Faculty Profiles - YAMAMOTO Hideki

Papers - YAMAMOTO Hideki

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ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer. International journal

Hibiki Umeda, Kunitoshi Shigeyasu, Toshiaki Takahashi, Kazuya Moriwake, Yoshitaka Kondo, Kazuhiro Yoshida, Sho Takeda, Shuya Yano, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Hideki Yamamoto, Kosei Takagi, Masashi Kayano, Hiroyuki Michiue, Keiichiro Nakamura, Yoshiko Mori, Fuminori Teraishi, Hiroshi Tazawa, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

Molecular cancer 24 ( 1 ) 116 - 116 2025.4

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

BACKGROUND: Colorectal cancer (CRC) is considered the third most common type of cancer worldwide. Tumor-associated macrophages (TAMs) have been shown to promote drug resistance. Adenosine-to-inosine RNA-editing, as regulated by adenosine deaminase acting on RNA (ADAR), is a process that induces the posttranscriptional modification of critical oncogenes. The aim of this study is to determine whether the signals from cancer cells would induce RNA-editing in macrophages. METHODS: The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models. RESULTS: The intensity of the RNA-editing enzyme ADAR1 (Adenosine deaminase acting on RNA 1) in cancer and mononuclear cells indicated a strong positive correlation between the nucleus and cytoplasm. The ADAR1-positive mononuclear cells were positive for CD68 and CD163, a marker for M2 macrophages. Cancer cells transport pro-inflammatory cytokines or ADAR1 protein directly to macrophages via the exosomes, promoting RNA-editing in AZIN1 (Antizyme Inhibitor 1) and GLI1 (Glioma-Associated Oncogene Homolog 1) and resulting in M2 macrophage polarization. GLI1 RNA-editing in the macrophages induced by cancer cells promotes the secretion of SPP1, which is supplied to the cancer cells. This activates the NFκB pathway in cancer cells, promoting oxaliplatin resistance. When the JAK inhibitors were administered, oncogenic RNA-editing in the macrophages was suppressed. This altered the macrophage polarization from M2 to M1 and decreased oxaliplatin resistance in cancer cells. CONCLUSIONS: This study revealed that ADAR1-high TAMs are crucial in regulating drug resistance in CRC and that targeting ADAR1 in TAMs could be a promising treatment approach for overcoming drug resistance in CRC.

DOI： 10.1186/s12943-025-02312-y

Predictive marker for response to trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer patients. International journal

Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Sho Takeda, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Yuya Sakurai, Shunsuke Nakamura, Masafumi Takahashi, Kaori Nitta, Kazuhiro Yoshida, Yuki Matsumi, Hiroyuki Michiue, Hideki Yamamoto, Hiroyuki Kishimoto, Fuminori Teraishi, Ryohei Shoji, Nobuhiko Kanaya, Hajime Kashima, Yoshihiko Kakiuchi, Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

BMC cancer 25 ( 1 ) 1 - 1 2025.1

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

OBJECTIVE: Trifluridine/tipiracil (FTD/TPI) is one of the options for late-line treatment of colorectal cancer (CRC). However, the specific patient populations that would particularly benefit from it remain unclear. This study attempted to identify predictive markers of chemotherapy efficacy with trifluridine/tipiracil (FTD/TPI), focusing on the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) expression and neutrophil-lymphocyte ratio (NLR). METHODS: To assess the effectiveness of FTD/TPI in CRC patients, we retrospectively analyzed 72 CRC patients at Okayama University Hospital from 2014 to 2022. RESULTS: Adding bevacizumab to FTD/TPI resulted in a more prolonged progression-free survival (PFS), consistent with the SUNLIGHT study findings (p = 0.0028). Among the participants, those with a high NLR had a shorter PFS (p = 0.0395). Moreover, high ADAR1 expression was associated with longer PFS (p = 0.0151). In multivariate analysis, low ADAR1 (HR = 3.43, p = 0.01) and absence of bevacizumab (HR = 4.25, p = 0.01) were identified as factors shortening PFS. The high ADAR1 group demonstrated fewer cases of progressive disease and a higher proportion of stable disease than the low ADAR1 group (p = 0.0288). Low NLR and high ADAR1 were predictive markers of prolonged PFS in the bevacizumab-treated group (p = 0.0036). CONCLUSION: Low NLR and high ADAR1 were predictive markers for a positive response to the FTD/TPI plus bevacizumab regimen associated with prolonged PFS. The FTD/TPI plus bevacizumab regimen should be proactively implemented in the low NLR and high ADAR1 subgroups.

DOI： 10.1186/s12885-024-13370-8

P143: Original protocol for presumed germline pathogenic variants in cancer genome profiling tests

Mashu Futagawa, Hideki Yamamoto, Fumino Kato, Chika Fukano, Risa Osumi, Yusaku Urakawa, Tetsuya Okazaki, Shuta Tomida, Daisuke Ennishi, Akira Hirasawa

Genetics in Medicine Open 3 102987 - 102987 2025

Genotypes and phenotypes of neurofibromatosis type 1 patients in Japan: A Hereditary Tumor Cohort Study. International journal

Mashu Futagawa, Tetsuya Okazaki, Eiji Nakata, Chika Fukano, Risa Osumi, Fumino Kato, Yusaku Urakawa, Hideki Yamamoto, Toshifumi Ozaki, Akira Hirasawa

Human genome variation 11 ( 1 ) 42 - 42 2024.11

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

Neurofibromatosis type 1 (NF1) presents with a broad spectrum of clinical manifestations, including an increased risk of tumor development and hypertension. Comprehensive data on genotype‒phenotype correlations in patients with NF1 are limited. Therefore, in this study, we aimed to elucidate the detailed genetic and clinical characteristics of NF1 in a hereditary tumor cohort. We performed sequencing and copy number assays in a clinical laboratory and analyzed the clinical data of 44 patients with suspected NF1. Germline pathogenic variants were detected in 36 patients (81.8%), and 20.7% of the variants were novel. Notably, 40.0% of adult patients presented with malignancies; female breast cancer occurred in 20.0% of patients, which was a higher rate than that previously reported. Hypertension was observed in 30.6% of the adult patients, with one patient experiencing sudden death and another developing pheochromocytoma. Three patients with large deletions in NF1 exhibited prominent cutaneous, skeletal, and neurological manifestations. These results highlight the importance of regular surveillance, particularly for patients with malignancies and hypertension. Our findings provide valuable insights for genetic counseling and clinical management, highlighting the multiple health risks associated with NF1 and the need for comprehensive and multidisciplinary care.

DOI： 10.1038/s41439-024-00299-4

NTRK融合遺伝子とERBB2 amplificationが合併したマイクロサテライト安定型大腸癌

重安邦俊, 高橋利明, 山本英喜, 垣内慶彦, 松三雄騎, 近藤喜太, 寺石文則, 黒田新士, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 62回 ICCJ3 - 6 2024.10

がんゲノム医療の現状と未来～多遺伝子パネル検査の臨床導入のインパクト～多遺伝子パネル検査を活用した遺伝性腫瘍診療がんの診断・治療・予防に活かす

山本英喜, 平沢晃

日本癌治療学会学術集会抄録集 62回 CCSY1 - 2 2024.10

小児・AYA世代がんのゲノム医療小児・AYA世代の肉腫におけるゲノム医療の意義

中田英二, 遠西大輔, 二宮貴一朗, 冨田秀太, 山本英喜, 岡崎哲也, 平沢晃, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 62回 OSY16 - 2 2024.10

肉腫におけるゲノム医療の進歩 C-CATデータを用いた肉腫のゲノム解析

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 国定俊之, 藤原智洋, 二川摩周, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 8 ) S1727 - S1727 2024.9

新たながん遺伝子パネル検査 TruSight Oncology 500(TSO500)の臨床的意義(Clinical relevance of novel comprehensive genomic profiling assay - TruSight Oncology 500(TSO500))

遠西大輔, 冨田秀太, 松井啓隆, 藤野泰輝, 檜井孝夫, 杉本健樹, 川上耕史, 松本光史, 山本弥寿子, 曳野肇, 二宮貴一朗, 山本英喜, 柳井広之, 平沢晃, 豊岡伸一, 豊岡伸一

日本癌学会総会記事 83回 P - 2114 2024.9

BRAF-mutant microsatellite-stable rectal cancer with acquired KRAS mutation leading to drug resistance in liver metastasis. Reviewed International journal

Kunitoshi Shigeyasu, Hideki Yamamoto, Toshiaki Takahashi, Kazuya Moriwake, Masashi Kayano, Sho Takeda, Yuki Matsumi, Yuzo Umeda, Yoshitaka Kondo, Fuminori Teraishi, Kazuya Yasui, Tomokazu Fuji, Shunsuke Kagawa, Toshiyoshi Fujiwara

International cancer conference journal 13 ( 3 ) 189 - 192 2024.7

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

BRAF-mutant microsatellite-stable colorectal cancer (CRC), metastasized to distant sites, is associated with a poor prognosis. However, the BEACON CRC regimen, comprising a BRAF inhibitor, MEK inhibitor, and anti-EGFR antibody, offered a prolonged prognosis. Nonetheless, resistance to this regimen may occur, as observed in our reported case of CRC, where a KRAS mutation was identified in addition to the BRAF V600E mutation. Here, we present a case of 74-year-old woman with rectal cancer (pT4bN1bM0 Stage IIIc) harboring the BRAF V600E mutation. After resection of the primary tumor and during adjuvant chemotherapy using CAPOX (capecitabine and oxaliplatin), liver and lung metastases became apparent, and a companion diagnosis test revealed the presence of a BRAF V600E mutation. The new lesions were deemed resistant to the CAPOX regimen, and we decided to introduce encorafenib and cetuximab. After resection of liver metastases, encorafenib and cetuximab were reintroduced, but a new lesion appeared in hepatic S7, indicating resistance to the encorafenib and cetuximab regimen. The resistant liver metastasis was subsequently resected. To elucidate the resistance mechanism, we conducted a comprehensive analysis using the FoundationOne CDx cancer gene panel test, revealing the presence of a KRAS Q61H mutation alongside the BRAF V600E mutation. Subsequent liquid biopsy after liver recurrence confirmed the persistence of the KRAS Q61H mutation. Our results highlight the significance of cancer genome profiling tests (CGP tests) and liquid biopsies in guiding treatment strategies for BRAF-mutant colorectal cancer. Therefore, CGP testing offers valuable information for treatment, even if it does not lead to new drug administrations.

DOI： 10.1007/s13691-024-00678-2

神経線維腫症1型を中心とした遺伝性骨・軟部腫瘍に対する専門外来の有用性

中田英二, 二川摩周, 平沢晃, 山本英喜, 国定俊之, 板野拓人, 藤原智洋, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1614 - S1614 2024.6

多職種から見た骨・軟部腫瘍治療の現状と課題肉腫発生ハイリスク患者に対する遺伝性骨・軟部腫瘍外来の取り組み

二川摩周, 中田英二, 山本英喜, 深野智華, 加藤芙美乃, 大住理沙, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1579 - S1579 2024.6

加速する骨・軟部腫瘍に対するゲノム医療: 現状と課題肉腫におけるゲノム医療の現状と課題

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 藤原智洋, 国定俊之, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1457 - S1457 2024.6

加速する骨・軟部腫瘍に対するゲノム医療: 現状と課題肉腫におけるゲノム医療の現状と課題

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 藤原智洋, 国定俊之, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1457 - S1457 2024.6

多職種から見た骨・軟部腫瘍治療の現状と課題肉腫発生ハイリスク患者に対する遺伝性骨・軟部腫瘍外来の取り組み

二川摩周, 中田英二, 山本英喜, 深野智華, 加藤芙美乃, 大住理沙, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1579 - S1579 2024.6

神経線維腫症1型を中心とした遺伝性骨・軟部腫瘍に対する専門外来の有用性

中田英二, 二川摩周, 平沢晃, 山本英喜, 国定俊之, 板野拓人, 藤原智洋, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1614 - S1614 2024.6

遺伝性骨・軟部腫瘍外来における肉腫発生at-risk者への取り組み

二川摩周, 中田英二, 山本英喜, 深野智華, 加藤芙美乃, 大住理沙, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本レックリングハウゼン病学会学術大会プログラム・抄録集 15回 25 - 25 2024.2

がん遺伝子パネル検査と病理診断がん遺伝子パネル検査で検出されるgermline findingsの遺伝性腫瘍症候群診断への活用

山本英喜, 平沢晃

病理と臨床 42 ( 1 ) 45 - 54 2024

がんゲノム医療における遺伝子診療部門の役割と提言〜広島市民病院遺伝子診療外来の活動概要と開設後の検証から〜

山本英喜, 平沢晃, 二川摩周, 塩崎滋弘

広島市立広島市民病院医誌 40 15 - 19 2024

Ligneous periodontitis exacerbated by Behçet's disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report. International journal

Yuki Shinoda-Ito, Anna Hirai, Kazuhiro Omori, Hidetaka Ideguchi, Hideki Yamamoto, Fumino Kato, Kyoichi Obata, Tatsuo Ogawa, Keisuke Nakano, Takato Nakadoi, Eri Katsuyama, Soichiro Ibaragi, Tadashi Yamamoto, Hitoshi Nagatsuka, Akira Hirasawa, Shogo Takashiba

BMC oral health 23 ( 1 ) 843 - 843 2023.11

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

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

DOI： 10.1186/s12903-023-03586-8

神経線維腫症1型による叢状神経線維腫に対するセルメチニブの有効性

中田英二, 藤原智洋, 国定俊之, 二川摩周, 山本英喜, 十川麗美, 加藤芙美乃, 片山晴喜, 板野拓人, 近藤彩奈, 平沢晃, 尾崎敏文

中国・四国整形外科学会雑誌 35 ( 3 ) 428 - 428 2023.11

がんゲノム医療における多遺伝子パネル検査(MGPT)の導入にむけた現状と課題

平沢晃, 山本英喜

日本臨床検査医学会誌 71 ( 補冊 ) 087 - 087 2023.10

症例報告からPrecision Medicineへ-第1部- 肝転移にKRAS変異を有するBRAF変異マイクロサテライト安定性直腸癌(BRAF-mutant microsatellite stable rectal cancer with KRAS mutation in liver metastasis)

重安邦俊, 山本英喜, 楳田祐三, 黒田新士, 寺石文則, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 61回 ICCJ1 - 4 2023.10

When and how to enlighten citizens on genetics and hereditary cancer: a web survey of online video viewers. International journal

Reimi Sogawa, Takahito Wada, Noriyuki Yamashita, Mariko Kochi, Mashu Futagawa, Fumino Kato, Yusaku Urakawa, Yayoi Tanimura, Hideki Yamamoto, Shuta Tomida, Shinji Kosugi, Akira Hirasawa

Journal of community genetics 2023.9

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

With the rapid expansion of genomic medicine, more citizens are compelled to think about genetics in their daily lives. This study aims to explore appropriate types of educational media and methods to enlighten activities for genetics and hereditary cancer. We presented an 18-min YouTube video on genetics and hereditary cancer to participants at a scientific event, Science Agora 2020, and administered a web questionnaire to investigate their opinions about when and how citizens should start learning about genetics and hereditary cancer. We recruited 133 participants who watched the video, and 26.3% (35/133) responded to the questionnaire. Most of them were evaluated to understand and appreciate the contents of the video. They identified websites, or videos as suitable learning media, irrespective of their sex, age, or profession. They highlighted upper elementary school or junior high school as appropriate educational stages to start learning about genetics and hereditary cancer to facilitate collecting their own genetic information by themselves. Our findings show that educational institutions should provide opportunities to learn about genetics and hereditary cancers, especially for upper elementary school and junior high school students, using learning media, such as videos, depending on their level or demand.

DOI： 10.1007/s12687-023-00663-x

Biobank Update Invited

H. Yamamoto, A. Hirasawa

Obsterical and Gynecological Practice 72 ( 9 ) 915 - 921 2023.9

網羅的がんゲノム医療時代の遺伝性腫瘍診療と遺伝カウンセリング遺伝性腫瘍のリスク評価・診断のための多遺伝子パネル検査受検例の施設横断的な検討(Hereditary tumor syndromes and genetic counseling in the era of cancer genomic medicine Cross-institutional case review of multi-gene panel testing for risk assessments and diagnosis of hereditary tumors)

山本英喜, 藤田裕子, 田村和朗, 浦川優作, 二川摩周, 十川麗美, 加藤芙美乃, 植野さやか, 重安邦俊, 原賀順子, 小川千加子, 河内麻里子, 深野智華, 甲斐恭平, 塩崎滋弘, 平沢晃

日本癌学会総会記事 82回 821 - 821 2023.9

がんゲノム医療における遺伝リテラシー向上に向けた取り組み

十川麗美, 二川摩周, 加藤芙美乃, 山下範之, 浦川優作, 植野さやか, 深野智華, 山本英喜, 冨田秀太, 平沢晃

BIO Clinica 38 ( 7 ) 635 - 637 2023.7

Language：Japanese Publisher：(株)北隆館

近年の遺伝子解析技術の進歩に伴い,個人が自身のゲノムや遺伝情報を入手する機会は急速に増加している。そのため,医療従事者のみならず,市民もゲノム情報に対する正しい知識を持つことが急務である。筆者らは,医療従事者・学生・市民を対象に,遺伝リテラシーの向上を目的とした取り組みを行ってきた。本稿では,その取り組みの一部を紹介する。(著者抄録)

Musculoskeletal Tumor 骨・軟部腫瘍骨・軟部腫瘍におけるがん遺伝子プロファイリング検査骨・軟部腫瘍診療におけるがん遺伝子パネルの役割

中田英二, 藤原智洋, 国定俊之, 尾崎敏文, 豊岡伸一, 遠西大輔, 山本英喜, 二宮貴一朗, 冨田秀太, 平沢晃, 二川摩周, 田端雅弘

癌と化学療法 50 ( 3 ) 314 - 320 2023.3

ADAR1 is a promising risk stratification biomarker of remnant liver recurrence after hepatic metastasectomy for colorectal cancer. Reviewed International journal

Nanako Hata, Kunitoshi Shigeyasu, Yuzo Umeda, Shuya Yano, Sho Takeda, Kazuhiro Yoshida, Tomokazu Fuji, Ryuichi Yoshida, Kazuya Yasui, Hibiki Umeda, Toshiaki Takahashi, Yoshitaka Kondo, Hiroyuki Kishimoto, Yoshiko Mori, Fuminori Teraishi, Hideki Yamamoto, Hiroyuki Michiue, Keiichiro Nakamura, Hiroshi Tazawa, Toshiyoshi Fujiwara

Scientific reports 13 ( 1 ) 2078 - 2078 2023.2

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

Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy.

DOI： 10.1038/s41598-023-29397-z

多遺伝子パネル検査を用いた遺伝性腫瘍診断の後方視的検討

藤田裕子, 田村和朗, 平沢晃, 山本英喜, 伊藤絢子, 多田陽香, 山根美代子, 三木利恵, 井上豊子, 永谷たみ, 和仁洋治, 高木慎二郎, 渡邉貴紀, 甲斐恭平

姫路赤十字病院誌 47 74 - 77 2023

Language：Japanese Publisher：姫路赤十字病院図書学術委員会

がんのうち遺伝性腫瘍は約10%である.遺伝性腫瘍の診断を目的とした遺伝学的検査として,多遺伝子パネル検査(MGPT:multi-gene panel testing)が自費診療下で臨床導入されている.当院でMGPTを提案された26例のうち22例が実施し,7例に遺伝性腫瘍原因遺伝子の病的バリアントが同定され,遺伝性腫瘍と診断された.同定された遺伝子はPALB2,ATM,MSH2,APC,RAD51D,BRCA2,CDH1であり,本人および血縁者の健康管理につながった.遺伝性腫瘍診断のためMGPTを実施するに至った状況は,従来の保険診療下での遺伝学的検査で診断がつかなかった場合や,コンパニオン診断およびがん遺伝子パネル検査が契機になった場合など多様であった.将来の本邦の遺伝性腫瘍の診断を考えるとき,本邦においてもMGPTが広く活用できる体制構築が強く求められる.(著者抄録)

Liquid Biopsy Revealed HBOC Pedigree and Led to Medical Management Among the Relatives.

Chikako Ogawa, Akira Hirasawa, Reimi Sogawa, Kayoko Hasuoka, Shuta Tomida, Mashu Futagawa, Yusaku Urakawa, Mariko Kochi, Hideki Yamamoto, Keiichiro Nakamura, Hisashi Masuyama

Acta medica Okayama 76 ( 4 ) 479 - 483 2022.8

Language：English

A hereditary breast and ovarian cancer (HBOC) pedigree was detected via liquid biopsy, and cancer prevention was initiated for the patient's daughter, after receiving a definitive result from BRCA genetic testing. A 48-yearold woman with ovarian cancer was administered precision medicine, which used cell-free DNA from plasma. The results revealed a pathogenic variant of BRCA1 as a presumed germline pathogenic mutation. We confirmed the germline pathological variant BRCA1 c.81-1G> A and suggested treatment with a PARP inhibitor. One of her three children had the variant, was diagnosed as an unaffected pathogenic variant carrier, and was advised to initiate surveillance.

DOI： 10.18926/AMO/63908

Biobank and residual sample use for medical research Invited

134 ( 2 ) 119 - 122 2022.8

遺伝性腫瘍に対する多遺伝子パネル検査

山本英喜, 平沢晃

病理と臨床 40 ( 臨時増刊号 ) 390 - 398 2022.4

Hemothorax and Bloody Ascites Caused by Vascular Ehlers-Danlos Syndrome. International journal

Shuichi Tanaka, Hiroyuki Honda, Kou Hasegawa, Koji Tomita, Reimi Sogawa, Hideki Yamamoto, Takao Hiraki, Akira Hirasawa, Fumio Otsuka

The American journal of medicine 135 ( 7 ) e210-e211 - e211 2022.3

Homologous Recombination Deficiencies and Hereditary Tumors International journal

Hideki Yamamoto, Akira Hirasawa

International Journal of Molecular Sciences 23 ( 1 ) 348 2022

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

DOI： 10.3390/ijms23010348

Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report Reviewed

Mashu Futagawa, Hideki Yamamoto, Mariko Kochi, Yusaku Urakawa, Reimi Sogawa, Fumino Kato, Mika Okazawa-Sakai, Daisuke Ennishi, Katsunori Shinozaki, Hirofumi Inoue, Hiroyuki Yanai, Akira Hirasawa

Hereditary Cancer in Clinical Practice 19 ( 1 ) 2021.12

Authorship：Corresponding author Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title><sec>
<title>Background</title>
<italic>RAD51D</italic> (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including <italic>BRCA</italic> impairment, there is no clear evidence of the relationship between <italic>RAD51D</italic> variants and the risk of sarcoma development.

</sec><sec>
<title>Case presentation</title>
A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of <italic>RAD51D</italic> c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the <italic>RAD51D</italic> splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of <italic>RAD51D</italic> with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3′-end of intron 9 of <italic>RAD51D</italic>. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered <italic>RAD51D</italic>, this case provided novel evidence for the relationship of a <italic>RAD51D</italic> splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of <italic>RAD51D</italic> c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma.

</sec><sec>
<title>Conclusions</title>
We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of <italic>RAD51D</italic> as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline <italic>RAD51D</italic> splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

</sec>

DOI： 10.1186/s13053-021-00205-x

Other Link： https://link.springer.com/article/10.1186/s13053-021-00205-x/fulltext.html

Pembrolizumab‐caused polyradiculoneuropathy as an immune‐related adverse event Reviewed International journal

Takashi Kurashige, Mineyo Mito, Hideki Yamamoto, Tomohito Sugiura, Takashi Onoe, Kazuya Kuraoka, Kikuo Nakano, Tsuyoshi Torii

Neuropathology 41 ( 4 ) 266 - 272 2021.8

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

Immune-related adverse events (irAEs) commonly involve the gastrointestinal tract, endocrine glands, skin, and liver, and rarely the nervous system. The pathomechanism of irAEs in the nervous system is unclear, and so characterizing these severe toxic effects is a priority, even if irAEs are uncommon in the nervous system. Our patient presented subacute muscle weakness and dysesthesia with colitis as irAEs caused by pembrolizumab, one of the anti-programmed death-1 (PD-1) antibodies. Electromyography revealed abundant fibrillations and fasciculations of upper and lower extremities and severe reduction in motor unit potentials; however, antineutrophil cytoplasmic antibodies, rheumatoid factor, autoantibodies against Hu and Yo, and anti-ganglioside antibodies, such as GQ1b, were undetectable in the serum. Although he was treated with high-dose glucocorticoids, antibiotics, and a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, he developed colonic perforation. The total colorectal resection was performed, and the resected colon showed mucosal defect and perforation. He died of lung aspergillosis. Postmortem examination revealed CD8-positive lymphocyte infiltration around neurons of dorsal root ganglia. The sciatic nerve displayed the widening of myelin laminae and thinning of myelinated fibers but not a decrease in the density of myelinated nerve fibers. In the sural nerve, the density of myelinated fibers slightly decreased, and some fibers showed less densely myelinated laminae. Drug safety information, including previous randomized trials of anti-PD-1 and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies, showed that patients treated with anti-PD-1 antibodies appeared to have more frequent and severe peripheral neuropathies compared to those in patients who received anti-CTLA-4 antibodies (1.59% vs. 0.69%; Fisher exact test, P < 0.001; three severe events vs. zero severe events). The present results and drug safety information suggest that the pathomechanism of irAEs caused by anti-PD-1 antibodies is different from that by anti-CTLA-4 antibodies. The neurological irAEs might be clues to solving the pathomechanism of irAEs.

DOI： 10.1111/neup.12729

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/neup.12729

SMAD4 Germline Pathogenic Variant-Related Gastric Juvenile Polyposis with Adenocarcinoma Treated with Laparoscopic Total Gastrectomy: A Case Report International journal

Yuya Sakurai, Satoru Kikuchi, Kunitoshi Shigeyasu, Yoshihiko Kakiuchi, Takehiro Tanaka, Hibiki Umeda, Masaki Sakamoto, Sho Takeda, Shuya Yano, Mashu Futagawa, Fumino Kato, Reimi Sogawa, Hideki Yamamoto, Shinji Kuroda, Yoshitaka Kondo, Fuminori Teraishi, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Akira Hirasawa, Toshiyoshi Fujiwara

American Journal of Case Reports 22 e932241 2021.5

Language：English Publishing type：Research paper (scientific journal) Publisher：International Scientific Information, Inc.

BACKGROUND Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. CASE REPORT A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. CONCLUSIONS JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

DOI： 10.12659/ajcr.932241

遺伝性平滑筋腫症-腎細胞癌症候群関連腎細胞癌の術後骨転移に対してイピリムマブ・ニボルマブ併用療法が有効であった1例

渡部智文, 榮枝一磨, 津川昌也, 関戸崇了, 富永悠介, 高本篤, 定平卓也, 小林泰之, 荒木元朗, 渡邉豊彦, 小田和歌子, 黒田直人, 十川麗美, 山本英喜, 平沢晃, 那須保友

西日本泌尿器科 83 ( 1 ) 31 - 36 2021.4

Language：Japanese Publisher：西日本泌尿器科学会

症例は45歳,男性。X-1年9月に肉眼的血尿と右腰痛を主訴に当院を受診し,単純CTで右腎上極に長径5cm大の腫瘤を認めた。腹部造影CTでは動脈相で早期濃染,後期相でwashout patternを伴う内部不整な腫瘤を同部位に認めたが,明らかなリンパ節・他臓器転移を認めなかった。右腎癌cT1bN0M0 Stage Iと診断し,同年10月に腹腔鏡下右腎摘除術を施行した。病理所見は,腫瘍細胞は淡明細胞や好酸性細胞が乳頭状・管状の構造を取り,細胞質に好酸性の核小体および核周囲明庭を認めた。Fumarate hydratase(FH)免疫染色陰性でFH欠損腎細胞癌と診断した。術後2ヵ月で多発骨転移を認め,International Metastatic RCC Database Consortium(IMDC) intermediate riskと判断し,イピリムマブ・ニボルマブ併用療法を開始した。4コース施行後,CT上新規の転移巣や転移巣の増大を認めなかった。遺伝学的検査でFH遺伝子の病的バリアントを認め,腎細胞癌の家族歴と合わせ,遺伝性平滑筋腫症-腎細胞癌症候群(hereditary leiomyomatosis and renal cell carcinoma syndrome;HLRCC)関連腎細胞癌と診断した。現在ニボルマブ単剤投与を継続中で,骨転移増悪や新規遠隔転移は認めていない。(著者抄録)

グルココルチコイド反応性アルドステロン症の1家系に発症前診断しえた2例

中野靖浩, 岩田菜穂子, 長谷川高誠, 越智可奈子, 山本紘一郎, 高瀬了輔, 長谷川功, 堀口繁, 山本英喜, 平沢晃, 大塚文男

日本内分泌学会雑誌 96 ( 3 ) 782 - 782 2021.1

Dual analyses of DNA-seq and RNA-seq identified two independent transcripts caused by a single nucleotide variant of MUTYH c.934-2A>G in advanced colon cancer Reviewed

Yamamoto H, Hinoi T, Wakatsuki T, Miyabe I, Yamamoto G, Kakuta M, Zaitsu J, Kuraoka K, Taniyama K, Akagi K

The OFFICIAL JOURNAL OF JAPANESE SOCIETY OF LABORATORY MEDICINE 68 ( 12 ) 973 - 979 2020.12

CYP11B1/B2キメラ遺伝子を確認した家族性アルドステロン症小児例

中野靖浩, 岩田菜穂子, 長谷川高誠, 越智可奈子, 山本紘一郎, 高瀬了輔, 長谷川功, 堀口繁, 山本英喜, 平沢晃, 大塚文男

日本内分泌学会雑誌 96 ( 2 ) 535 - 535 2020.10

遺伝性腫瘍-最新情報と今後の方向性がん遺伝子パネル検査によるがん個別化医療と遺伝性腫瘍への実効果

山本英喜, 久保寿夫, 冨田秀太, 遠西大輔, 豊岡伸一, 平沢晃

日本癌学会総会記事 79回 S21 - 5 2020.10

A case of Turcot's syndrome type 1 with loss of immunoexpression of MSH6 in colon cancer and liver metastasis due to secondary somatic mutation in coding mononucleotide (C)8 tract: a case report. Reviewed International journal

Shintaro Akabane, Takao Hinoi, Kiwamu Akagi, Hideki Yamamoto, Haruki Sada, Yosuke Shimizu, Wataru Shimizu, Takeshi Sudo, Takashi Onoe, Kohei Ishiyama, Takahisa Suzuki, Hirofumi Tazawa, Naoto Hadano, Toshihiro Misumi, Masato Kojima, Haruna Kubota, Daiki Taniyama, Kazuya Kuraoka, Hirotaka Tashiro

BMC medical genetics 21 ( 1 ) 141 - 141 2020.7

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

BACKGROUND: Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes. CASE PRESENTATION: A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot's syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis. CONCLUSION: This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot's syndrome type 1.

DOI： 10.1186/s12881-020-01079-x

ゲノム医療におけるエキスパートパネル【がんゲノム医療中核拠点病院でのエキスパートパネル】岡山大学のエキスパートパネル

柳井広之, 都地友紘, 谷口恒平, 西田賢司, 井上博文, 松岡博美, 平沢晃, 河内麻里子, 山本英喜, 冨田秀太, 遠西大輔

病理と臨床 38 ( 6 ) 527 - 530 2020

Spontaneous regression of transverse colon cancer with high-frequency microsatellite instability: a case report and literature review Reviewed

Nozomi Karakuchi, Manabu Shimomura, Kazuhiro Toyota, Takao Hinoi, Hideki Yamamoto, Seiji Sadamoto, Koichi Mandai, Hiroyuki Egi, Hideki Ohdan, Tadateru Takahashi

World Journal of Surgical Oncology 17 ( 1 ) 2019.12

CD204-Positive Tumor-associated Macrophages Relate to Malignant Transformation of Colorectal Adenoma

DAIKI TANIYAMA, KIYOMI TANIYAMA, KAZUYA KURAOKA, HIDEKI YAMAMOTO, JUNICHI ZAITSU, AKIHISA SAITO, NAOYA SAKAMOTO, KAZUHIRO SENTANI, NAOHIDE OUE, WATARU YASUI

Anticancer Research 39 ( 6 ) 2767 - 2775 2019.6

Low grade dysplasiaを伴う胃底腺ポリープの１例

在津潤一, 倉岡和矢, 山本英喜, 斉藤彰久, 谷山清己

診断病理 36 ( 2 ) 87 - 93 2019

Overexpression of topoisomerase II alpha protein is a factor for poor prognosis in patients with luminal B breast cancer

Hideo Shigematsu, Shinji Ozaki, Daisuke Yasui, Hideki Yamamoto, Junichi Zaitsu, Daiki Taniyama, Akihisa Saitou, Kazuya Kuraoka, Taizo Hirata, Kiyomi Taniyama

Oncotarget 9 ( 42 ) 26701 - 26710 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Impact Journals LLC

Background: The prognostic value and the best method of testing of topoisomerase II alpha (TOP2A) status have not been established in modern tailored therapy based on breast cancer subtype. Results: The frequencies of TOP2A overexpression and TOP2A amplified were 55.8% and 9.5%, respectively. TOP2A overexpression correlated strongly with nonluminal A subtype (χ2-test, p &lt
0.001). TOP2A overexpression was significantly associated with relapse-free survival in luminal B breast cancer (n = 316
log rank test, p &lt
0.001) but not in other breast cancer subtypes. Cox regression analysis showed that TOP2A overexpression is a significant prognostic factor in luminal B breast cancer (hazard ratio (HR) 4.00, 95% confidence interval (CI) 1.65-9.54, p = 0.002). TOP2A amplified was recognized in HER2 positive breast cancer (p &lt
0.001). In HER2 positive breast cancer, TOP2A amplified (HR 0.30, 95% CI 0.085-1.07, p = 0.063) appeared to be a better prognostic factor. Conclusion: In modern tailored therapy, TOP2A overexpression can be a poor prognostic factor in luminal B breast cancer. In contrast, TOP2A amplified could be a better prognostic factor in HER2 positive breast cancer. Materials and methods: Between May 2005 and April 2015, a total of 643 consecutive non-metastatic invasive breast cancers were evaluated for TOP2A amplified using fluorescence in situ hybridization analysis (FISH) and for TOP2A overexpression using the immunohistochemistry assay. FISH ratios of 2 or higher were designated as TOP2A amplified, and TOP2A staining &gt
10% was defined as TOP2A overexpression. The prognostic values of TOP2A amplified and TOP2A overexpression were retrospectively evaluated.

DOI： 10.18632/oncotarget.25468

当院における子宮頸部異形成に対するCO2レーザー蒸散術の治療成績

三浦聡美, 澤崎隆, 高畑敬之, 中村紘子, 藤澤宏樹, 菅亜里紗, 安村奈緒子, 吉田美帆, 佐伯由美, 戸田環, 山本英喜, 在津潤一, 谷山大樹, 齋藤彰久, 倉岡和矢, 谷山清己

広島県臨床細胞学会誌 39 41 - 44 2018

当院における泌尿器細胞診新報告様式導入に伴う報告状況と異型細胞所見の検討

佐伯由美, 倉岡和矢, 安村奈緒子, 藤澤宏樹, 菅亜里紗, 吉田美帆, 戸田環, 谷山大樹, 在津潤一, 山本英喜, 齋藤彰久, 谷山清己

広島県臨床細胞学会誌 39 13 - 19 2018

Autocrine VEGF isoforms differentially regulate endothelial cell behavior Reviewed

Yamamoto, H, Rundqvist, H, Branco, C, Johnson, R.S

Frontiers in Cell and Developmental Biology Sep 21 ( 4:99 ) 2016

Hypoxia-mediated CD24 expression is correlated with gastric cancer aggressiveness by promoting cell migration and invasion Reviewed

Nobuaki Fujikuni, Hideki Yamamoto, Kazuaki Tanabe, Yutaka Naito, Naoya Sakamoto, Yuka Tanaka, Kazuyoshi Yanagihara, Naohide Oue, Wataru Yasui, Hideki Ohdan

CANCER SCIENCE 105 ( 11 ) 1411 - 1420 2014.11

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

CD24 is a heavily glycosylated cell surface protein that is expressed in putative stem cells and is overexpressed in various human malignancies, yet the significant roles of CD24 in gastric cancer development are still elusive. We investigated the involvement of CD24 in gastric cancer aggressiveness, which is attributed to its heterogeneity. Cultured gastric cancer cells showed diverse expression patterns in CD24, whereas other defined cell surface markers, such as CD44 and CD133, were homogenous. Purely sorted CD24-negative gastric cancer cells showed strong alteration into the CD24-positive cell type in an autochthonous manner, and reached to steady expression levels. Our clinicopathological study revealed that CD24 positivity was an independent prognostic factor in both intestinal and diffuse types of gastric cancer. CD24 expression was correlated with the advanced stages, invasiveness, and lymph node metastasis of gastric cancer. Silencing of CD24 in cultured cells significantly decreased cell migration and invasion. Hypoxic treatment upregulated CD24 expression, and simultaneously induced cell motility and invasion of gastric cancer cells. Hypoxic treatment-induced CD24 expression was significantly attenuated by knockdown of hypoxia-inducible transcription factors. These data suggest that CD24-negative cells are capable of gaining cell motility and invasiveness through the induction of CD24, which is mediated by hypoxia. CD24 would be an attractive marker to define not only the heterogeneity but also the aggressiveness of gastric cancer cells. The mechanisms by which hypoxia induces CD24 expression would also be a potential therapeutic target for gastric cancer.

File： Fujikuni_et_al-2014-Cancer_Science.pdf

DOI： 10.1111/cas.12522

Triple-tube-ostomy: A novel technique for the surgical treatment of iatrogenic duodenal perforation Reviewed

Nobuaki Fujikuni, Kazuaki Tanabe, Hideki Yamamoto, Takahisa Suzuki, Noriaki Tokumoto, Hideki Ohdan

Case Reports in Gastroenterology 5 ( 3 ) 672 - 679 2011.9

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

Although duodenal perforation is currently an infrequent complication of medical procedures, its incidence in the future predictably will increase as endoscopic treatment of duodenal neoplasms becomes more frequently used. In some cases, duodenal perforation is difficult to treat even surgically. We report here a novel technique called 'triple-tube-ostomy' for the treatment of iatrogenic duodenal perforation. Since November 2009, there have been three cases of iatrogenic perforation of the duodenum, due to various causes, which we have treated with our novel technique. The main principles of the technique are biliary diversion, decompression of the duodenum, and early enteral nutrition. All patients who underwent the triple-tube-ostomy procedure had good postoperative courses, with few complications. The novel surgical technique we describe in this report is safe, reliable, easy to learn and perform, and led to a good postoperative course in all cases where we performed it. Copyright © 2011 S. Karger AG.

DOI： 10.1159/000335742

99mTc-MIBIシンチグラム陰性原発性副甲状腺機能亢進症に対して術中intact-PTH測定により内視鏡補助下手術をしえた１例 Reviewed

山本英喜, 内田一徳, 春田直樹, 小川喜輝, 清水一雄

日本内視鏡外科学会雑誌 16 ( 3 ) 317 - 322 2011

Combination therapy with docetaxel and S-1 as a first-line treatment in patients with advanced or recurrent gastric cancer: a retrospective analysis

Kazuaki Tanabe, Takahisa Suzuki, Noriaki Tokumoto, Hideki Yamamoto, Kazuhiro Yoshida, Hideki Ohdan

World Journal of Surgical Oncology 8 ( 1 ) 2010.12

Thoracoscopic-assisted repair of a bochdalek hernia in an adult: a case report. Reviewed

Tokumoto N, Tanabe K, Yamamoto H, Suzuki T, Miyata Y, Ohdan H

Journal of medical case reports 4 366 2010.11

Preliminary trial of adjuvant surgery for advanced gastric cancer Reviewed

T. Suzuki, K. Tanabe, J. Taomoto, H. Yamamoto, N. Tokumoto, K. Yoshida, H. Ohdan

Oncology Letters 1 ( 4 ) 743 - 747 2010.7

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

In patients with stage IV gastric cancer, systemic chemotherapy is the key treatment. Combination chemotherapy (cis-diamminedichloride platinum plus S-1 and docetaxel plus S-1) results in long-term survival in clinical practice. In selected cases, additional (adjuvant) surgery may result in further long-term survival. This study aimed to evaluate the effcacy of adjuvant surgery following the response to chemotherapy for advanced gastric cancer. Based on response to chemotherapy, the indications for adjuvant surgery (surgery after the response to chemotherapy) are that resection is expected to be curative rather than palliative, provided that no other distant metastases occur. The study included 20 advanced gastric cancer patients who had undergone gastrectomies after the response to the combination chemotherapy of docetaxel and S-1, between September 2003 and December 2008 at Hiroshima University Hospital. At a median follow-up of 980 days, the median overall survival was 855 days. A 2- and 3-year survival was observed in 80 and 54.9% of patients, respectively, following macroscopic curative surgery. In the palliative group, the median overall survival was 510 days, but a 3-year survival was not observed. In the partial response group, the median overall survival was 865 days and a 3-year survival was observed in 37% of patients. One-year survival was not observed in the stable disease group. The patient survival in the partial response group was statistically more prolonged than in the stable disease group. The median overall survival in patients with liver metastasis was 865 days, while that in patients with peritoneal dissemination was 510 days. In conclusion, adjuvant surgery may be effective in gastric cancer patients diagnosed as stage IV by means of liver or distant lymph node metastasis, except in cases of peritoneal dissemination.

DOI： 10.3892/ol_00000130

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase Reviewed

H. Yamamoto, N. Oue, A. Sato, Y. Hasegawa, H. Yamamoto, A. Matsubara, W. Yasui, A. Kikuchi

ONCOGENE 29 ( 14 ) 2036 - 2046 2010.4

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

Wnt5a is a representative ligand that activates the beta-catenin-independent pathway in Wnt signaling. Although it has been reported that abnormal activation of the Wnt/beta-catenin-dependent pathway is often observed in human prostate cancer, the involvement of the b-catenin-independent pathway in this cancer is unclear. Abnormal expression of Wnt5a and beta-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by immunohistochemical analyses. Simultaneous expression of Wnt5a and b-catenin was observed in only five cases, suggesting their exclusive expression. The positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer, but that of b-catenin was not. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines reduced and stimulated, respectively, their invasion activities, and the invasion activity required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy. Oncogene (2010) 29, 2036-2046; doi: 10.1038/onc.2009.496; published online 18 January 2010

File： Wnt5a & PCa; Yamamoto H et al; Oncogene 2010 front.pdf

DOI： 10.1038/onc.2009.496

外観上傷のない腹腔鏡下胆嚢摘出術単孔式腹腔鏡下手術 Reviewed

山本英喜, 内田一徳, 大下彰彦, 小川喜輝, 春田直樹, 大段秀樹

広島医学 63 ( 7 ) 505 - 508 2010

A New Method for Intraluminal Gastrointestinal Stromal Tumor Resection Using Laparoscopic Seromuscular Dissection Technique

Kazuaki Tanabe, Yuji Urabe, Noriaki Tokumoto, Takahisa Suzuki, Hideki Yamamoto, Shiro Oka, Shinji Tanaka, Hideki Ohdan

Digestive Surgery 27 ( 6 ) 461 - 465 2010

Laminin gamma 2 Mediates Wnt5a-Induced Invasion of Gastric Cancer Cells Reviewed

Hideki Yamamoto, Yasuhiko Kitadai, Hideki Yamamoto, Naohide Oue, Hideki Ohdan, Wataru Yasui, Akira Kikuchi

GASTROENTEROLOGY 137 ( 1 ) 242 - 252 2009.7

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

BACKGROUND & AIMS: Wnt5a expression stimulates in vitro migration and invasion of cultured gastric cancer cells by an unknown mechanism and is also correlated with aggressiveness of gastric tumors. The aim of this study was to show that Wnt5a is involved in metastasis of gastric cancer cells in vivo and to explore the molecular mechanism by which Wnt5a regulates migration and invasion. METHODS: In an experimental liver metastasis assay, Wnt5a-knockdown gastric cancer cells were injected into the spleens of nude mice. Microarray anatyses were used to compare expression patterns between mouse fibroblast L cells that stably express wild-type and a inurant form of Wnt5a to investigate Wnt5a-dependent gene expression. The expression of genes found to be regulated by Writ5a was investigated in cultured gastric cancer cells. Immunohistochemical analyses were performed to measure levels of Wnt-regulated gene products in 153 gastric cancer samples. RESULTS: Knockdown of Wnt5a in gastric cancer cells reduced the number of liver metastases that formed in nude mice. Microarray analyses indicated that Wnt5a activity induced expression of the gene encoding laminin gamma 2, a subunit of the epithelial basement membrane protein laminin-5. Wnt5a induced the expression of laminin gamma 2 through the activation of protein kinase C and c-Jun-N-terminal kinase. The invasive activity of gastric cancer cells depended on laminin gamma 2; Wnt5a expression levels correlated with those of laminin gamma 2 in diffuse-scattered type gastric tumor samples from patients. CONCLUSIONS: Wnt5a contributes to gastric cancer progression by increasing metastatic potential. Wnt5a up-regulates laminin gamma 2 to mediate gastric cancer cell aggressiveness.

File： Hideki Yamamoto; Wnt5a & GCa (Gastroenterology).pdf

DOI： 10.1053/j.gastro.2009.02.003

Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling Reviewed

Hideki Yamamoto, Hiroshi Sakane, Hideki Yamamoto, Tatsuo Michiue, Akira Kikuchi

DEVELOPMENTAL CELL 15 ( 1 ) 37 - 48 2008.7

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

Wnt and Dickkopf (Dkk) regulate the stabilization of beta-catenin antagonistically in the Wnt signaling pathway; however, the molecular mechanism is not clear. In this study, we found that Wnt3a. acts in parallel to induce the caveolin-dependent internalization of low-density-lipoprotein receptor-related protein 6 (LRP6), as well as the phosphorylation of LRP6 and the recruitment of Axin to LRP6 on the cell surface membrane. The phosphorylation and internalization of LRP6 occurred independently of one another, and both were necessary for the accumulation of beta-catenin. In contrast, Dkk1, which inhibits Wnt3a-dependent stabilization of beta-catenin, induced the internalization of LRP6 with clathrin. Knockdown of clathrin suppressed the Dkk1-dependent inhibition of the Wnt3a response. Furthermore, Dkk1 reduced the distribution of LRP6 in the lipid raft fraction where caveolin is associated. These results indicate that Wnt3a and Dkk1 shunt LRP6 to distinct internalization pathways in order to activate and inhibit the beta-catenin signaling, respectively.

File： Dev Cell 2008; Wnt3a & Dkk1; Yamamoto H, Sakane H, Yamamoto H et al.pdf

DOI： 10.1016/j.devcel.2008.04.015

TS-1/Weekly CDDP併用化学放射線療法が著効した進行食道癌の１例

坂口善久, 椛島章, 山本英喜, 島袋林春, 小島康知, 山村晋史, 西崎隆, 田代英哉, 松坂俊光

31 2159 - 2162 2004

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