm by the addition of deferoxamine mesylate, an iron-chelating agent, to the mixture, thus confirming the formation of the iron chelate of the glycated protein in the mixture. The lipid peroxide level was increased markedly in endothelial cells and slightly in smooth muscle cells from bovine aorta incubated in the medium containing glycated fetal bovine serum-iron chelate. Morphological observation by phase-contrast microscopy and scanning electron microscopy revealed that the glycated fetal bovine serum-iron chelate caused intense damage to the endothelial cells. These results indicate that glycated protein-iron chelate provokes lipid peroxidation, which explains at least in part the mechanism of atherogenesis found in diabetic patients.

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T Sasaguri, N Arima, A Tanimoto, S Shimajiri, T Hamada, Y Sasaguri .  A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells .  ATHEROSCLEROSIS138 ( 2 ) 247 - 253   1998.6Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Effect of interleukin 4 (IL-4) on the production of matrix metalloproteinase 1 (MMP-1) by normal and immortalized human intimal smooth muscle cells (SMC) was investigated. The production of the precursors of MMP-1 by intimal SMC was enhanced in a dose-dependent manner by addition of IL-4 to the culture medium, whereas the cytokine also showed an inhibitory effect on DNA synthesis in the cells. In addition, mRNA of IL-4 was found in the atherosclerotic and nonatherosclerotic areas of the intima. Although the production of MMP-1 and the proliferation of SMC are thought to play an important role in reconstruction of the intima during atherogenesis, our results suggest a possible role of IL-4 induced MMP-1 in inhibiting tissue remodeling caused by a variety of arterial disorders including atherosclerosis. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0021-9150(97)00296-7

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M Kato, A Tanimoto, N Arima, M Morimatsu, Y Sasaguri .  Response to platelet-derived growth factor by phenotypically different cultured human aortic smooth muscle cells .  BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL44 ( 4 ) 815 - 823   1998.4Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS AUST  

We investigated the effects of PDGF on DNA synthesis and mitogen-activated protein (MAP) kinase activity, and demonstrated that the adult intimal SMC was concentration-dependently stimulated by all PDGF isoforms in terms of both [H-3]thymidine incorporation and MAP kinase activation, with PDGF-BB and -AB being more potent than PDGF-AA. The intimal SMCs and the neonatal SMCs showed a similar response with regard to MAP kinase activation. On the other hand, the intimal SMCs expressed many more PDGF receptors than the adult medial SMCs, which expressed a greater amount of PDGF-A chain mRNA and showed a lesser response to PDGFs. These results suggest that the intimal SMCs have a relatively high potential to react to exogenous PDGFs, whereas the adult medial SMCs depend on endogenous or autocrine secretion of PDGF-AA.

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Tetsuo Hamada, Akihide Tanimoto, Nobuyuki Arima, Yoshihiro Ide, Takakazu Sasaguri, Shohei Shimajiri, Yoshitaka Murata, Ke-Yong Wang, Yasuyuki Sasaguri .  Pathological study of splenomegaly associated with cadmium-induced anemia in rats .  Journal of UOEH20 ( 1 ) 11 - 19   1998.3Reviewed

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：University of Occupational and Environmental Health  

Splenomegaly was observed both in male and female Sprague-Dawley rats after 1 week of exposure to CdCl2 (0.6 mg Cd/kg/day). Spleen weight reached about double that in controls by 8 weeks of Cd exposure. Histopathological examination of the enlarged spleen revealed that iron- and lipid-laden histiocytes were clustered in the periarterial lymphatic sheath, and the red pulp appeared to be expanded. It is noteworthy that electron microscopy revealed marked poikilocytosis and Heinz body formation in red blood cells (RBCs) in both the sinus and cord. Histiocytes were swollen by a granular substance in the cytoplasm and also many secondary lysosomes. These morphological findings indicate that degradation of damaged RBCs induced by exposure to Cd might be promoted in the spleen and possibly cause splenomegaly. This RBC damage-hemolysis-splenomegaly sequence is also considered to be associated with the etiology of Cd-induced anemia. In addition to the abnormal RBC degradation, nuclei of lymphocytes in the Cd- exposed spleen exhibited high electron density, consistent with a preapoptotic state suggesting the immunosuppressive effect of Cd.

DOI： 10.7888/juoeh.20.11

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濱田 哲夫, 谷本 昭英, 有馬 信之 .  カドミウム誘発貧血症ラットにおける脾腫の病理学的研究 .  産業医科大学雑誌20 ( 1 ) 11 - 19   1998.3

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Publisher：産業医科大学  

Cd誘発貧血症の発症機序について検討した.ラットでは脾腫はCdの慢性投与により,1週間後には明らかとなり,その重量は8週間では対照の約2倍となった.腫大脾の電子顕微鏡的検索ではハインツ小体(HB)の形成と著明なPCが目立った.Cdは初めに赤血球膜異常ついでPC増多症を引き起こし,この異常赤血球が脾で処理されるため皮腫が招来されることが示された

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Y Ide, A Tanimoto, Y Sasaguri, R Padmanabhan .  Hepatitis C virus NS5A protein is phosphorylated in vitro by a stably bound protein kinase from HeLa cells and by cAMP-dependent protein kinase A-alpha catalytic subunit .  GENE201 ( 1-2 ) 151 - 158   1997.11Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Hepatitis C virus (HCV) has a positive-strand RNA genome that codes for a polyprotein precursor, which is processed co-and post-translationally by cellular and viral proteinases into three structural and at least six non-structural (NS) proteins. The NS5A protein, expressed in mammalian cells, exists in two phosphorylated forms of 56-kDa and 58-kDa. In this study, we provide evidence for a stable association between NS5A and a protein kinase from HeLa cells and hepatocellular carcinoma (HepG2) cells by co-immunoprecipitation and by affinity to immobilized glutathione-S-transferase (GST)-NS5A fusion protein produced in E. coli. This protein kinase could phosphorylate in vitro the native NS5A on serine residues, (GST)-NS5A, histone H1, and casein as substrates. In addition, the GST-NS5A was also phosphorylated in vitro by the cAMP-dependent protein kinase A-alpha catalytic subunit. (C) 1997 Elsevier Science B.V.

DOI： 10.1016/S0378-1119(97)00440-X

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T Hamada, A Tanimoto, Y Sasaguri .  Apoptosis induced by cadmium .  APOPTOSIS2 ( 4 ) 359 - 367   1997.8Invited Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RAPID SCIENCE PUBLISHERS  

Cell death resulting from cadmium (Cd) intoxication has been confirmed to occur through apoptosis by morphological and biochemical studies, However it is still not clear whether Cd itself or metallothionein (MT) induced by Cd is the major factor responsible for the apoptosis, Although apoptosis is inducible by exposure of cells to various stimuli, the common pathway involved is generally accepted to be activation of endonucleases that induce internucleosomal cleavage of DNA, resulting in the 'ladder' formation observed upon agarose gel electrophoresis and the chromatin condensation seen by electron microscopy. Cd does not seem to activate the endonuclease in vitro. However, Cd itself can be associated with apoptosis through indirect oxidative stress by inhibition of antioxidant enzymes and possible interaction with zinc finger protein, In addition to the direct effect of Cd, MT appears to play dual roles in apoptosis induction: one as a Cd carrier by which Cd accumulates in the nucleus, and the other as an inhibitor of zinc finger proteins, which include transcriptional factors related to apoptosis such as the product of the apoptosis resistance gene A20. In this review, we demonstrated that the mode of cell death following Cd exposure is associated with intracellular movement of Cd and MT. A possible mechanism for Cd-induced apoptosis is also discussed.

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A Tanimoto, Y Ide, N Arima, Y Sasaguri, R Padmanabhan .  The amino terminal deletion mutants of hepatitis C virus nonstructural protein NS5A function as transcriptional activators in yeast .  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS236 ( 2 ) 360 - 364   1997.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

To investigate the biological function of hepatitis C virus (HCV)-NS5A, the NS5A was fused at its N-terminus with the DNA binding domain (DBD) of yeast transcriptional activator GAL4 (GAL4-DBD). The GAL4-DBD alone had no transcriptional activation function. However, a mutant of the GAL4-DBD/NS5A fusion protein, in which 129 amino acid residues were deleted from the N-terminus of NS5A, exhibited strong transcriptional activation in yeast cells, bearing the Escherichia coli lacZ reporter gene encoding the beta-galactosidase under the transcriptional control of GAL4 promoter and TATA box. Further mutational analysis of NS5A revealed that the region between the amino acid residues 130 to 352 were critical for optimal level of transactivation. This region includes two acidic domains and one proline-rich region which have been shown to be involved in the function of several transcriptional activators. (C) 1997 Academic Press.

DOI： 10.1006/bbrc.1997.6967

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N Arima, Shima, I, S Shimajiri, Y Sasaguri, T Sasaguri, A Tanimoto, T Hamada, M Morimatsu .  Phenotypes of human esophageal squamous cell carcinoma based on matrix metalloproteinase production .  INTERNATIONAL JOURNAL OF ONCOLOGY10 ( 2 ) 269 - 277   1997.2Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT JOURNAL ONCOLOGY  

We investigated the effects of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) on cell growth and on regulation of matrix metalloproteinases (MMPs) in four cell lines of human esophageal squamous cell carcinomas (TE8, TE9, TE10, and TE11). EGF stimulated the production of proforms of gelatinase B (MMP-9) by three cell lines that could synthesize EGF by themselves, with TE9 being the exception. Particularly, both the production of MMP-9 and DNA synthesis in TE10 were stimulated significantly by EGF. TGF-beta slightly stimulated DNA synthesis in two cell lines, TE9 and TE11, and TGF-beta secretion by TE9 was detected. The production of proforms of gelatinases A (MMP-2) and MMP-9 was gradually induced by TGF-beta in a concentration-dependent manner in all the cell lines except for TE9. Flow cytometric analysis revealed that all the lines expressed both EGF- and TGF-beta-receptors. In conclusion, our present results indicate that at least there are possibly two distinct phenotypes in human esophageal squamous cell carcinoma: one (TE10) depends on autocrine EGF production that enhances DNA synthesis and MMP-9 production; and the other (TE9) on autocrine TGF-beta that stimulates DNA synthesis but not in relation to gelatinase production.

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T Tanaka, K Hara, A Tanimoto, K Kasai, T Kita, N Tanaka, T Takayasu .  Determination of arsenic in blood and stomach contents by inductively coupled plasma/mass spectrometry (ICP/MS) .  FORENSIC SCIENCE INTERNATIONAL81 ( 1 ) 43 - 50   1996.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Inductively coupled plasma/mass spectrometry (ICP/MS) was used and evaluated for the practical analysis of the arsenic content of body fluid samples without ashing. The calibration curve for arsenic in blood solution was shown to have good sensitivity, linearity and reproducibility. Blood obtained from normal volunteers was determined by ICP/MS, and compared with that determined by atomic absorption spectrometry (AAS). The arsenic contents determined by ICP/MS showed a linear correlation with that determined by AAS. Furthermore, arsenic was determined in the blood and supernatant of stomach contents obtained from a suicide autopsy case resulting from ingestion of an arsenic compound. It was therefore concluded that ICP/MS could be used rapidly and conveniently in the field of forensic toxicology in acute metal poisoning cases.

DOI： 10.1016/0379-0738(96)01942-1

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A Tanimoto, T Sasaguri, N Arima, H Hashimoto, T Hamada, Y Sasaguri .  Endometrial stromal sarcoma of the uterus with rhabdoid features .  PATHOLOGY INTERNATIONAL46 ( 3 ) 231 - 237   1996.3Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

A case of endometrial stromal sarcoma of the uterus with rhabdoid features, occurring in a 57 year old woman is reported. Electron microscopy and immunohistochemistry revealed that the rhabdoid cells contained intermediate filaments which were positive for vimentin, cytokeratin, alpha-smooth muscle actin, and muscle specific actin, but not for myoglobin and desmin. This indicated that the tumor in this case differed somewhat from the three rhabdoid tumors and an endometrial stromal sarcoma with rhabdoid differentiation previously reported and that, therefore, these tumors were heterogeneous.

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T Hamada, T Sasaguri, A Tanimoto, N Arima, S Shimajiri, T Abe, Y Sasaguri .  Apoptosis of human kidney 293 cells is promoted by polymerized cadmium-metallothionein .  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS219 ( 3 ) 829 - 834   1996.2Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Transformed human kidney cells (293 cells) exposed to 12.5 to 37.5 mu M CdCl2 showed apoptosis as confirmed by characteristic electron microscopic features, a ladder on gel electrophoresis of extracted DNA, and fragmentation of nucleosomes as detected by enzyme linked immunosorbent assay (ELISA). Higher concentrations of Cd were less effective in inducing apoptosis. Furthermore, addition of the protein extract from the serum-free medium used for Cd-exposure promoted apoptosis exhibiting the same features as that after Cd-exposure. The apoptosis induced by the protein was dose-dependent. The molecular weight of the protein (Cd-protein) was shown to be 40 kDa by gel filtration. Two-dimensional electrophoresis revealed the Cd-protein as a single spot with a molecular weight of 6 kDa and pI of 4.5. Competitive ELISA showed that the Cd-protein reacted with anti-metallothionein antibody. The present findings suggest that apoptosis is induced not only by Cd itself but also by polymerized metallothionein molecules (MT) released from cells into the medium. (C) 1996 Academic Press, Inc.

DOI： 10.1006/bbrc.1996.0318

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R Nakano, N Murahashi, Y Sasaguri, A Tanimoto, M Soejima, N Arima, T Hamada .  Establishment and characterization of immortalized human coronary endothelial cells .  BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL36 ( 4 ) 715 - 722   1995.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

We established an immortalized cell line from endothelial cells derived from a human coronary artery, isolated at autopsy from 76-year-old male, by transfecting the cells with origin-minus simian virus 40 DNA. These cells showed SV40 T antigen in the nuclei and Ulex europaeus I agglutinin and factor VIII-related antigen, as endothelial cell markers, in their cytoplasm. This cell line synthesized prostacyclin, tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) as well as produced the preform of matrix metalloproteinase 1, which was activated by cultivating the cells with plasminogen. These findings reveal that this immortalized endothelial cell line retains characteristics of human coronary endothelial cells, indicating that this cell line is useful for studying atherogenesis of the coronary artery.

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T HAMADA, T SASAGURI, M HISAOKA, K HIRAKATA, A TANIMOTO, H NAKATA, Y SASAGURI, H HASHIMOTO .  MILD EMPHYSEMA - A NOVEL METHOD USING FORMALIN-FIXED LUNGS FOR COMPUTED-TOMOGRAPHY AND PATHOLOGICAL ANALYSES .  VIRCHOWS ARCHIV-AN INTERNATIONAL JOURNAL OF PATHOLOGY426 ( 6 ) 597 - 602   1995.7Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

We evaluated a navel method of computed tomography (CT) analysis using formalin-fixed lungs of autopsy cases with mild emphysema. Eight formalin-inflated lungs (FILs) obtained at autopsy were examined using CT after draining off the formalin and air inflation with an air pump, and subjected to pathological study including pathological scoring of emphysema and microscopic image analysis (MIA). Satisfactory CT examination was carried out within 5 h of lung fixation. The mean alveolar area determined by MIA correlated highly with the lung volume (r=O.845) and CT score (r=0.722). This method is simple compared with conventional polyethylene glycol fixation for CT and enables CT examination of resected lungs without anxiety about biohazards.

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T TAKAGISHI, Y SASAGURI, R NAKANO, N ARIMA, A TANIMOTO, H FUKUI, M MORIMATSU .  EXPRESSION OF THE HISTAMINE H1 RECEPTOR GENE IN RELATION TO ATHEROSCLEROSIS .  AMERICAN JOURNAL OF PATHOLOGY146 ( 4 ) 981 - 988   1995.4Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Histamine in serum and arterial tissue contributes to the pathogenesis of atherosclerosis and the formation of coronary artery vasospasm As the effect of histamine at a given site will be mediated by its specific receptors, we investigated by in situ hybridization and Northern blot analysis the expression and localization of human histamine H1 receptor mRNA in the arterial wall and in cultured human aortic intimal smooth muscle cells (SMC) and immortalized SMC (ISS10) and endothelial cells (SE1). In situ hybridization showed that SMC and endothelial cells expressed H1 receptor mRNA in vivo and that the expression was increased in SMC in the thickened intima of atherosclerotic foci in both the aorta and coronary artery By Northern blot analysis, we also detected histamine H1 receptor mRNA in cultured SMC, ISS10, and SE1 and found that platelet-derived growth factor stimulated SMC to increase their expression of the mRNA in vitro. These results suggest that up-regulation of histamine H1 receptor expression by platelet-derived growth factor plays an important role in the initiation and progression of cardiovascular diseases.

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T HAMADA, T SASAGURI, A TANIMOTO, N ARIMA, R NAKANO, H MIYAYAMA, Y SASAGURI .  OVARIAN MUCINOUS CYSTADENOCARCINOMA WITH SARCOMA-LIKE MURAL NODULES .  JOURNAL OF SURGICAL ONCOLOGY58 ( 3 ) 201 - 207   1995.3Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

A rare case of ovarian mucinous cystadenocarcinoma with sarcoma-like mural nodules is reported. Macroscopically, nodular or granular lesions were scattered over the inner surface of a huge, multilocular tumor in the left ovary. The histopathological features were consistent with those of previously documented cases, except significant squamous metaplasia in the present case. The pleomorphic sarcoma-like cells showed a positive reaction for vimentin and alpha-antichymotrypsin but were negative for carcinoembryonic antigen and common epithelial membrane antigen by immunohistochemistry. Electron microscopically, the tumor cells had neither desmosomes nor secretory granules, but they possessed abundant intermediate filaments. Both immunostaining and ultrastructure suggested that the sarcoma-like nodules were derived from reactive proliferation of fibrohistiocytic cells. The fibrohistiocytic reaction seemed to occur in response to hemorrhage, because hemorrhage was reported to be associated with the mural nodules in most of the previous cases as well as ours. (C) 1995 Wiley-Liss, Inc.

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K SAGAWA, M MOCHIZUKI, K MASUOKA, K KATAGIRI, T KATAYAMA, T MAEDA, A TANIMOTO, S SUGITA, T WATANABE, K ITOH .  IMMUNOPATHOLOGICAL MECHANISMS OF HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-1 (HTLV-I) UVEITIS - DETECTION OF HTLV-I-INFECTED T-CELLS IN THE EYE AND THEIR CONSTITUTIVE CYTOKINE PRODUCTION .  JOURNAL OF CLINICAL INVESTIGATION95 ( 2 ) 852 - 858   1995.2Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

The immunopathology of human T cell lymphotropic virus type 1 (HTLV-I) uveitis was addressed by using T cell clones (TCC) established from the intraocular fluid of patients with HTLV-I uveitis. Proviral DNA of HTLV-I was identified in 55 out of 94 (59%) or 13 out of 36 (36%) TCC from the ocular fluid or the peripheral blood of these patients, respectively. Most of HTLV-I-infected TCC had a CD3(+) CD4(+) CD8(-) phenotype. HTLV-I infection on TCC was confirmed by analysis of the viral mRNA, nucleotide sequence, virus-associated proteins, and virus particles. HTLV-I-infected TCC, but not HTLV-I negative TCC, constitutively produced high amounts of IL-6 (1,336 +/- 1,050 pg/ml) and TNF-alpha (289 +/- 237 pg/ml) in the absence of any stimuli. HTLVI-infected TCC from the ocular lesion also constitutively produced high amounts of IL-1 alpha (12,699 pg/ml), IL-2 (61 pg/ml), IL-3 (428 pg/ml), IL-8 (1,268 pg/ml), IL-10 (28 pg/ml ), IFN-gamma (5,095 pg/ml), and GM-CSF (2,886 pg/ml). Hydrocortisone, a drug effective in vivo for the treatment of HTLV-I uveitis, severely depressed cytokine production in vitro in most cases. In summary, the results demonstrated direct evidence of HTLV-I infection of the eye and suggest that cytokines produced by HTLV-I-infected T cells are responsible for the intraocular inflammation in patients with HTLV-I uveitis.

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R Kouzuma, H Tasaki, T Komura, Y Nakashima, A Kuroiwa, A Tanimoto, O Koide .  Combined treatment of probucol with diltiazem regresses atherosclerosis induced by 1% cholesterol diet in rabbit aorta .  ARTERY21 ( 6 ) 337 - 351   1995Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ARTERY PUBLISHING  

To clarify whether probucol, an antioxidant, or diltiazem, a Ca2+ antagonist, favorably affect the regression of established atherosclerosis, rabbits were fed a 1% cholesterol diet for 10 weeks, then a standard diet for an additional 25 weeks (regression period). During the regression period, rabbits were grouped into a saline (S) group (n=8, 1 ml saline/d), a probucol (P) group (n=8, 1000 mg/d probucol), or a probucol and diltiazem (P+D) group (n=8, probucol 1000 mg/d in diet and diltiazem 30mg/d). We measured cholesterol in serum, lipoprotein fractions, and serum triglyceride or phospholipid concentration and found no significant differences among the three groups at 10, 15, or 35 weeks. After 10 weeks of the atherogenic diet, the ratio of macroscopic atherosclerotic lesions in aortic intima rose to 36.6 +/- 5.6%. After the regression period, the S group developed more atherosclerotic lesions (48.6 +/- 6.49%). The P+D and P groups, however, had decreased scores of 24.3 +/- 5.5% (p&lt;0.05 vs. S) and 32.3 +/- 5.6%, respectively. Moreover, these decreased scores were well correlated with the decrease in aortic tissue lipid compositions, but not the parameters for extracellular matrices. We concluded that P+D or P therapy might be effective in regressing established atherosclerosis by removing lipid contents but not extracellular matrices.

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S KATO, Y SASAGURI, S AZAGAMI, R NAKANO, T HAMADA, N ARIMA, A TANIMOTO, M MORIMATSU .  AMBIENT-PRESSURE STIMULATES IMMORTALIZED HUMAN AORTIC ENDOTHELIAL-CELLS TO INCREASE DNA-SYNTHESIS AND MATRIX METALLOPROTEINASE-1 (TISSUE COLLAGENASE) PRODUCTION .  VIRCHOWS ARCHIV-AN INTERNATIONAL JOURNAL OF PATHOLOGY425 ( 4 ) 385 - 390   1994.11Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

In the present study, we investigated the effect of ambient pressure on [H-3]-thymidine incorporation and on the production of matrix metalloproteinase 1 (tissue collagenase/proMMP-1) using human aortic endothelial cells immortalized with simian virus 40 (SE-1). Incubation of cells at ambient pressures of 50 and 100 mmHg for 24 h slightly increased [H-3]-thymidine incorporation when directly compared with normal culture conditions. The amount of [H-3]-thymidine incorporated in SE-1 reached a maximum at 150 mmHg, while a further increase in pressure to 200 mmHg decreased incorporation. The same ambient pressure slightly stimulated human aortic intimal smooth muscle cells (SMC) to increase [3H]-thymidine incorporation but not medial SMC. Immunoblot analysis also showed that ambient pressure, ranging from 50 to 200 mmHg, like 12-O-tetradecanoyl-phorbol-13-acetate stimulated SE-1 to produce proMMP-1, an effect not seen with either intimal or medial SMC. The amount of proMMP-1 produced also reached a maximum level at 150 mmHg. We postulate that human endothelial cells are ambient pressure sensitive and that relatively lower ambient pressures play an important role in the growth of endothelial cells, while higher pressures injure endothelial cells, resulting in the initiation of atherosclerosis. This cell line may prove useful in the investigation of both the physiological and pathological roles of blood pressure on endothelial cell function.

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T HAMADA, A TANIMOTO, S IWAI, H FUJIWARA, Y SASAGURI .  CYTOPATHOLOGICAL CHANGES INDUCED BY CADMIUM-EXPOSURE IN CANINE PROXIMAL TUBULAR CELLS - A CYTOCHEMICAL AND ULTRASTRUCTURAL-STUDY .  NEPHRON68 ( 1 ) 104 - 111   1994.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

A highly sensitive cytochemical method for demonstrating intracellular Cd using 8-hydroxyquinoline was developed and applied in the cytopathological study of primary-cultured renal tubular cells from beagle kidneys. The Cd-8-hydroxyquinoline emitted a yellowish-green fluorescence which first appeared in the cytoplasm within 30 min and in the nucleus about 60-90 min after exposure to 100 mM CdCl2. It was noteworthy that intranuclear Cd was stained in the nucleolar regions. The sensitivity of the cytochemical method for Cd was estimated to be about 1.0 pg Cd/cell. Ultrastructural features of the dead cells were consistent with those of apoptosis. We conclude that Cd absorbed by proximal tubular cells rapidly reaches to the nuclei and affects nuclear as well as cytoplasmic metabolism.

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Y NAKANO, MORIMOTO, I, O ISHIDA, T FUJIHIRA, A MIZOKAMI, A TANIMOTO, N YANAGIHARA, F IZUMI, S ETO .  THE RECEPTOR, METABOLISM AND EFFECTS OF ANDROGEN IN OSTEOBLASTIC MC3T3-E1 CELLS .  BONE AND MINERAL26 ( 3 ) 245 - 259   1994.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

We investigated the androgen receptor (AR), metabolism and effects of androgens in osteoblastic MC3T3-E1 cells. AR was proved as a transcript of a IO-kb mRNA and as a 110-kDa protein. An immunocytochemical study showed that AR was located mainly in the nuclei. Specific binding of [H-3]DHT was observed in both the nuclear and cytosol fractions. MC3T3-E1 cells possessed approximately 1190 binding sites per cell and most of the sites (1150 sites) situated in the nucleus. The apparent K-d value in the nuclear fraction was 1.35 nM for [H-3]DHT binding, and it was similar to that for [H-3]testosterone. In the competition analysis, there was not much difference in the displacement of the [H-3] DHT binding from AR between the addition of radioinert DHT and testosterone. In studies of 5 alpha-reductase activity and aromatase activity of the cells, both activities were lower than the respective values in classical androgen target tissues. Androgens stimulated the incorporation of [H-3]thymidine into the cell, and DHT and testosterone had a similar potency on the cell proliferation. Thus, these results suggest testosterone itself acts mainly on the osteoblasts without conversion to DHT.

DOI： 10.1016/S0169-6009(08)80173-0

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T EZAKI, T OKAMURA, Y YOSHIDA, M KODATE, T SHIRAKUSA, A TANIMOTO, R HIRATSUKA .  FOREIGN-BODY GRANULOMA MIMICKING AN EXTRAHEPATICALLY GROWING LIVER-TUMOR - REPORT OF A CASE .  SURGERY TODAY-THE JAPANESE JOURNAL OF SURGERY24 ( 9 ) 829 - 832   1994Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

We herein describe a 74-year-old woman with a foreign-body granuloma mimicking a liver tumor. Imaging studies revealed a pedunculated left lobe mass in the setting of chronic liver disease. She had a past history of a cholecystectomy as well as a previous gynecological operation. A left lateral segmentectomy was performed because of the possibility of a rupture. The dissected specimen showed a foreign-body granuloma caused by gauze. We believe this case to be a very unique granuloma, which should be kept in mind whenever making a diagnosis of a liver tumor particularly in a patient with chronic liver disease, who has a past history of abdominal surgery.

DOI： 10.1007/BF01636316

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O YAMAMOTO, A TANIMOTO, H YASUDA, Y SUENAGA, M ASAHI .  A COMBINED OCCURRENCE OF NEUROENDOCRINE CARCINOMA OF THE SKIN AND A BENIGN APPENDAGEAL NEOPLASM .  JOURNAL OF CUTANEOUS PATHOLOGY20 ( 2 ) 173 - 176   1993.4Reviewed

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A 76-year-old Japanese male presented with a subcutaneous nodule in the dorsal cubital region of the right arm. The center of the nodule showed typical features of neuroendocrine carcinoma of the skin. The peripheral portion showed epithelial islands of squamoid cells with horn cysts suggestive of benign appendageal tumor with pilar differentiation. The coexistence of two skin neoplasms in the same lesion would suggest that both tumors developed from common pluripotential stem cell.

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A TANIMOTO, T HAMADA, O KOIDE .  CELL-DEATH AND REGENERATION OF RENAL PROXIMAL TUBULAR CELLS IN RATS WITH SUBCHRONIC CADMIUM INTOXICATION .  TOXICOLOGIC PATHOLOGY21 ( 4 ) 341 - 352   1993Reviewed

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Language：English   Publishing type：Doctoral thesis   Publisher：SOC TOXICOLOGIC PATHOLOGISTS  

Male Sprague-Dawley rats were injected subcutaneously with 0.6 mg cadmium (Cd)/kg/day for 8 wk. The subsequent changes in renal proximal tubules were studied histologically, histochemically, and ultrastructurally. The urinary and tissue Cd concentrations were determined by atomic absorption spectrophotometry. After 4 wk of exposure, apoptosis was observed predominantly in segment S3 along with epithelial regeneration in the affected tubules, and these changes gradually became more pronounced as the experimental period was prolonged. The apoptotic cells were shed into the lumen and were found to contain a large quantity of Cd. Apoptotic cells were counted in paraffin sections after various periods of exposure to Cd. Nuclear bromodeoxyuridine uptake, mitotic count, and nuclear density were used as indicators of tubular regeneration. A correlation was found between the numerical increase of apoptotic cells and the rate of urinary Cd excretion, and the rate of increase in the tissue Cd concentration had a tendency to reduce after 4 wk as the rate of urinary Cd increased. These observations suggest that apoptosis might be helpful for the efficient excretion of Cd into urine. Progressive increases in the preceding indicators of regeneration were observed. From our results, it appears that Cd-induced tubular damage, i.e., cell deletion due to apoptosis, is reversible as a result of marked epithelial regeneration. On the basis of these histological changes, the critical concentration of Cd required to produce renal tubular damage was estimated to be 600 mu g/g dry tissue.

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T SASAGURI, M SOEJIMA, Y HINO, H SHIRAISHI, H DATE, M TAKASUGI, A TANIMOTO, A HORIE .  SYSTEMIC NECROTIZING VASCULITIS WITH RENAL INVOLVEMENT ACCOMPANIED BY REMARKABLE EOSINOPHILIA - A CASE WITH OVERLAPPING FEATURES OF POLYARTERITIS-NODOSA AND ALLERGIC GRANULOMATOUS-ANGIITIS .  JAPANESE JOURNAL OF MEDICINE30 ( 5 ) 477 - 482   1991.9Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 71-year-old woman was clinically suspected of allergic granulomatous angiitis (AGA) because of preceding allergic diseases including bronchial asthma, remarkable eosinophilia (14,300/mm3), mononeuritis multiplex, positive rheumatoid factor, elevated serum immunoglobulin E, and eosinophilic inflammation of the kidney. Autopsy findings, however, were characteristic of polyarteritis nodosa (PAN). Necrotizing angiitis was present in several organs except for the lung; focal and segmental glomerular lesions with crescent formation were observed in the kidney, and granuloma formation was not found. This case may be an intermediate type between PAN and AGA (an overlap syndrome) and provide useful information on the clinical entities of systemic necrotizing vasculitis.

DOI： 10.2169/internalmedicine1962.30.477

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T HAMADA, S NAKANO, S IWAI, A TANIMOTO, K ARIYOSHI, O KOIDE .  PATHOLOGICAL-STUDY ON BEAGLES AFTER LONG-TERM ORAL-ADMINISTRATION OF CADMIUM .  TOXICOLOGIC PATHOLOGY19 ( 2 ) 138 - 147   1991Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC TOXICOLOGIC PATHOLOGISTS  

Histopathological, histochemical, and electron microscopic examinations were performed on beagles after a long-term oral cadmium (Cd) administration of &gt; 8 years. Although renal atrophy was remarkable in groups receiving doses of 50 and 100 mg/kg body weight/day, bone lesions could not be demonstrated by roentgenological and histopathologic examination. It was noticed that concomitant regeneration or recovery and cell death of the epithelium occurred in the proximal convoluted tubules. The cell death was consistent with apoptosis, a special feature of cell death, which was shown to play a major part in the tubular damage of cadmium by electron microscopic examination. Fatty degeneration of the pars recta tubules was seen to show dose-dependence. The intrarenal cadmium was localized predominantly in the cytoplasm of the proximal tubular epithelium by histochemical and ultracentrifugal cell fractionation examinations. Although no remarkable changes were found in the other organs, aggregates of siderophages in the liver and focal hemorrhage in the spleen, known as spontaneous lesions, might be related to Cd intoxication. In conclusion, the present study revealed that no bone lesions occur with Cd administration in adult beagles in spite of long-term administration. An excessive cell death to regeneration or recovery in the proximal tubules might result in the renal cortical atrophy. No remarkable changes were seen in the glomeruli and distal nephrons, which were in good agreement with Cd distribution.

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A. Tanimoto, T. Hamada, H. Kanesaki, K. Matsuno, O. Koide .  Multiple primary cancers in a case of chronic arsenic poisoning. An autopsy report .  Journal of UOEH12 ( 1 ) 89 - 99   1990Reviewed

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Language：English   Publishing type：Research paper (scientific journal)  

This is an autopsy report of multiple primary cancers observed in a patient who had clinically been diagnosed as chronic arsenic poisoning. An 88-year-old man, non-smoker, had worked in an arsenic mine for 6 years from the age of 47. He had undergone operations for Bowen's disease and gastric cancer at ages 80 and 86, respectively. At autopsy, squamous cell carcinoma of the lung and a polypoid lesion in the piriform recess were found. Furhermore, microscopic examination revealed latent prostatic adenocarcinoma and oncocytoma in the kidney. The polypoid lesion of the piriform recess appeared to originate from the duct of the minor salivary gland in the pharynx, showing an adenoid cystic carcinoma-like pattern with squamous cell carcinoma in part. The cause of death was thought to be respiratory failure due to bronchopneumonia and pulmonary edema as well as hydrothorax, and chronic heart failure following ischemic heart diseas. Bowen's disease was followed by four internal malignant tumors, even though the etiological relation between these cancers and arsenic is not clear.

DOI： 10.7888/juoeh.12.89

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T HAMADA, A TANIMOTO, M KAIDO, S MATSUMOTO, K IRIBE, O KOIDE .  DIFFUSE PLEURAL RHABDOMYOSARCOMA WITH PERSISTENT PLEURAL EFFUSION .  ACTA PATHOLOGICA JAPONICA39 ( 12 ) 803 - 809   1989.12Reviewed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

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小出 紀, 海道 昌宣, 谷本 昭英 .  Cushing病に合併した急性壊死性膵炎の一例(第30回CPC) .  臨牀と研究66 ( 4 ) 1250 - 1254   1989.4

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Publisher：大道学館出版部  

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Nakano S, Iwai S, Tanimoto A, Koide O .  An ultrastructural observation of malignant mesothelioma cells in pleural effusion. .  Journal of Clinical Electron Microscopy22   5 - 6   1989Reviewed

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Language：English   Publishing type：Research paper (other academic)  

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Tetsuo Hamada, Akihide Tanimoto, Masanobu Kaido, Shigeru Matsumoto, Kaneshige Iribe, Osamu Koide .  Diffuse Pleural Rhabdomyosarcoma with Persistent Pleural Effusion .  Pathology International39 ( 12 ) 803 - 809   1989

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A unique case of embryonal rhabdomyosarcoma arising at the left pleura of a 7‐year‐old Japanese girl is reported. The present case was characterized by persistent pleural effusion, and the malignant cells incidentally found in it were the first diagnostic clue. The tumor showed a rare growth pattern involving diffuse thickening of the parietal pleura. Biopsy of the thickened parietal pleura upon thoracotomy revealed embryonal rhabdomyosarcoma largely composed of immature mesenchymal cells. Immunohistochemical demonstration of creatinine phos‐phokinase MM was most helpful among several types of immunostain for the histopathological diagnosis. Ultra‐structurally, thin filaments with primitive Z bands could be seen in some tumor cells. Intensive clinical examination revealed only diffuse thickening of the parietal pleura, which was reduced by chemotherapy. This is the first documented case of rhabdomyosarcoma arising at the pleura. Previous reports of rhabdomyosarcoma arising at unusual sites are reviewed and the histogenesis of this tumor is briefly discussed. Acta Pathol Jpn 39: 803 809, 1989. Copyright © 1989, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.1440-1827.1989.tb02433.x

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