Faculty Profiles - HIRASAWA Akira

Papers - HIRASAWA Akira

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CD63 as a potential biomarker for patients with ovarian cancer. International journal

Keiichiro Nakamura, Naoyuki Ida, Akira Hirasawa, Kazuhiro Okamoto, Thuy Ha Vu, Dao Thi Hai Ly, Hisashi Masuyama

European journal of obstetrics, gynecology, and reproductive biology 306 87 - 93 2025.1

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

INTRODUCTION: Exosomes play an important role in regulating physiological processes and mediating the systemic dissemination of various types of cancer. We investigated the association of exosomal tetraspanins CD9, CD63, and CD81 in patients with ovarian cancer (OC). MATERIAL AND METHODS: We measured the plasma tetraspanins CD9, CD63, and CD81 by enzyme-linked immunosorbent assay in 91 patients who underwent treatment for OC between April 2018 and March 2024. Additionally, we analyzed clinical pathologic factors, chemotherapy response, and prognosis. RESULTS: In terms of stages, CD63 expression was significantly higher in patients with stage IV compared to those with stage I OC (p = 0.003). In terms of histological type, CD63 expression was significantly higher in high-grade serous carcinoma (HGSC) than in clear cell carcinoma (CCC) with OC (p = 0.009). Furthermore, CD63 levels were significantly higher in advanced-stage, HGSC than in patients with early-stage, non-HGSC and early-stage, HGSC OC (p = 0.045 and p = 0.002, respectively). In the Neoadjuvant chemotherapy (NAC) of 12 patients with OC assessed as having either a partial response (PR) or complete response (CR), CD63 was significantly decreased (p = 0.043), whereas perforin was significantly increased (p = 0.001). In the NAC of 16 patients with OC, CD63 of the response rate to chemotherapy tended to differ between the progressive disease (PD) and PR/CR groups (p = 0.056). A moderate inverse correlation was observed between CD63 and perforin levels (R = 0.638, R2 = 0.428, p = 0.008). CONCLUSIONS: CD63 could be a potential biomarker for all types of OC patients.

DOI： 10.1016/j.ejogrb.2025.01.011

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

Molecular and functional profiling of primary normal ovarian cells defines insights into cancer development and drug responses. International journal

Emilia Piki, Alice Dini, Frida Rantanen, Franziska Bentz, Lassi Paavolainen, Harlan Barker, Juuli Raivola, Akira Hirasawa, Olli Kallioniemi, Astrid Murumägi, Daniela Ungureanu

Molecular therapy. Oncology 32 ( 4 ) 200903 - 200903 2024.12

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

Patients with ovarian cancer, especially the high-grade serous ovarian cancer (HGSOC) subtype, face poor prognosis due to late diagnosis and treatment resistance. Owing to the high heterogeneity of HGSOC, identifying the origin of the disease and optimal treatments is difficult. Here, we characterized two primary immortalized human ovarian cell lines, human ovarian surface epithelium (HOSE)1C and HOSE2C, comparing their molecular profiling with representative HGSOC cells. We identified molecular features associated with normal and malignant phenotype of ovarian cells by applying single-cell transcriptomics, high-content image-based cell painting, and high-throughput drug testing. Our findings reveal distinct transcriptomic and morphological profiles for the two HOSEs, with a stromal phenotype. Moreover, their responses to the tumor microenvironment differ, exemplified by STAT1 and GREM1 upregulation in HOSE1C and HOSE2C, respectively. We identified selective activation of ERK/MEK targeted inhibitors in cancer cells compared to HOSEs. This study offers insights into the normal and malignant ovarian cells, shedding light on cancer development and drug responses.

DOI： 10.1016/j.omton.2024.200903

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

Knowledge and Awareness of Cancer Genome Profiling Tests among Japanese Patients with Cancer. International journal

Yuko Kawasaki, Tamotsu Sudo, Kazuo Tamura, Saki Hinoshita, Kayoko Hasuoka, Satoko Miyawaki, Nao Matsutani, Akira Hirasawa, Atsuko Uchinuno

Clinics and practice 14 ( 5 ) 2105 - 2115 2024.10

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

(1) Background: The number of patients with cancer undergoing cancer genome profiling is increasing; however, it remains unclear how accurately they understand the details of the tests and treatments. This study aimed to clarify the awareness of cancer genome profiling tests among patients with cancer who visited cancer genome medical clinics. (2) Methods: A questionnaire survey was conducted on awareness, anxiety, sources of information, and psychological states concerning cancer genome profiling tests. (3) Results: In total, 265 patients with cancer (117 men, 142 women, 6 no response, average age of 58.29 ± 11.9 years) were included in the study, of which 218 (82.3%) were aware of the term "cancer genomic medicine" and 90 (34.0%) were aware of its details. Thus, only a few respondents understood that cancer genome profiling tests facilitate the discovery of secondary findings and of genes associated with hereditary tumors. Regarding their psychological state when visiting the cancer genome clinic, the respondents were anxious about standard treatment and prognosis limits. (4) Conclusions: From the viewpoint of advance care planning, we suggest that medical professionals build a support system that links palliative care and cancer treatment and coordinates genetic counseling at an early stage.

DOI： 10.3390/clinpract14050166

Nationwide survey of the secondary findings in cancer genomic profiling: survey including liquid biopsy. International journal

Saki Shimada, Takahiro Yamada, Akari Minamoto, Manami Matsukawa, Ichiro Yabe, Hiroshi Tada, Katsutoshi Oda, Arisa Ueki, Satomi Higashigawa, Maki Morikawa, Yuki Sato, Akira Hirasawa, Masanobu Ogawa, Tomohiro Kondo, Masahiro Yoshioka, Masashi Kanai, Manabu Muto, Shinji Kosugi

Journal of human genetics 70 ( 1 ) 33 - 40 2024.9

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

We surveyed the status of the secondary finding (SF) disclosure in comprehensive genome profiling (CGP) in 2020. The situation has changed: increase in the number of hospitals that provide CGP, an update to the Comprehensive Tumor Genomic Profiling: Materials for Review of Secondary Findings (CTGPMRSF), and the addition of a liquid biopsy test, FoundationOne® Liquid CDx (F1L). Moreover, the actual situation was unclear because the 2020 survey did not include all designated and cooperative hospitals. Herein, we conducted a questionnaire survey of all designated-core, designated, and cooperative hospitals to identify the current status and challenges concerning SF in the CGP in 2022. A total of 82.1% of the hospitals responded and 77.7% of the response was from cooperative hospitals. Approximately 80% of the hospitals used CTGPMRSF. SF disclosure, confirmatory test implementation, and SF confirmation rates were 12.4%, 31.6%, and 46.6% for FoundationOne® CDx (F1CDx), respectively, and 6.8%, 31.8%, and 70.7% for F1L, respectively. The implementation rate of the confirmatory test was substantially higher in hospitals with genetic experts and in hospitals that could conduct confirmatory tests on the same day. Our survey provides insight into how SF is handled in Japan. The percentage of cases leading to confirmatory tests has gradually increased, although challenges such as insurance coverage limitations and varied understanding of SF among patients and healthcare providers persist. With the increasing use of whole-genome analysis, our findings will provide valuable insights into establishing an effective SF disclosure system.

DOI： 10.1038/s10038-024-01294-x

[Diagnosis of Hereditary Tumors Using Multi Gene Panel Testing(MGPT)-Current Status and Issues in Japan or Worldwide].

Akira Hirasawa

Gan to kagaku ryoho. Cancer & chemotherapy 51 ( 7 ) 677 - 680 2024.7

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

Pathogenic variant carriers of hereditary tumors have the risk of developing cancer in multiple organs, and genetic testing can be used as an opportunity to conduct surveillance for early detection of cancer and to prevent the development of new cancers and it becomes possible to develop individualized preventive strategies including risk-reductive surgery. Multi gene panel testing(MGPT), which simultaneously measures several dozen to more than 100 genes, has been widely used to diagnose of hereditary tumors in worldwide since around 2014. Although, MGPTs has not been approved under the Pharmaceutical and Medical Devices Act in Japan. MGPTs for hereditary tumors can be expected to become the mainstream of diagnosis for hereditary tumors in near future.

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

Assessing the efficacy of target adaptive sampling long-read sequencing through hereditary cancer patient genomes. International journal

Wataru Nakamura, Makoto Hirata, Satoyo Oda, Kenichi Chiba, Ai Okada, Raúl Nicolás Mateos, Masahiro Sugawa, Naoko Iida, Mineko Ushiama, Noriko Tanabe, Hiromi Sakamoto, Shigeki Sekine, Akira Hirasawa, Yosuke Kawai, Katsushi Tokunaga, Shin-Ichi Tsujimoto, Norio Shiba, Shuichi Ito, Teruhiko Yoshida, Yuichi Shiraishi

NPJ genomic medicine 9 ( 1 ) 11 - 11 2024.2

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

Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.

DOI： 10.1038/s41525-024-00394-z

神経線維腫症1型患者由来ヒトiPS細胞株の樹立

大澤太郎, 中田英二, 岡本真幸, 山田大祐, 二川摩周, 高尾知佳, 平沢晃, 尾崎敏文, 宝田剛志

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 24 - 24 2024.2

HBOCに対するリスク低減卵管卵巣摘出術及び乳腺外科手術の合同実施に関する当院での取り組み

花谷智美, 原賀順子, 小川千加子, 長尾昌二, 杉原花子, 谷佳紀, 白河伸介, 依田尚之, 松岡敬典, 中村圭一郎, 平沢晃, 増山寿

日本産科婦人科学会雑誌 76 ( 臨増 ) S - 500 2024.2

Patient survey on cancer genomic medicine in Japan under the national health insurance system. International journal

Hidenori Kage, Nana Akiyama, Hyangri Chang, Aya Shinozaki-Ushiku, Mirei Ka, Junichi Kawata, Manabu Muto, Yusuke Okuma, Natsuko Okita, Katsuya Tsuchihara, Junko Kikuchi, Hidekazu Shirota, Hideyuki Hayashi, Toshio Kokuryo, Shinichi Yachida, Akira Hirasawa, Makoto Kubo, Hirotsugu Kenmotsu, Masahiko Tanabe, Tetsuo Ushiku, Kaori Muto, Yasuyuki Seto, Katsutoshi Oda

Cancer science 115 ( 3 ) 954 - 962 2024.1

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

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy.

DOI： 10.1111/cas.16065

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

多遺伝子パネル検査を用いて治療方針を決定した若年の非浸潤性乳管癌患者の一例

鈴木陽子, 岩谷胤生, 仁科卓也, 吉本皓一, 宇野摩耶, 中本翔伍, 高橋侑子, 突沖貴宏, 岩本高行, 伊波茂道, 平沢晃, 枝園忠彦

日本臨床外科学会雑誌 84 ( 11 ) 1830 - 1830 2023.11

多遺伝子パネル検査を用いて治療方針を決定した若年の非浸潤性乳管癌患者の一例

鈴木陽子, 岩谷胤生, 仁科卓也, 吉本皓一, 宇野摩耶, 中本翔伍, 高橋侑子, 突沖貴宏, 岩本高行, 伊波茂道, 平沢晃, 枝園忠彦

日本臨床外科学会雑誌 84 ( 11 ) 1830 - 1830 2023.11

ベーチェット病を併発したプラスミノーゲン低下症に伴うLigneous歯周炎患者の臨床的・遺伝学的考察

平井杏奈, 伊東有希, 井手口英隆, 大森一弘, 加藤芙美乃, 山本英喜, 平沢晃, 山本直史, 高柴正悟

日本歯周病学会会誌 65 ( 秋季特別 ) 178 - 178 2023.10

がんゲノムプロファイリング検査のための超音波内視鏡下採取膵癌組織でのMOSEの取組み

永谷たみ, 小倉千尋, 下舞裕美, 廣尾嘉樹, 春名勝也, 木村祥佳, 堀田真智子, 伏見聡一郎, 井上博文, 平沢晃, 和仁洋治

日本臨床細胞学会雑誌 62 ( Suppl.2 ) 536 - 536 2023.10

ベーチェット病を併発したプラスミノーゲン低下症に伴うLigneous歯周炎患者の臨床的・遺伝学的考察

平井杏奈, 伊東有希, 井手口英隆, 大森一弘, 加藤芙美乃, 山本英喜, 平沢晃, 山本直史, 高柴正悟

日本歯周病学会会誌 65 ( 秋季特別 ) 178 - 178 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 14 ( 6 ) 575 - 581 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

Comprehensive genomic profiling of Japanese patients with thoracic malignancies: A single-center retrospective study. International journal

Tetsu Hirakawa, Mihoko Doi, Kosuke Hamai, Ryo Katsura, Shinya Miyake, Suguru Fujita, Sayaka Ueno, Ken Masuda, Takuya Tanimoto, Takashi Nishisaka, Takao Hinoi, Akira Hirasawa, Nobuhisa Ishikawa

Respiratory investigation 61 ( 6 ) 746 - 754 2023.9

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

BACKGROUND: Few studies have been conducted on comprehensive genomic profiling (CGP) panels in Japanese patients with thoracic malignancies after completing standard treatment. Consequently, its value in clinical practice remains unclear. METHODS: We conducted a retrospective study of Japanese patients with thoracic malignancies who underwent CGP between June 2019 and November 2022 at our hospital. We evaluated the detection rate of actionable genetic alterations and percentage of patients who received genomically-matched therapy. Furthermore, we examined the value of the CGP panel in patients who underwent multiplex gene-panel testing prior to their initial treatment. This study was performed in accordance with the principles of the Declaration of Helsinki. RESULTS: The study included 56 patients, of whom 47 (83.9%) had actionable genetic alterations and 8 (14.3%) received genomically-matched therapy. Of these, four patients were treated with approved drugs and three patients were treated with investigational agents. In addition, one patient was treated with approved drugs using the patient-directed care system. Of the 17 patients who had multiplex gene-panel testing performed at the start of their initial therapy, two (11.8%) were newly identified by the CGP panel and subsequently received genomically-matched therapy. EGFR L718Q and MET amplification were observed in two of the seven patients with epidermal growth factor receptor-tyrosine kinase inhibitor resistance. CONCLUSIONS: The CGP panel could identify genetic alterations, thereby facilitating genomically-matched therapy, even in patients with thoracic malignancies who could not be identified using multiplex gene-panel testing.

DOI： 10.1016/j.resinv.2023.08.005

Proposal for combined macroscopic and microscopic on-site evaluation (cMOSES) of fresh tissue from liver tumor biopsies for histopathological diagnosis and comprehensive genomic panel testing. International journal

Tami Nagatani, Yoji Wani, Soichiro Fushimi, Yu Matsuo, Shiho Murakami, Toshifumi Tada, Shinichiro Nakamura, Hirofumi Inoue, Maki Tanioka, Hiroyuki Okada, Akira Hirasawa

Pathology international 73 ( 12 ) 612 - 614 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

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with DNA mismatch repair deficient (dMMR) tumors, third edition.

Saori Mishima, Yoichi Naito, Kiwamu Akagi, Naomi Hayashi, Akira Hirasawa, Tomoro Hishiki, Ataru Igarashi, Masafumi Ikeda, Shigenori Kadowaki, Hiroaki Kajiyama, Motohiro Kato, Hirotsugu Kenmotsu, Yasuhiro Kodera, Keigo Komine, Takafumi Koyama, Osamu Maeda, Mitsuru Miyachi, Hiroshi Nishihara, Hiroyuki Nishiyama, Shouichi Ohga, Wataru Okamoto, Eiji Oki, Shigeru Ono, Masashi Sanada, Ikuo Sekine, Tadao Takano, Kayoko Tao, Keita Terashima, Katsuya Tsuchihara, Yasushi Yatabe, Takayuki Yoshino, Eishi Baba

International journal of clinical oncology 28 ( 10 ) 1237 - 1258 2023.8

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

BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02397-9

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with high tumor mutational burden tumors.

Saori Mishima, Yoichi Naito, Kiwamu Akagi, Naomi Hayashi, Akira Hirasawa, Tomoro Hishiki, Ataru Igarashi, Masafumi Ikeda, Shigenori Kadowaki, Hiroaki Kajiyama, Motohiro Kato, Hirotsugu Kenmotsu, Yasuhiro Kodera, Keigo Komine, Takafumi Koyama, Osamu Maeda, Mitsuru Miyachi, Hiroshi Nishihara, Hiroyuki Nishiyama, Shouichi Ohga, Wataru Okamoto, Eiji Oki, Shigeru Ono, Masashi Sanada, Ikuo Sekine, Tadao Takano, Kayoko Tao, Keita Terashima, Katsuya Tsuchihara, Yasushi Yatabe, Takayuki Yoshino, Eishi Baba

International journal of clinical oncology 28 ( 8 ) 941 - 955 2023.8

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

The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02360-8

肉腫診療におけるがん遺伝子パネルの有用性

中田英二, 藤原智洋, 国定俊之, 遠西大輔, 山本英喜, 二宮貴一朗, 冨田秀太, 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 97 ( 8 ) S1894 - S1894 2023.8

A case of ovarian carcinosarcoma with a germline pathogenic variant of BRCA2 involving a perforated appendix with an abscess. International journal

Ayaka Saito, Eiko Yamashita, Urara Sakurai, Akira Hirasawa, Maki Tanioka, Kazuya Tamura, Satoshi Umezawa

The journal of obstetrics and gynaecology research 49 ( 10 ) 2553 - 2557 2023.7

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

We report a case of rare and aggressive ovarian carcinosarcoma with a germline pathogenic BRCA2 variant. A patient with a history of breast cancer who developed an inflammatory ovarian tumor with peritonitis carcinomatosis involving the appendix suffered from cachexia. Following three cycles of weekly paclitaxel and carboplatin chemotherapy, emergency surgery was required owing to sepsis. Bilateral salpingo-oophorectomy, total hysterectomy, appendectomy, and small intestine adhesiolysis were performed. Histologically, the tumor comprised an admixture of carcinomatous and sarcomatous components, with involvement of the appendix, which had caused perforation and abscess formation. The final diagnosis was ovarian carcinosarcoma with a germline pathogenic BRCA2 variant, c.658_659del (p.Val220fs). The patient responded completely to adjuvant chemotherapy. A combination of chemotherapy and surgery might be beneficial to patients with ovarian carcinosarcoma and germline pathogenic BRCA2 variants with a poor general condition. This is the first report of ovarian carcinosarcoma with a germline pathogenic BRCA2 variant that responded favorably to chemotherapy.

DOI： 10.1111/jog.15736

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors.

Yoichi Naito, Saori Mishima, Kiwamu Akagi, Naomi Hayashi, Akira Hirasawa, Tomoro Hishiki, Ataru Igarashi, Masafumi Ikeda, Shigenori Kadowaki, Hiroaki Kajiyama, Motohiro Kato, Hirotsugu Kenmotsu, Yasuhiro Kodera, Keigo Komine, Takafumi Koyama, Osamu Maeda, Mitsuru Miyachi, Hiroshi Nishihara, Hiroyuki Nishiyama, Shouichi Ohga, Wataru Okamoto, Eiji Oki, Shigeru Ono, Masashi Sanada, Ikuo Sekine, Tadao Takano, Kayoko Tao, Keita Terashima, Katsuya Tsuchihara, Yasushi Yatabe, Takayuki Yoshino, Eishi Baba

International journal of clinical oncology 28 ( 7 ) 827 - 840 2023.7

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

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

DOI： 10.1007/s10147-023-02345-7

婦人科遺伝性腫瘍とデータシェアリング Invited

平沢晃

HORMONE FRONTIER IN GYNECOLOGY 30 ( 2 ) 45 - 52 2023.6

Survey of the Current Status of the Secondary Findings Disclosure Process for Tumor Genomic Profiling: A Multicenter Questionnaire Survey

島田咲, 島田咲, 山田崇弘, 山田崇弘, 山田崇弘, 源明理, 松川愛未, 松川愛未, 矢部一郎, 青木洋子, 織田克利, 植木有紗, 東川智美, 森川真紀, 佐藤友紀, 平沢晃, 小川昌宣, 小川昌宣, 近藤知大, 吉岡正博, 金井雅史, 武藤学, 小杉眞司, 松川愛未, 矢部一郎, 青木洋子, 織田克利, 植木有紗, 東川智美, 森川真紀, 佐藤友紀, 平沢晃, 小川昌宣, 近藤知大, 吉岡正博, 金井雅史, 小杉眞司

日本遺伝カウンセリング学会誌 44 ( 2 ) 92 - 92 2023.6

Human resources for administrative work to carry out a comprehensive genomic profiling test in Japan. International journal

Hidenori Kage, Katsutoshi Oda, Manabu Muto, Katsuya Tsuchihara, Natsuko Okita, Yusuke Okuma, Junko Kikuchi, Hidekazu Shirota, Hideyuki Hayashi, Toshio Kokuryo, Daisuke Sakai, Akira Hirasawa, Makoto Kubo, Hirotsugu Kenmotsu, Nana Akiyama, Aya Shinozaki-Ushiku, Masahiko Tanabe, Tetsuo Ushiku, Kiyoshi Miyagawa, Yasuyuki Seto

Cancer science 114 ( 7 ) 3041 - 3049 2023.5

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

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of \24,000/h for physicians and \2800/h for nonphysicians, mean labor cost was \78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (\3,951,854 vs. \1,687,167 vs. \487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden.

DOI： 10.1111/cas.15833

今,再考するROSEの意義 EUS-FNA検体のゲノム医療における有用性と限界

井上博文, 松岡博美, 實平悦子, 松岡昌志, 安村早優美, 田中健大, 寺澤裕之, 松本和幸, 加藤博也, 平沢晃

日本臨床細胞学会雑誌 62 ( Suppl.1 ) 187 - 187 2023.5

今,再考するROSEの意義 EUS-FNA検体のゲノム医療における有用性と限界

井上博文, 松岡博美, 實平悦子, 松岡昌志, 安村早優美, 田中健大, 寺澤裕之, 松本和幸, 加藤博也, 平沢晃

日本臨床細胞学会雑誌 62 ( Suppl.1 ) 187 - 187 2023.5

マイクロアレイ染色体検査にてCharcot-Marie-Tooth病責任領域の重複が認められたMiller-Dieker症候群の遺伝カウンセリング

十川麗美, 秋山倫之, 衛藤英理子, 二川摩周, 加藤芙美乃, 山本英喜, 平沢晃, 大守伊織, 小林勝弘

脳と発達 55 ( Suppl. ) S302 - S302 2023.5

The DNA integrity number and concentration are useful parameters for successful comprehensive genomic profiling test for cancer using formalin-fixed paraffin embedded tissue. International journal

Emmy Yanagita, Hiroshi Yamada, Tetsuro Kobayashi, Eriko Aimono, Kohei Nakamura, Akira Hirasawa, Hiroshi Nishihara

Pathology international 73 ( 5 ) 198 - 206 2023.3

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

The acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision-Rapid. Through the PleSSision-Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin-fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision-Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/μL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.

DOI： 10.1111/pin.13318

[Ⅲ. The Role of Comprehensive Genomic Profiling in Sarcoma].

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Shinichi Toyooka, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Akira Hirasawa, Mashu Futagawa, Masahiro Tabata

Gan to kagaku ryoho. Cancer & chemotherapy 50 ( 3 ) 314 - 320 2023.3

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study. International journal

Eun-Young Kang, Ashley Weir, Nicola S Meagher, Kyo Farrington, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Adelyn Bolithon, Gordana Popovic, Betty Leung, Katrina Tang, Neil Lambie, Joshua Millstein, Jennifer Alsop, Michael S Anglesio, Beyhan Ataseven, Ellen Barlow, Matthias W Beckmann, Jessica Berger, Christiani Bisinotto, Hans Bösmüller, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Sara Y Brucker, Michael E Carney, Yovanni Casablanca, Alicia Cazorla-Jiménez, Paul A Cohen, Thomas P Conrads, Linda S Cook, Penny Coulson, Madeleine Courtney-Brooks, Daniel W Cramer, Philip Crowe, Julie M Cunningham, Cezary Cybulski, Kathleen M Darcy, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Rhonda Farrell, Sian Fereday, Anna Fischer, María J García, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Marcel Grube, Paul R Harnett, Shariska Petersen Harrington, Philipp Harter, Arndt Hartmann, Jonathan L Hecht, Sebastian Heikaus, Alexander Hein, Florian Heitz, Joy Hendley, Brenda Y Hernandez, Susanna Hernando Polo, Sabine Heublein, Akira Hirasawa, Estrid Høgdall, Claus K Høgdall, Hugo M Horlings, David G Huntsman, Tomasz Huzarski, Andrea Jewell, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Dineo Khabele, Felix K F Kommoss, Roy F P M Kruitwagen, Diether Lambrechts, Nhu D Le, Marcin Lener, Jenny Lester, Yee Leung, Anna Linder, Liselore Loverix, Jan Lubiński, Rashna Madan, G Larry Maxwell, Francesmary Modugno, Susan L Neuhausen, Alexander Olawaiye, Siel Olbrecht, Sandra Orsulic, José Palacios, Celeste Leigh Pearce, Malcolm C Pike, Carmel M Quinn, Ganendra Raj Mohan, Cristina Rodríguez-Antona, Matthias Ruebner, Andy Ryan, Stuart G Salfinger, Naoko Sasamoto, Joellen M Schildkraut, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Yurii B Shvetsov, Naveena Singh, Gabe S Sonke, Linda Steele, Colin J R Stewart, Karin Sundfeldt, Anthony J Swerdlow, Aline Talhouk, Adeline Tan, Sarah E Taylor, Kathryn L Terry, Aleksandra Tołoczko, Nadia Traficante, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld, Ignace Vergote, Robert A Vierkant, Chen Wang, Lynne R Wilkens, Stacey J Winham, Anna H Wu, Javier Benitez, Andrew Berchuck, Francisco J Candido Dos Reis, Anna DeFazio, Peter A Fasching, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Beth Y Karlan, Stefan Kommoss, Usha Menon, Hans-Peter Sinn, Annette Staebler, James D Brenton, David D Bowtell, Paul D P Pharoah, Susan J Ramus, Martin Köbel

Cancer 129 ( 5 ) 697 - 713 2022.12

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

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

DOI： 10.1002/cncr.34582

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma. International journal

Astrid Murumägi, Daniela Ungureanu, Suleiman Khan, Mariliina Arjama, Katja Välimäki, Aleksandr Ianevski, Philipp Ianevski, Rebecka Bergström, Alice Dini, Anna Kanerva, Riitta Koivisto-Korander, Johanna Tapper, Heini Lassus, Mikko Loukovaara, Andrus Mägi, Akira Hirasawa, Daisuke Aoki, Vilja Pietiäinen, Teijo Pellinen, Ralf Bützow, Tero Aittokallio, Olli Kallioniemi

British journal of cancer 128 ( 4 ) 678 - 690 2022.12

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

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

DOI： 10.1038/s41416-022-02067-z

Handling of Germline Findings in Clinical Comprehensive Cancer Genomic Profiling.

Mika Okazawa-Sakai, Yasuko Yamamoto, Mashu Futagawa, Miki Okamura, Satoko Miyawaki, Tomohiro Nishina, Kazuhiro Takehara, Toshiyuki Kozuki, Shuta Tomida, Ichinosuke Hyodo, Shozo Ohsumi, Akira Hirasawa

Acta medica Okayama 76 ( 6 ) 673 - 678 2022.12

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

Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved.

DOI： 10.18926/AMO/64117

がんゲノムプロファイリング検査による大腸癌でのBRAF阻害薬の適応判断

山本英喜, 重安邦俊, 河内麻里子, 座間味義人, 平沢晃

日本臨床薬理学会学術総会抄録集 43回 1 - 6 2022.12

RAS/BRAF解析においてPCR-rSSO法とNGS法の併用による補完性が示された大腸癌の二例

山本英喜, 重安邦俊, 柳井広之, 井上博文, 松岡博美, 青江伯規, 東影明人, 藤井敬子, 大塚文男, 草野展周, 平沢晃

日本臨床検査医学会誌 70 ( 補冊 ) 258 - 258 2022.10

がんゲノム医療における「連携」主に患者、家族・血縁者との連携にかかる課題について全国がんプロ協議会・ゲノム医療部会報告

平沢晃

癌と化学療法 49 ( 9 ) 1000 - 1001 2022.9

Language：Japanese Publisher：(株)癌と化学療法社

医療者間の連携、医療者と患者の連携および患者と家族間の連携はがん診療全般でも必要事項ではあり、がんゲノム医療のもつ特性を考えた連携を構築することが望ましい。わが国のがんゲノム医療の定義で提唱されているとおり、がん未発症者を含むがん発症予防が可能になって初めて国民の確実ながん死低減が可能になる。(著者抄録)

骨・軟部肉腫に対するがんゲノムプロファイリング検査から検出されるpresumed germline pathogenic variantsの意義

二川摩周, 中田英二, 十川麗美, 加藤芙美乃, 浦川優作, 河内麻里子, 山本英喜, 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 96 ( 8 ) S1770 - S1770 2022.9

[Panel Discussion - Problems in the Cancer Genomic Medicine].

Chikashi Ishioka, Manabu Muto, Shinichi Yachida, Hidekazu Shirota, Akira Hirasawa, Kiyoshi Miyagawa, Kazuto Ashizawa, Ichiro Kinoshita, Hiroshi Nishihara, Nariaki Matsuura, Akihiro Sakurai

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 9 ) 1014 - 1017 2022.9

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

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

骨・軟部腫瘍の基礎科学のトピックスクリニカルシークエンスによる肉腫のゲノム医療

中田英二, 藤原智洋, 国定俊之, 二川摩周, 遠西大輔, 久保寿夫, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 96 ( 8 ) S1533 - S1533 2022.9

[The Cooperation with Medical Staff, Medical Staff and Patients, and Patients and Their Families in Cancer Precision Medicine].

Akira Hirasawa

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 9 ) 1000 - 1001 2022.9

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

Alteration in peritoneal cells with the chemokine CX3CL1 reverses age-associated impairment of recognition memory. International journal

Yoshinori Takei, Yoko Amagase, Keiko Iida, Tomohiro Sagawa, Ai Goto, Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Akio Matsumoto, Shinichi Kawai, Atsushi Sugiyama, Tatsuyuki Takada, Akira Hirasawa

GeroScience 44 ( 4 ) 2305 - 2318 2022.8

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

Cognitive function progressively declines with advancing age. The aging process can be promoted by obesity and attenuated by exercise. Both conditions affect levels of the chemokine CX3CL1 in peripheral tissues; however, its role in cognitive aging is unknown. In the current study, we administered CX3CL1 into the peritoneal cavity of aged mice to investigate its impact on the aging process. In the peritoneal cavity, CX3CL1 not only reversed the age-associated accumulation of cells expressing the senescence marker p16INK4a but also increased peritoneal phagocytic activity, indicating that CX3CL1 affected the phenotypes of peritoneal cells. In the hippocampus of aged mice, intraperitoneal administration of CX3CL1 increased the number of Type-2 neural stem cells and promoted brain-derived neurotrophic factor (BDNF) expression. This treatment, furthermore, improved novel object recognition memory impaired with advancing age. Intraperitoneal transplantation of peritoneal cells from CX3CL1-treated aged mice improved novel object recognition memory in recipient aged mice. It indicates that peritoneal cells have a critical role in the CX3CL1-induced improvement of recognition memory in aged mice. Vagotomy inhibited the CX3CL1-induced increase in BDNF expression, demonstrating that the vagus nerve is involved in the hippocampal BDNF expression induced by intraperitoneal administration of CX3CL1. Thus, our results demonstrate that a novel connection among the peritoneal cells, the vagus nerve, and the hippocampus can reverse the age-associated decline in recognition memory.

DOI： 10.1007/s11357-022-00579-3

がん遺伝子パネル検査の現状と課題がんゲノム医療overview 国民のがん死低減をめざして

平沢晃

日本婦人科腫瘍学会雑誌 40 ( 3 ) 120 - 124 2022.7

Language：Japanese Publisher：(公社)日本婦人科腫瘍学会

がんゲノム医療は「がん患者の腫瘍部および正常部のゲノム情報を用いて治療の最適化・予後予測・発症予防をおこなう医療(未発症者も対象とすることがある。またゲノム以外のマルチオミックス情報も含める)」と定義される(がんゲノム医療推進コンソーシアム懇談会報告書〜国民参加型がんゲノム医療の構築に向けて〜厚生労働省HP平成29年6月27日)。「治療の最適化」についてはがん医療へコンパニオン診断の導入から、2019年6月のがん遺伝子パネル検査の保険収載を契機に、個別化治療に到達する道筋が整備されてきている。一方でがんゲノム医療は定義にあるように「がん未発症者」を含む「がん発症予防」を含む概念である。がん発症高リスクのがん未発症者に対する介入が可能になってはじめて、国民の確実ながん死低減が可能になるといえる。婦人科診療を窓口に個々のゲノム情報に応じて未発症者も既発症者の区別なく対応していき、「治療の最適化・予後予測・発症予防」によって最終的に国民のがん死低減に寄与することが可能になる。(著者抄録)

Cancer precision medicine and germline findings.

植野さやか, 平沢晃

月刊糖尿病・内分泌代謝科 55 ( 1 ) 126 - 135 2022.7

Surveillance for tumorous lesions in neurofibromatosis type 1

二川摩周, 二川摩周, 中田英二, 十川麗美, 加藤芙美乃, 浦川優作, 河内麻里子, 山本英喜, 山本英喜, 藤原智洋, 国定俊之, 尾崎敏文, 平沢晃, 平沢晃

日本遺伝カウンセリング学会誌 43 ( 2 ) 92 - 92 2022.6

Genetic counseling for parents who wish a prenatal diagnosis for their second child although the previous child’s chromosomal abnormality was occurred in de novo

衛藤英理子, 三苫智裕, 横畑理美, 三島桜子, 大平安希子, 桐野智江, 谷和祐, 牧尉太, 早田桂, 増山寿, 秋山倫之, 大守伊織, 十川麗美, 河内麻里子, 平沢晃

日本遺伝カウンセリング学会誌 43 ( 2 ) 95 - 95 2022.6

Development and evaluation of a teaching material to improve general literacy for cancer precision medicine

十川麗美, 十川麗美, 和田敬仁, 榎朗兆, 岩本結香子, 黒飛恵子, 金井雅史, 近藤知大, 近藤知大, 本田明夏, 山田崇弘, 平沢晃, 武藤学, 小杉眞司

日本遺伝カウンセリング学会誌 43 ( 1 ) 15 - 27 2022.5

成人になって診断のついたHajdu-Cheney症候群の一例

二川奈都子, 長谷川高誠, 西田圭一郎, 平沢晃, 河内麻里子

日本内分泌学会雑誌 98 ( 1 ) 377 - 377 2022.4

Current status and issues related to secondary findings in the first public insurance covered tumor genomic profiling in Japan: multi-site questionnaire survey. International journal

Akari Minamoto, Takahiro Yamada, Saki Shimada, Ichiro Kinoshita, Yoko Aoki, Katsutoshi Oda, Arisa Ueki, Satomi Higashigawa, Maki Morikawa, Yuki Sato, Akira Hirasawa, Masanobu Ogawa, Tomohiro Kondo, Masahiro Yoshioka, Masashi Kanai, Manabu Muto, Shinji Kosugi

Journal of human genetics 67 ( 10 ) 557 - 563 2022.3

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

In June 2019, the Japanese National Health Insurance (NHI) system introduced coverage for two types of tumor genomic profiling (TGP): FoundationOneⓇ CDx (F1) and OncoGuide™ NCC OncoPanel System (NCCOP). TGP sometimes reveals germline variants that are potentially pathogenic as secondary findings (SFs). We conducted a questionnaire-based survey to find out the operational statuses of F1 and NCCOP at institutions where TGP was performed to elucidate issues related to SFs. Responses were received from 97 of 112 institutions (86.6%). As of May 31, 2020, 88 (90.7%) and 78 (80.4%) institutions started performing F1 and NCCOP, respectively. Since F1 only examines tumor samples, germline confirmatory testing is necessary to determine whether they are actually germline pathogenic variants (GPVs). When physicians are obtaining informed consent all but 2.3% of the patients requested SF disclosure. Conversely, when presumed germline pathogenic variants (PGPVs) were detected, 46.2% were not willing to receive confirmatory tests as they wanted to prioritize cancer treatment over SFs investigation, while only 23.3% underwent confirmatory tests. Problems in cancer genomic medicine reported by clinical genetics departments included short-staffing (n = 10), insufficient interdepartmental cooperation (n = 9), inconsistent understanding of genetics among healthcare professionals (n = 8), and low utilization rate of SFs due to lack of insurance coverage for confirmatory tests and post-test health checkups (n = 8). Solutions include; determining the appropriate timing to confirm patient intent on SF disclosure, covering confirmatory tests for PGPVs by the NHI, and establishing cooperation between the oncology and clinical genetics departments.

DOI： 10.1038/s10038-022-01028-x

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples. International journal

Tomoko Akahane, Kenta Masuda, Akira Hirasawa, Yusuke Kobayashi, Arisa Ueki, Miho Kawaida, Kumiko Misu, Kohei Nakamura, Shimpei Nagai, Tatsuyuki Chiyoda, Wataru Yamagami, Shigenori Hayashi, Fumio Kataoka, Kouji Banno, Kokichi Sugano, Hajime Okita, Kenjiro Kosaki, Hiroshi Nishihara, Daisuke Aoki

Journal of gynecologic oncology 33 ( 4 ) e50 2022.3

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

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

DOI： 10.3802/jgo.2022.33.e50

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 2022.3

がんゲノム中核拠点病院における、がん遺伝子パネルで同定されたGermline Findingsに対する診療システムの構築

中田英二, 二川摩周, 国定俊之, 藤原智洋, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 96 ( 2 ) S439 - S439 2022.3

Hereditary gynecologic tumors and precision cancer medicine. International journal

Chikako Ogawa, Akira Hirasawa, Naoyuki Ida, Keiichiro Nakamura, Hisashi Masuyama

The journal of obstetrics and gynaecology research 48 ( 5 ) 1076 - 1090 2022.2

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

Gynecologic cancers are more often caused by genetic factors than other cancers. Genetic testing has become a promising avenue for the prevention, prognosis, and treatment of cancers. This review describes molecular features of gynecologic tumors linked to hereditary syndromes, gives an overview of the current state of clinical management, and clarifies the role of gynecology in the treatment of hereditary tumors. Typical hereditary gynecologic tumors include hereditary breast and ovarian cancer, Lynch syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. Multigene panel testing, which analyzes a preselected subset of genes for genetic variants, has recently become the first-choice test because it can provide more accurate risk assessment than a single test. Furthermore, comprehensive genomic cancer profiling enables personalized cancer treatment and aids in germline findings.

DOI： 10.1111/jog.15197

ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors. International journal

Sayaka Ueno, Tamotsu Sudo, Akira Hirasawa

International journal of molecular sciences 23 ( 1 ) 2022.1

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

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

DOI： 10.3390/ijms23010523

Homologous Recombination Deficiencies and Hereditary Tumors. International journal

Hideki Yamamoto, Akira Hirasawa

International journal of molecular sciences 23 ( 1 ) 2021.12

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

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

Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Kodai Abe, Arisa Ueki, Yusaku Urakawa, Minoru Kitago, Tomoko Yoshihama, Yoshiko Nanki, Yuko Kitagawa, Daisuke Aoki, Kenjiro Kosaki, Akira Hirasawa

Hereditary Cancer in Clinical Practice 19 ( 1 ) 2021.12

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

Background: Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation: Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions: Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

DOI： 10.1186/s13053-020-00160-z

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

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 ) 48 - 48 2021.11

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

BACKGROUND: RAD51D (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 BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. CASE PRESENTATION: 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 RAD51D 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 RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D 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 RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. CONCLUSIONS: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D 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 RAD51D 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.

DOI： 10.1186/s13053-021-00205-x

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. International journal

Eun Young Kang, Joshua Millstein, Gordana Popovic, Nicola S Meagher, Adelyn Bolithon, Aline Talhouk, Derek S Chiu, Michael S Anglesio, Betty Leung, Katrina Tang, Neil Lambie, Marina Pavanello, Annalyn Da-Anoy, Diether Lambrechts, Liselore Loverix, Siel Olbrecht, Christiani Bisinotto, Jesus Garcia-Donas, Sergio Ruiz-Llorente, Monica Yagüe-Fernandez, Robert P Edwards, Esther Elishaev, Alexander Olawaiye, Sarah Taylor, Beyhan Ataseven, Andreas du Bois, Philipp Harter, Jenny Lester, Claus K Høgdall, Sebastian M Armasu, Yajue Huang, Robert A Vierkant, Chen Wang, Stacey J Winham, Sabine Heublein, Felix K F Kommoss, Daniel W Cramer, Naoko Sasamoto, Lilian van-Wagensveld, Maria Lycke, Constantina Mateoiu, Janine Joseph, Malcolm C Pike, Kunle Odunsi, Chiu-Chen Tseng, Celeste L Pearce, Sanela Bilic, Thomas P Conrads, Arndt Hartmann, Alexander Hein, Michael E Jones, Yee Leung, Matthias W Beckmann, Matthias Ruebner, Minouk J Schoemaker, Kathryn L Terry, Mona A El-Bahrawy, Penny Coulson, John L Etter, Katherine LaVigne-Mager, Juergen Andress, Marcel Grube, Anna Fischer, Nina Neudeck, Greg Robertson, Rhonda Farrell, Ellen Barlow, Carmel Quinn, Anusha Hettiaratchi, Yovanni Casablanca, Ramona Erber, Colin J R Stewart, Adeline Tan, Yu Yu, Jessica Boros, Alison H Brand, Paul R Harnett, Catherine J Kennedy, Nikilyn Nevins, Terry Morgan, Peter A Fasching, Ignace Vergote, Anthony J Swerdlow, Francisco J Candido Dos Reis, G Larry Maxwell, Susan L Neuhausen, Arantzazu Barquin-Garcia, Francesmary Modugno, Kirsten B Moysich, Philip J Crowe, Akira Hirasawa, Florian Heitz, Beth Y Karlan, Ellen L Goode, Peter Sinn, Hugo M Horlings, Estrid Høgdall, Karin Sundfeldt, Stefan Kommoss, Annette Staebler, Anna H Wu, Paul A Cohen, Anna DeFazio, Cheng-Han Lee, Helen Steed, Nhu D Le, Simon A Gayther, Kate Lawrenson, Paul D P Pharoah, Gottfried Konecny, Linda S Cook, Susan J Ramus, Linda E Kelemen, Martin Köbel

Virchows Archiv : an international journal of pathology 480 ( 4 ) 855 - 871 2021.11

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

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

DOI： 10.1007/s00428-021-03232-0

Prospective feasibility study of neoadjuvant dose-dense paclitaxel plus carboplatin with bevacizumab therapy followed by interval debulking surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer patients.

Naomi Iwasa-Inoue, Hiroyuki Nomura, Fumio Kataoka, Tatsuyuki Chiyoda, Tomoko Yoshihama, Yoshiko Nanki, Kensuke Sakai, Yusuke Kobayashi, Wataru Yamagami, Tohru Morisada, Akira Hirasawa, Daisuke Aoki

International journal of clinical oncology 27 ( 2 ) 441 - 447 2021.10

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

BACKGROUND: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. METHODS: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. RESULTS: Twenty-four patients were included in this study. The median age was 55.5 years (37-80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. CONCLUSIONS: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

DOI： 10.1007/s10147-021-02050-3

参照配列の違いからゲノム解析結果が異なる解釈に至った遺伝学的検査の一例

山本英喜, 加藤芙美乃, 浦川優作, 河内麻里子, 二川摩周, 十川麗美, 植野さやか, 平沢晃

日本臨床検査医学会誌 69 ( 補冊 ) 183 - 183 2021.10

Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120-dependent inhibition of CCK. International journal

Yuki Murata, Norio Harada, Shigenobu Kishino, Kanako Iwasaki, Eri Ikeguchi-Ogura, Shunsuke Yamane, Tomoko Kato, Yoshinori Kanemaru, Akiko Sankoda, Tomonobu Hatoko, Sakura Kiyobayashi, Jun Ogawa, Akira Hirasawa, Nobuya Inagaki

iScience 24 ( 9 ) 102963 - 102963 2021.9

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

Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.

DOI： 10.1016/j.isci.2021.102963

Hereditary pancreatic cancer.

Kodai Abe, Minoru Kitago, Yuko Kitagawa, Akira Hirasawa

International journal of clinical oncology 26 ( 10 ) 1784 - 1792 2021.9

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

Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.

DOI： 10.1007/s10147-021-02015-6

Incidence of germline variants in Lynch syndrome-related genes among Japanese endometrial cancer patients aged 40 years or younger.

Takeshi Makabe, Wataru Yamagami, Akira Hirasawa, Izumi Miyabe, Tomokazu Wakatsuki, Mari Kikuchi, Akemi Takahashi, Junko Noda, Go Yamamoto, Daisuke Aoki, Kiwamu Akagi

International journal of clinical oncology 26 ( 9 ) 1767 - 1774 2021.9

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

[Objective] Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair (MMR) genes. Endometrial cancer frequently precedes another LS-associated tumor. This study aimed to clarify the incidence and features of LS in young Japanese endometrial cancer patients.[Methods] Sixty-five patients aged 40 years or younger, who were diagnosed with endometrial cancer, were enrolled in this study. Targeted sequencing of a hereditary colorectal cancer-related gene panel including the MMR genes MLH1, MSH2, MSH6, and PMS2 was conducted on DNA samples extracted from blood cells.[Results] Overall, 6 missense variants (2 in MSH2, 2 in MSH6, and 2 in PMS2), 1 inframe deletion variant in MSH2, 1 splice variant in MSH2, and 1 two-base substitution in the 3' untranslated region in MLH1 were detected in 9 (13.8%) patients. Among these, the splice variant c.1276G > T (p.Ile411_Gly426del16) in MSH2 was annotated as pathogenic, while other variants were of uncertain significance. The patient with the pathogenic variant had a family history of endometrial and colorectal cancer and was diagnosed with endometrial cancer at age 35.[Conclusion] The incidence of LS among Japanese endometrial cancer patients of reproductive age (≤ 40 years) in this study was at least 1.5%; however, 12.3% of patients had variants of uncertain significance in MMR genes.

DOI： 10.1007/s10147-021-01953-5

Secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs: A case report. International journal

Kohei Taniguchi, Hiroyuki Yanai, Tatsuya Kaji, Toshio Kubo, Daisuke Ennishi, Akira Hirasawa, Tadashi Yoshino

Journal of cutaneous pathology 48 ( 8 ) 1069 - 1074 2021.8

Language：English

Secretory carcinoma of the skin is an extremely rare adnexal tumor, histopathologically identical to homologous lesions in the salivary glands and breast tissue. Although this tumor was previously reported as indolent, we report a case of secretory carcinoma of the skin with metastases and recurrence. The patient, a 31-year-old women, had a subcutaneous mass in the right axilla. The resected specimen contained a circumscribed mass, with proliferating tumor cells that exhibited prominent nucleoli. They exhibited glandular and papillary growth patterns and there were amphophilic secretions in the glands. Immunohistochemically, the tumor cells were positive for mammaglobin and S100. The tumor was surrounded by sweat glands and there was no mammary glandular tissue, suggesting that it was derived from axillary sweat glands. Accordingly, we made a diagnosis of secretory carcinoma of the skin. Four years after the operation, there were metastases in both lungs. The resected specimen revealed a tumor identical to that of the original skin tumor. Next-generation sequencing-based multiplex gene assay performed on the metastatic tissue revealed an ETV6-NTRK3 fusion gene. This is a rare case report of secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs.

DOI： 10.1111/cup.14028

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer.

Naohiro Tomita, Hideyuki Ishida, Kohji Tanakaya, Tatsuro Yamaguchi, Kensuke Kumamoto, Toshiaki Tanaka, Takao Hinoi, Yasuyuki Miyakura, Hirotoshi Hasegawa, Tetsuji Takayama, Hideki Ishikawa, Takeshi Nakajima, Akiko Chino, Hideki Shimodaira, Akira Hirasawa, Yoshiko Nakayama, Shigeki Sekine, Kazuo Tamura, Kiwamu Akagi, Yuko Kawasaki, Hirotoshi Kobayashi, Masami Arai, Michio Itabashi, Yojiro Hashiguchi, Kenichi Sugihara

International journal of clinical oncology 26 ( 8 ) 1353 - 1419 2021.8

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

Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.

DOI： 10.1007/s10147-021-01881-4

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling. International journal

Arisa Ueki, Kokichi Sugano, Kumiko Misu, Eriko Aimono, Kohei Nakamura, Shigeki Tanishima, Nobuyuki Tanaka, Shuji Mikami, Akira Hirasawa, Miho Ando, Teruhiko Yoshida, Mototsugu Oya, Hiroshi Nishihara, Kenjiro Kosaki

International journal of molecular sciences 22 ( 15 ) 2021.7

Language：English

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.

DOI： 10.3390/ijms22157962

Preclinical diagnosis and identification of the chimeric CYP11B1/CYP11B2 gene in two pediatric cases of a Japanese family with glucocorticoid-remediable aldosteronism. International journal

Yasuhiro Nakano, Nahoko Iwata, Kanako Ogura-Ochi, Kosei Hasegawa, Akira Hirasawa, Fumio Otsuka

Hypertension research : official journal of the Japanese Society of Hypertension 44 ( 7 ) 891 - 893 2021.7

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 97 ( Suppl.Update ) 71 - 73 2021.7

Language：Japanese Publisher：(一社)日本内分泌学会

約20年前にCYP11B1/B2キメラ遺伝子を確認しグルココルチコイド反応性アルドステロン症(GRA)と診断された日本人1家系3例(発端者、母、妹)のうち、発端者が出産した5歳と3歳の男児に対し遺伝子検査を行った。その結果、男児2人ともキメラ遺伝子を検出しGRA保因者であることが明らかとなった。また、キメラ遺伝子の交叉部位について検討した結果、2児と発端者は同一のシークエンスで、交叉部位はエクソン3とイントロン5間であった。2児とも高血圧を認めないが低レニン・高アルドステロン症を伴っており、今後、成人期までの慎重な経過観察が必要である。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01160&link_issn=&doc_id=20210811280023&doc_link_id=10.1507%2Fendocrine.97.S.Update_71&url=https%3A%2F%2Fdoi.org%2F10.1507%2Fendocrine.97.S.Update_71&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

The American journal of case reports 22 e932241 2021.6

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

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

Best practices for the extraction of genomic DNA from formalin-fixed paraffin-embedded tumor tissue for cancer genomic profiling tests. International journal

Hirofumi Inoue, Shuta Tomida, Shigeru Horiguchi, Hironari Kato, Hiromi Matsuoka, Etsuko Sanehira, Masashi Matsuoka, Hiroyuki Yanai, Akira Hirasawa, Shinichi Toyooka

Pathology international 71 ( 5 ) 360 - 364 2021.5

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

Recently, two cancer genomic profiling tests have been approved in Japan and implemented in routine clinical practice: the FDA-approved FoundationOne CDx test, and the OncoGuide NCC Oncopanel test. The quality and quantity of DNA significantly affects the sequencing results; therefore, preparing a sufficient amount of high-quality DNA for clinical cancer genomic profiling tests is important. We examined the best practices for the extraction of cancer genomic DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues of pancreatic, lung and colon cancer specimens. We found that the quality of cancer genomic DNA extracted from 10-μm-thick FFPE samples improved significantly, compared with that from 4-μm-thick FFPE samples, suggesting that 10-μm-thick FFPE samples are preferable for clinical cancer genomic profiling tests. For convenience, we created a quick reference table for calculating the required number of FFPE slides.

DOI： 10.1111/pin.13086

SUCCESSFUL MANAGEMENT OF BONE METASTASES FROM HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA (HLRCC)-ASSOCIATED RENAL CELL CARCINOMA (HLRCC-RCC) BY USING COMBINED IMMUNOTHERAPY COMPRISING IPILIMUMAB PLUS NIVOLUMAB: A CASE REPORT

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(Web) 83 ( 1 ) 31 - 36 2021.4

RRSO検体におけるp53 signatureとSTICの特性に関する検討

赤羽智子, 増田健太, 平沢晃, 小林佑介, 永井晋平, 千代田達幸, 林茂徳, 片岡史夫, 冨永英一郎, 阪埜浩司, 田中守, 青木大輔

日本産科婦人科学会雑誌 73 ( 臨増 ) S - 570 2021.3

Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome International journal

Tomoko Yoshihama, Akira Hirasawa, Kokichi Sugano, Teruhiko Yoshida, Mineko Ushiama, Arisa Ueki, Tomoko Akahane, Yoshiko Nanki, Kensuke Sakai, Takeshi Makabe, Wataru Yamagami, Nobuyuki Susumu, Kaori Kameyama, Kenjiro Kosaki, Daisuke Aoki

International Cancer Conference Journal 10 ( 1 ) 6 - 10 2021.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title>There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a <italic>BRCA2</italic> pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic <italic>BRCA2</italic> variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.

DOI： 10.1007/s13691-020-00449-9

Other Link： http://link.springer.com/article/10.1007/s13691-020-00449-9/fulltext.html

最新産婦人科遺伝診療ABC 10.婦人科腫瘍領域における遺伝診療総論

坂井美佳, 坂井美佳, 竹原和宏, 平沢晃

産科と婦人科 88 ( 1 ) 65 - 72 2021

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

遺伝性乳がん卵巣がん症候群(HBOC)やLynch症候群を代表とする遺伝性腫瘍は婦人科腫瘍とのかかわりが深い。特にごく最近では2019年のBRCA1/2遺伝学的検査のコンパニオン診断とがんゲノム医療の保険診療化、そして2020年4月のHBOC診療の一部保険診療化に伴い、産婦人科医にとって遺伝性腫瘍の知識は不可欠なものとなっている。個々の遺伝情報を知ることは、がん治療および予防の観点から有用性が高い。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00525&link_issn=&doc_id=20201221170010&doc_link_id=%2Fae4sanke%2F2021%2F008801%2F011%2F0065-0072%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2021%2F008801%2F011%2F0065-0072%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Molecular Features and Clinical Management of Hereditary Gynecological Cancers. International journal

Arisa Ueki, Akira Hirasawa

International journal of molecular sciences 21 ( 24 ) 2020.12

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

Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests.

DOI： 10.3390/ijms21249504

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan International journal

Mio Tsuchiya, Takahiro Yamada, Rina Akaishi, Haruka Hamanoue, Akira Hirasawa, Maki Hyodo, Issei Imoto, Tomoki Kosho, Kenji Kurosawa, Hiromi Murakami, Kaname Nakatani, Fumio Nomura, Aiko Sasaki, Kenji Shimizu, Mariko Tamai, Hiroshi Umemura, Atsushi Watanabe, Akiko Yoshida, Hiroshi Yoshihashi, Junko Yotsumoto, Shinji Kosugi

JOURNAL OF HUMAN GENETICS 65 ( 12 ) 1045 - 1053 2020.12

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

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.

DOI： 10.1038/s10038-020-0802-2

Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution. International journal

Yusuke Kobayashi, Akira Hirasawa, Tatsuyuki Chiyoda, Arisa Ueki, Kenta Masuda, Kumiko Misu, Miho Kawaida, Shigenori Hayashi, Fumio Kataoka, Kouji Banno, Kenjiro Kosaki, Daisuke Aoki

Japanese journal of clinical oncology 51 ( 2 ) 213 - 217 2020.10

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

BACKGROUND: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. METHODS: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. RESULTS: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. CONCLUSIONS: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

DOI： 10.1093/jjco/hyaa173

Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. International journal

Yoshiko Nanki, Tatsuyuki Chiyoda, Akira Hirasawa, Aki Ookubo, Manabu Itoh, Masaru Ueno, Tomoko Akahane, Kaori Kameyama, Wataru Yamagami, Fumio Kataoka, Daisuke Aoki

Scientific reports 10 ( 1 ) 12581 - 12581 2020.7

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

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in < 3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs.

DOI： 10.1038/s41598-020-69488-9

Japan society of clinical oncology/Japanese society of medical oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese society of pediatric hematology/oncology.

Yoichi Naito, Saori Mishima, Kiwamu Akagi, Ataru Igarashi, Masafumi Ikeda, Susumu Okano, Shunsuke Kato, Tadao Takano, Katsuya Tsuchihara, Keita Terashima, Hiroshi Nishihara, Hiroyki Nishiyama, Eiso Hiyama, Akira Hirasawa, Hajime Hosoi, Osamu Maeda, Yasushi Yatabe, Wataru Okamoto, Shigeru Ono, Hiroaki Kajiyama, Fumio Nagashima, Yutaka Hatanaka, Mitsuru Miyachi, Yasuhiro Kodera, Takayuki Yoshino, Hiroya Taniguchi

International journal of clinical oncology 25 ( 3 ) 403 - 417 2020.3

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

BACKGROUND: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

DOI： 10.1007/s10147-019-01610-y

Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition. Reviewed

Saori Mishima, Hiroya Taniguchi, Kiwamu Akagi, Eishi Baba, Yutaka Fujiwara, Akira Hirasawa, Masafumi Ikeda, Osamu Maeda, Kei Muro, Hiroshi Nishihara, Hiroyki Nishiyama, Tadao Takano, Katsuya Tsuchihara, Yasushi Yatabe, Yasuhiro Kodera, Takayuki Yoshino

International journal of clinical oncology 25 ( 2 ) 217 - 239 2020.2

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

BACKGROUND: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. METHODS: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. RESULTS: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. CONCLUSION: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

DOI： 10.1007/s10147-019-01498-8

多発小腸GISTに対し手術を施行した神経線維腫症1型の1例 Reviewed

母里淑子, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃, 藤原俊義

家族性腫瘍 19 ( 2 ) 77 - 82 2020.2

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population. International journal

Kensuke Sakai, Chizu Tanikawa, Akira Hirasawa, Tatsuyuki Chiyoda, Wataru Yamagami, Fumio Kataoka, Nobuyuki Susumu, Chikashi Terao, Yoichiro Kamatani, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Michiaki Kubo, Nobuo Fuse, Takako Takai-Igarashi, Atsushi Shimizu, Akimune Fukushima, Aya Kadota, Kokichi Arisawa, Hiroaki Ikezaki, Kenji Wakai, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro Tsugane, Daisuke Aoki, Koichi Matsuda

Scientific reports 10 ( 1 ) 1197 - 1197 2020.1

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

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

DOI： 10.1038/s41598-020-58066-8

Establishment and characterization of a new malignant peritoneal mesothelioma cell line, KOG-1, from the ascitic fluid of a patient with pemetrexed chemotherapy resistance.

Tomoko Akahane, Akira Hirasawa, Issei Imoto, Aki Okubo, Manabu Itoh, Yoshiko Nanki, Tomoko Yoshihama, Eichiro Tominaga, Daisuke Aoki

Human cell 33 ( 1 ) 272 - 282 2020.1

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

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive form of malignant mesothelioma. Sufficient biological tools for studying the functional characteristics of this cancer have not been developed. Therefore, in this study, a novel human cancer cell line, KOG-1, was established from ascites fluids isolated from a 39-year-old Japanese woman with pemetrexed-resistant MPeM. Cells were dendritic or linear immediately after thawing, showed a jigsaw puzzle-like and spindle arrangement during growth, and formed monolayers without contact inhibition in two-dimensional (2D) culture. The population doubling time was 13.7 h. Karyotypic and molecular genetic analyses showed that chromosome numbers ranged from 62 to 142, with a peak of 73 with complicated copy number alterations. No germline BAP1 pathogenic variant was detected. Cells expressed various tumor markers of mesothelioma, such as calretinin, podoplanin, and Wilms tumor 1 (WT-1). Drug sensitivity and resistance testing with a set of 36 drugs using 2D and three-dimensional (3D) culture models demonstrated that KOG-1 cells showed high and low sensitivity to pemetrexed under 2D and 3D culture conditions, respectively, whereas control ovarian cancer cell lines showed low sensitivity to pemetrexed under both culture conditions. This newly established cell line will be a valuable biological resource to expand the feasibility of functional studies as well as drug testing for potential therapeutic purposes in MPeM.

DOI： 10.1007/s13577-019-00286-w

Familial Pancreatic Cancer with PALB2 and NBN Pathogenic Variant: A Case Report Reviewed International journal

阿部紘大, 植木有紗, 浦川優作, 北郷実, 吉浜智子, 南木佳子, 北川雄光, 青木大輔, 小崎健次郎, 平沢晃

日本癌学会学術総会抄録集(Web) 79th ( 1 ) 5 - 5 2020

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

<title>Abstract</title><sec>
<title>Background</title>
Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of <italic>BRCA1</italic> and/or <italic>BRCA2</italic> (<italic>BRCA1/2</italic>), <italic>PALB2</italic>, or <italic>ATM</italic>. Recently, some germline variants of familial pancreatic cancers (FPCs), including <italic>PALB2,</italic> have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis.

</sec><sec>
<title>Case presentation</title>
Here, we present the case of a female patient harboring pathogenic variants of <italic>PALB2</italic> and <italic>NBN</italic>, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a <italic>PALB2</italic> pathogenic variant and her daughter harbored the same <italic>NBN</italic> pathogenic variant. Given the <italic>PALB2</italic> and <italic>NBN</italic> variants, we designed surveillance strategies for the pancreas, breast, and ovary.

</sec><sec>
<title>Conclusions</title>
Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

</sec>

DOI： 10.1186/s13053-020-00160-z

Other Link： http://link.springer.com/article/10.1186/s13053-020-00160-z/fulltext.html

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome. International journal

Tomoko Kaneyasu, Seiichi Mori, Hideko Yamauchi, Shozo Ohsumi, Shinji Ohno, Daisuke Aoki, Shinichi Baba, Junko Kawano, Yoshio Miki, Naomichi Matsumoto, Masao Nagasaki, Reiko Yoshida, Sadako Akashi-Tanaka, Takuji Iwase, Dai Kitagawa, Kenta Masuda, Akira Hirasawa, Masami Arai, Junko Takei, Yoshimi Ide, Osamu Gotoh, Noriko Yaguchi, Mitsuyo Nishi, Keika Kaneko, Yumi Matsuyama, Megumi Okawa, Misato Suzuki, Aya Nezu, Shiro Yokoyama, Sayuri Amino, Mayuko Inuzuka, Tetsuo Noda, Seigo Nakamura

NPJ breast cancer 6 25 - 25 2020

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

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

DOI： 10.1038/s41523-020-0163-1

Training Medical Staff with Basic Skills for Data Science in Genomic Medicine

冨田秀太, 森田瑞樹, 山下範之, 平沢晃, 豊岡伸一

薬学雑誌(Web) 140 ( 5 ) 657 - 661 2020

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

The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

DOI： 10.1248/yakushi.19-00217-2

DV200 Index for Assessing RNA Integrity in Next-Generation Sequencing. International journal

Takehiro Matsubara, Junichi Soh, Mizuki Morita, Takahiro Uwabo, Shuta Tomida, Toshiyoshi Fujiwara, Susumu Kanazawa, Shinichi Toyooka, Akira Hirasawa

BioMed research international 2020 9349132 - 9349132 2020

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

Poor quality of biological samples will result in an inaccurate analysis of next-generation sequencing (NGS). Therefore, methods to accurately evaluate sample integrity are needed. Among methods for evaluating RNA quality, the RNA integrity number equivalent (RINe) is widely used, whereas the DV200, which evaluates the percentage of fragments of >200 nucleotides, is also used as a quality assessment standard. In this study, we compared the RINe and DV200 RNA quality indexes to determine the most suitable RNA index for the NGS analysis. Seventy-one RNA samples were extracted from formalin-fixed paraffin-embedded tissue samples (n = 30), fresh-frozen samples (n = 25), or cell lines (n = 16). After assessing RNA quality using the RINe and DV200, we prepared two kinds of stranded mRNA sequencing libraries. Finally, we calculated the correlation between each RNA quality index and the amount of library product (1st PCR product per input RNA). The DV200 measure showed stronger correlation with the amount of library product than the RINe (R2 = 0.8208 for the DV200 versus 0.6927 for the RINe). Receiver operating characteristic curve analyses revealed that the DV200 was the better marker for predicting efficient library production than the RINe using a threshold of >10 ng/ng for the amount of the 1st PCR product per input RNA (cutoff value for the RINe and DV200, 2.3 and 66.1%; area under the curve, 0.99 and 0.91; sensitivity, 82% and 92%; and specificity, 93% and 100%, respectively). Our results indicate that NGS libraries prepared using RNA samples with the DV200 value > 66.1% exhibit greater sensitivity and specificity than those prepared with the RINe values > 2.3. These findings suggest that the DV200 is superior to the RINe, especially for low-quality RNA, because it is a more consistent assessment of the amount of the 1st NGS library product per input.

DOI： 10.1155/2020/9349132

がんゲノム医療と実地臨床での課題

HIRASAWA AKIRA

日本婦人科腫瘍学会雑誌 37 ( 4 ) 666 - 667 2019.10

BRCA1/2遺伝子バリアントとがん発症・臨床病理学的特徴および発症リスク因子を明らかにするための卵巣がん未発症を対象としたバイオバンク・コホート研究（JGOG3024)

HIRASAWA AKIRA

BRCA1/2遺伝子バリアントとがん発症・臨床病理学的特徴および発症リスク因子を明らかにするための卵巣がん未発症を対象としたバイオバンク・コホート研究（JGOG3024) 18th 67 - 69 2019.8

Genome-wide DNA methylation profile of early-onset endometrial cancer: its correlation with genetic aberrations and comparison with late-onset endometrial cancer. International journal

Takeshi Makabe, Eri Arai, Takuro Hirano, Nanako Ito, Yukihiro Fukamachi, Yoriko Takahashi, Akira Hirasawa, Wataru Yamagami, Nobuyuki Susumu, Daisuke Aoki, Yae Kanai

Carcinogenesis 40 ( 5 ) 611 - 623 2019.7

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

The present study was performed to clarify the significance of DNA methylation alterations during endometrial carcinogenesis. Genome-wide DNA methylation analysis and targeted sequencing of tumor-related genes were performed using the Infinium MethylationEPIC BeadChip and the Ion AmpliSeq Cancer Hotspot Panel v2, respectively, for 31 samples of normal control endometrial tissue from patients without endometrial cancer and 81 samples of endometrial cancer tissue. Principal component analysis revealed that tumor samples had a DNA methylation profile distinct from that of control samples. Gene Ontology enrichment analysis revealed significant differences of DNA methylation at 1034 CpG sites between early-onset endometrioid endometrial cancer (EE) tissue (patients aged ≤40 years) and late-onset endometrioid endometrial cancer (LE) tissue, which were accumulated among 'transcriptional factors'. Mutations of the CTNNB1 gene or DNA methylation alterations of genes participating in Wnt signaling were frequent in EEs, whereas genetic and epigenetic alterations of fibroblast growth factor signaling genes were observed in LEs. Unsupervised hierarchical clustering grouped EE samples in Cluster EA (n = 22) and samples in Cluster EB (n = 12). Clinicopathologically less aggressive tumors tended to be accumulated in Cluster EB, and DNA methylation levels of 18 genes including HOXA9, HOXD10 and SOX11 were associated with differences in such aggressiveness between the two clusters. We identified 11 marker CpG sites that discriminated EB samples from EA samples with 100% sensitivity and specificity. These data indicate that genetically and epigenetically different pathways may participate in the development of EEs and LEs, and that DNA methylation profiling may help predict tumors that are less aggressive and amenable to fertility preservation treatment.

DOI： 10.1093/carcin/bgz046

遺伝子情報を用いた遺伝性乳癌卵巣癌の予防と治療 Reviewed

HIRASAWA AKIRA

病理と臨床 37 ( 6 ) 522 - 527 2019.6

女性がんの化学予防 Reviewed

HIRASAWA AKIRA

産科と婦人科増刊号 86 ( Suppl. ) 350 - 353 2019.4

Guidelines for office gynecology in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2017 edition. International journal

Ryuji Kawaguchi, Koji Matsumoto, Shigeo Akira, Ken Ishitani, Kazuhiro Iwasaku, Yutaka Ueda, Ryugo Okagaki, Hiroya Okano, Toshimichi Oki, Kaori Koga, Michiko Kido, Takumi Kurabayashi, Yasushi Kuribayashi, Yuichi Sato, Kaori Shiina, Yasushi Takai, Satoshi Tanimura, Osamu Chaki, Masakazu Terauchi, Yukiharu Todo, Yasuyuki Noguchi, Sayaka Nose-Ogura, Tsukasa Baba, Akira Hirasawa, Takuma Fujii, Tsuneo Fujii, Tetsuo Maruyama, Etsuko Miyagi, Kaoru Yanagida, Osamu Yoshino, Mitsutoshi Iwashita, Tsugio Maeda, Takashi Minegishi, Hiroshi Kobayashi

The journal of obstetrics and gynaecology research 45 ( 4 ) 766 - 786 2019.4

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

Six years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the third revised edition was published in 2017. The 2017 Guidelines includes 10 additional clinical questions (CQ), which brings the total to 95 CQ (12 on infectious disease, 28 on oncology and benign tumors, 27 on endocrinology and infertility and 28 on healthcare for women). Currently a consensus has been reached on the Guidelines and therefore the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding recommendation level (A, B, C) is indicated.

DOI： 10.1111/jog.13831

がんゲノム医療と女性ヘルスケア Reviewed

HIRASAWA AKIRA

医学のあゆみ 269 ( 1 ) 85 - 88 2019.4

婦人科がんとがんゲノム医療 Reviewed

HIRASAWA AKIRA

Pharma Medica 37 ( 2 ) 9 - 14 2019.2

婦人科における遺伝性腫瘍 Reviewed

HIRASAWA AKIRA

産婦人科の実際 68 ( 2 ) 187 - 191 2019.2

Sentinel Node Navigation Surgery for Endometrial Cancer

Susumu Nobuyuki, Yamagami Wataru, Kataoka Fumio, Hirano Takuro, Makabe Takeshi, Sakai Kensuke, Chiyoda Tatsuyuki, Nomura Hiroyuki, Hirasawa Akira, Aoki Daisuke

SURGERY FOR GYNECOLOGIC CANCER 295 - 312 2019

Genome-wide DNA methylation profile of young-onset endometrial cancer

Makabe Takeshi, Arai Eri, Hirasawa Akira, Yamagami Wataru, Susumu Nobuyuki, Aoki Daisuke, Kanai Yae

CANCER SCIENCE 109 1304 - 1304 2018.12

遺伝性乳癌卵巣癌に対するリスク低減卵管卵巣摘出後のQOLに関する検討 Reviewed

谷本慧子, 平沢晃, 牧田和也, 岩田卓, 堀場裕子, 横田めぐみ, 小川真里子, 弟子丸亮太, 柳本茂久, 高松潔, 青木大輔

日本女性医学学会雑誌 26 ( 1 ) 45 - 47 2018.11

Synchronous endometrial and ovarian cancer in Lynch syndrome with a MSH2 germline mutation: A case report. Reviewed International journal

Takashi Takeda, Kouji Banno, Megumi Yanokura, Mayuka Anko, Arata Kobayashi, Asako Sera, Takayuki Takahashi, Masataka Adachi, Yusuke Kobayashi, Shigenori Hayashi, Hiroyuki Nomura, Akira Hirasawa, Eiichiro Tominaga, Daisuke Aoki

Molecular and clinical oncology 9 ( 5 ) 479 - 484 2018.11

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

Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with MSH2 mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of MSH2 (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This MSH2 mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC.

DOI： 10.3892/mco.2018.1723

遺伝性腫瘍・家族性腫瘍

HIRASAWA AKIRA

日本医師会雑誌 147 ( 7 ) 1401 - 1406 2018.10

GENOME-WIDE DNA METHYLATION ANALYSIS IN YOUNG-ONSET ENDOMETRIAL CANCER

Makabe T, Arai E, Hirasawa A, Yamagami W, Nobuyuki S, Aoki D, Kanai Y

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 79 - 79 2018.9

THE EFFICACY OF REPEATED HORMONAL THERAPY FOR INTRAUTERINE RECURRENCE FOLLOWING FERTILITY PRESERVING HORMONAL THERAPY FOR ENDOMETRIAL CANCER OR ATYPICAL ENDOMETRIAL HYPERPLASIA. Reviewed

Hirano T, Yamagami W, Susumu N, Makabe T, Sakai K, Ninomiya T, Chiyoda T, Nomura H, Kataoka F, Hirasawa A, Banno K, Aoki D

INTERNATIONAL JOURNAL OF GYNECOLOGIC CANCER 28 ( S2 ) 1092 - 1092 2018.9

UNSUCCESSFUL HIGH-DOSE HORMONAL THERAPY FOR ENDOMETRIAL CANCER OR ATYPICAL ENDOMETRIAL HYPERPLASIA. Reviewed

Tamagawa M, Yamagami W, Hirano T, Makabe T, Sakai K, Ninomiya T, Chiyoda T, Nomura H, Kataoka F, Hirasawa A, Banno K, Susumu N, Aoki D

INTERNATIONAL JOURNAL OF GYNECOLOGIC CANCER 28 ( S2 ) 1189 - 1189 2018.9

がんゲノム医療とHBOC

HIRASAWA AKIRA

日本HBOCコンソーシアムニュースレター 6 2018.9

婦人科疾患ゲノム異常の探索と女性ヘルスケアの個別化

HIRASAWA AKIRA

101 64 - 67 2018.8

GSTP1 rs1695 is associated with both hematological toxicity and prognosis of ovarian cancer treated with paclitaxel plus carboplatin combination chemotherapy: a comprehensive analysis using targeted resequencing of 100 pharmacogenes. Reviewed International journal

Yoshihama T, Fukunaga K, Hirasawa A, Nomura H, Akahane T, Kataoka F, Yamagami W, Aoki D, Mushiroda T

Oncotarget 9 ( 51 ) 29789 - 29800 2018.7

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

Purpose: To find genetic variants that predicted toxicity and/or efficacy of paclitaxel plus carboplatin combination therapy (TC therapy). Patients and methods: In a retrospective case-control study, we analyzed 320 patients who had received TC therapy for gynecological cancers (ovarian, fallopian tube, peritoneal, uterine, and cervical cancers) and collected their germline DNA. We performed a comprehensive pharmacogenomic analysis using a targeted resequencing panel of 100 pharmacogenes. For 1,013 variants passing QC, case-control association studies and survival analyses were conducted. Results: GSTP1 rs1695 showed the smallest p value for hematotoxicity association, and the 105Ile wild type allele had a significantly higher risk of severe hematotoxicity (neutropenia G4, thrombocytopenia ≥ G3 and anemia ≥ G3) than the 105Val allele (p=0.00034, odds ratio=5.71 (95% confidence interval:1.77-18.44)). Next, we assessed 5-year progression-free survival (PFS) and overall survival (OS) in 56 advanced ovarian cancer patients who received tri-weekly TC as a first-line chemotherapy. Patients with the 105Ile/105Ile genotype showed significantly better PFS (p=0.00070) and OS (p=0.0012) than those with the 105Ile/105Val or 105Val/105Val genotype. Conclusion: Our study indicates that the GSTP1 rs1695 105Ile/105Ile genotype is associated with both severe hematotoxicity and high efficacy of TC therapy, identifying a possible prognostic indicator for patients with TC therapy.

DOI： 10.18632/oncotarget.25712

有害事象によりベバシズマブ投与を中止した婦人科がん症例の検討 Reviewed

大野あゆみ, 千代田達幸, 野村弘行, 同前愛, 早乙女啓子, 冨永英一郎, 岩田卓, 山上亘, 片岡史夫, 平沢晃, 田中守, 青木大輔

東京産科婦人科学会会誌 67 ( 3 ) 396 - 400 2018.7

遺伝性腫瘍に対するリスク低減卵管卵巣摘出術－RRSOの臨床試験やその適応、手技の実際と留意すべきポイント－

AOKI DAISUKE

産婦人科の実際 67 ( 5 ) 549 - 556 2018.5

遺伝性乳がん

AOKI DAISUKE

White 6 ( 1 ) 15 - 22 2018.5

遺伝性乳癌卵巣癌症候群に対するリスク低減卵管卵巣摘出後の漢方療法に関する検討 Reviewed

平沢晃, 牧田和也, 岩田卓, 堀場裕子, 横田めぐみ, 小川真里子, 弟子丸亮太, 柳本茂久, 青木大輔

産婦人科漢方研究のあゆみ 35 ( 35 ) 189 - 191 2018.4

Is repeated high-dose medroxyprogesterone acetate (MPA) therapy permissible for patients with early stage endometrial cancer or atypical endometrial hyperplasia who desire preserving fertility? Reviewed International journal

Wataru Yamagami, Nobuyuki Susumu, Takeshi Makabe, Kensuke Sakai, Hiroyuki Nomura, Fumio Kataoka, Akira Hirasawa, Kouji Banno, Daisuke Aoki

JOURNAL OF GYNECOLOGIC ONCOLOGY 29 ( 2 ) e21 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：KOREAN SOC GYNECOLOGY ONCOLOGY & COLPOSCOPY

Objective: Reports on the repeated administration of medroxyprogesterone acetate (MPA) for intrauterine recurrence after fertility-preserving therapy for atypical endometrial hyperplasia (AEH) and early grade 1 endometrioid carcinoma (G1) are lacking. We aimed to clarify the outcomes of repeated MPA therapy in cases of intrauterine recurrence after fertility-preserving therapy with MPA against AEH/early G1.Methods: Patients with AEH or stage IA well-differentiated endometrioid carcinoma without myometrial invasion who underwent first-line MPA therapy for primary lesions or intrauterine recurrence were divided into initial treatment and repeated treatment groups (162 and 82 patients, respectively). Oral MPA administration (400-600 mg/day) was continued until pathological tumor disappearance. Data regarding clinicopathological factors, adverse events, and outcomes following the initial and repeated hormonal treatments were extracted from medical records and analyzed.Results: Complete response rates in the initial and repeated treatment groups were 98.5% and 96.4%, respectively, among patients with AEH, and were 90.7% and 98.1%, respectively, among patients with G1. In the initial treatment group, 5-year recurrence-free survival (RFS) rates were 53.7% and 33.2% among patients with AEH and G1, respectively. In the repeated treatment group, RFS rates were 14.0% and 11.2% among patients with AEH and G1, respectively. Among patients with AEH, the pregnancy rate tended to be lower in the repeated treatment group than in the initial treatment group (11.1% vs. 29.2%; p=0.107), while no significant group difference was observed among patients with G1 (20.8% vs. 22.7%).Conclusion: Repeated treatment is sufficiently effective for intrauterine recurrence after hormonal therapy for AEH/early G1.

DOI： 10.3802/jgo.2018.29.e21

婦人科疾患ゲノム異常の探索と女性ヘルスケアの個別化 Invited Reviewed

HIRASAWA AKIRA

日本女性医学学会雑誌 25 ( 2 ) 156 - 158 2018.2

ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death Reviewed International journal

Mari Ueno, Takayuki Shiomi, Satsuki Mochizuki, Miyuki Chijiiwa, Masayuki Shimoda, Yae Kanai, Fumio Kataoka, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki, Yasunori Okada

CANCER SCIENCE 109 ( 2 ) 471 - 482 2018.2

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

ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance.

DOI： 10.1111/cas.13469

Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (Translated Version). Reviewed

Hideyuki Ishida, Tatsuro Yamaguchi, Kohji Tanakaya, Kiwamu Akagi, Yasuhiro Inoue, Kensuke Kumamoto, Hideki Shimodaira, Shigeki Sekine, Toshiaki Tanaka, Akiko Chino, Naohiro Tomita, Takeshi Nakajima, Hirotoshi Hasegawa, Takao Hinoi, Akira Hirasawa, Yasuyuki Miyakura, Yoshie Murakami, Kei Muro, Yoichi Ajioka, Yojiro Hashiguchi, Yoshinori Ito, Yutaka Saito, Tetsuya Hamaguchi, Megumi Ishiguro, Soichiro Ishihara, Yukihide Kanemitsu, Hiroshi Kawano, Yusuke Kinugasa, Norihiro Kokudo, Keiko Murofushi, Takako Nakajima, Shiro Oka, Yoshiharu Sakai, Akihiko Tsuji, Keisuke Uehara, Hideki Ueno, Kentaro Yamazaki, Masahiro Yoshida, Takayuki Yoshino, Narikazu Boku, Takahiro Fujimori, Michio Itabashi, Nobuo Koinuma, Takayuki Morita, Genichi Nishimura, Yuh Sakata, Yasuhiro Shimada, Keiichi Takahashi, Shinji Tanaka, Osamu Tsuruta, Toshiharu Yamaguchi, Kenichi Sugihara, Toshiaki Watanabe

Journal of the anus, rectum and colon 2 ( Suppl I ) S1-S51 2018

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

Hereditary colorectal cancer accounts for less than 5% of all colorectal cancer cases. Some of the unique characteristics that are commonly encountered in cases of hereditary colorectal cancer include early age at onset, synchronous/metachronous occurrence of the cancer, and association with multiple cancers in other organs, necessitating different management from sporadic colorectal cancer. While the diagnosis of familial adenomatous polyposis might be easy because usually 100 or more adenomas that develop in the colonic mucosa are in this condition, Lynch syndrome, which is the most commonly associated disease with hereditary colorectal cancer, is often missed in daily medical practice because of its relatively poorly defined clinical characteristics. In addition, the disease concept and diagnostic criteria for Lynch syndrome, which was once called hereditary non-polyposis colorectal cancer, have changed over time with continual research, thereby possibly creating confusion in clinical practice. Under these circumstances, the JSCCR Guideline Committee has developed the "JSCCR Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (HCRC)," to allow delivery of appropriate medical care in daily practice to patients with familial adenomatous polyposis, Lynch syndrome, or other related diseases. The JSCCR Guidelines 2016 for HCRC were prepared by consensus reached among members of the JSCCR Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR Guidelines 2016 for HCRC.

DOI： 10.23922/jarc.2017-028

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group. Reviewed International journal

Sarah M Nielsen, Diana M Eccles, Iris L Romero, Fahd Al-Mulla, Judith Balmaña, Michela Biancolella, Rien Bslok, Maria Adelaide Caligo, Mariarosaria Calvello, Gabriele Lorenzo Capone, Pietro Cavalli, T L Chris Chan, Kathleen B M Claes, Laura Cortesi, Fergus J Couch, Miguel de la Hoya, Simona De Toffol, Orland Diez, Susan M Domchek, Ros Eeles, Anna Efremidis, Florentia Fostira, David Goldgar, Andreas Hadjisavvas, Thomas V O Hansen, Akira Hirasawa, Claude Houdayer, Petra Kleiblova, Sophie Krieger, Conxi Lázaro, Maria Loizidou, Siranoush Manoukian, Arjen R Mensenkamp, Setareh Moghadasi, Alvaro N Monteiro, Luigi Mori, April Morrow, Nadia Naldi, Henriette R Nielsen, Olufunmilayo I Olopade, Nicholas S Pachter, Edenir I Palmero, Inge S Pedersen, Maria Piane, Marianna Puzzo, Mark Robson, Maria Rossing, Maria Christina Sini, Angela Solano, Jana Soukupova, Gianluca Tedaldi, Manuel Teixeira, Mads Thomassen, Maria Grazia Tibiletti, Amanda Toland, Therese Törngren, Erica Vaccari, Liliana Varesco, Ana Vega, Yvonne Wallis, Barbara Wappenschmidt, Jeffrey Weitzel, Amanda B Spurdle, Arcangela De Nicolo, Encarna B Gómez-García

JCO precision oncology 2 2018

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

Purpose: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Results: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Conclusion: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

DOI： 10.1200/PO.18.00091

Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer. Invited Reviewed International journal

Akira Hirasawa, Issei Imoto, Takuya Naruto, Tomoko Akahane, Wataru Yamagami, Hiroyuki Nomura, Kiyoshi Masuda, Nobuyuki Susumu, Hitoshi Tsuda, Daisuke Aoki

Oncotarget 8 ( 68 ) 112258 - 112267 2017.12

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

Pathogenic germline BRCA1, BRCA2 (BRCA1/2), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1), 8 (3.5%; BRCA2), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D), 2 (0.9%; ATM), 1 (0.4%; MRE11A), 1 (FANCC), and 1 (GABRA6). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2. Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

DOI： 10.18632/oncotarget.22733

Efficacy and safety of dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube or peritoneal cancer Reviewed International journal

Tomoko Yoshihama, Hiroyuki Nomura, Naomi Iwasa, Fumio Kataoka, Shiho Hashimoto, Yoshiko Nanki, Takuro Hirano, Takeshi Makabe, Kensuke Sakai, Wataru Yamagami, Akira Hirasawa, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 ( 11 ) 1019 - 1023 2017.11

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

Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) is currently one of the preferred treatment options for advanced ovarian, fallopian tube or peritoneal cancer. This study was conducted to evaluate the clinical efficacy and safety of dose-dense paclitaxel plus carboplatin therapy (ddTC therapy) as NAC for these cancers.A retrospective study was conducted in 25 patients with Stage III/IV ovarian, fallopian tube or peritoneal cancer who received ddTC therapy as NAC. For ddTC therapy, paclitaxel (80 mg/m(2)) was administered intravenously on Days 1, 8 and 15 and carboplatin (AUC 6.0 mg/ml x min) was administered intravenously on Day 1 every 3 weeks. IDS was performed after three cycles of ddTC therapy, and ddTC therapy was also continued after surgery.With ddTC therapy as NAC, the response rate was 92% and disease progression did not occur in any patient. Grade 4 hematologic toxicity and >= Grade 3 non-hematologic toxicity both occurred in 8% of the patients, but no patient discontinued NAC because of adverse events. When IDS was performed, the complete surgery rate was 64% and the optimal surgery rate was 96%. >= Grade 3 perioperative complications occurred in 16% of the patients, but there were no perioperative deaths. Median overall survival was 35.7 months and median progression-free survival was 17.7 months.This study showed that ddTC therapy was considerably effective and tolerable as NAC. The complete surgery rate was high with IDS, and perioperative complications were acceptable.

DOI： 10.1093/jjco/hyx118

治療薬解説 PARP阻害薬

AOKI DAISUKE

カレントテラピー 35 ( 9 ) 74 - 77 2017.9

A Comparison of Dye Versus Fluorescence Methods for Sentinel Lymph Node Mapping in Endometrial Cancer Reviewed International journal

Wataru Yamagami, Nobuyuki Susumu, Fumio Kataoka, Takeshi Makabe, Kensuke Sakai, Tomomi Ninomiya, Michiko Wada, Hiroyuki Nomura, Akira Hirasawa, Kouji Banno, Tadaki Nakahara, Kaori Kameyama, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 27 ( 7 ) 1517 - 1524 2017.9

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

Objective Sentinel nodes (SNs) have been observed in several reports from Japan and overseas in cases with endometrial cancer; however, no consensus has been reached regarding the types of tracers or the method of their injection. A combination of the radioisotope (RI) and dye method is considered to be desirable. We assessed SN mapping using either dye or near-infrared fluorescence imaging to clarify a suitable method in cases of endometrial cancer.Methods Patients were enrolled from 92 patients diagnosed with endometrial cancer and having no extrauterine metastasis by the preoperative imaging between 2009 and 2014 at our institution. To identify the SNs, we performed 3 methods using either dye or fluorescence solutions in conjunction with a RI method. In the dye method, we injected indocyanine green in the uterine subserosa, visually identifying SNs as stained green. In the fluorescence method, a dilute indocyanine green solution (0.5 mg, fluorescence A or 0.25 mg, fluorescence B, each per 10 mL of solvent) was injected and the SN identified by the HyperEye Medical System.Results The SN detection rates were 100%, 100%, and 96% using dye and fluorescence A or B solution, respectively. Pelvic SNs were detected by the 3 methods in 98%, 100%, and 96% of cases and para-aortic SNs in 65%, 88%, and 74%, respectively. Fluorescence A solution was somewhat better than dye in detecting para-aortic SNs, although not significantly so (P = 0.07). The sensitivity and negative predictive values for detecting SNs with metastases with the dye method were 92% and 98% compared with 100% and 100%, respectively, for both fluorescence solutions.Conclusions Although both dye and fluorescence methods performed well, no method perfectly identified para-aortic SNs. The concomitant use of the RI method is required to detect para-aortic SNs.

DOI： 10.1097/IGC.0000000000000997

遺伝性卵巣がん

AOKI DAISUKE

成人病と生活習慣病 47 ( 7 ) 861 - 866 2017.7

医療機器に生じたトラブル

AOKI DAISUKE

産婦人科の実際 66 ( 6 ) 767 - 771 2017.6

Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer. International journal

Kenta Masuda, Akira Hirasawa, Haruko Irie-Kunitomi, Tomoko Akahane, Arisa Ueki, Yusuke Kobayashi, Wataru Yamagami, Hiroyuki Nomura, Fumio Kataoka, Eiichiro Tominaga, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

Japanese journal of clinical oncology 47 ( 5 ) 401 - 406 2017.5

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

Background: A patient's medical history and familial cancer history are important information for assessing the risk of hereditary cancer. We have generated a self-administered questionnaire for patients with gynecologic cancer. This pilot study analyzed the usefulness of this questionnaire and the rates of patients that meet the Society of Gynecologic Oncology criteria in ovarian cancer and endometrial cancer patients. Method: Ovarian or endometrial cancer patients were recruited for this study. After informed consent was obtained, participants completed the questionnaire. Genetic risks were assessed from the data of each patient's questionnaire by Society of Gynecologic Oncology guideline. Clinical and pathological findings were compared between the genetic risk groups. Results: A total of 105 patients were identified with ovarian cancer and 56 patients with endometrial cancer eligible for this study. According to the Society of Gynecologic Oncology guideline, of the 105 ovarian cancer patients, 25 patients (23%) had a 20-25% risk and three patients (2.9%) had a 5-10% risk of hereditary breast and ovarian cancer syndrome. A further 22 patients (21%) had a 5-10% risk of Lynch syndrome. Two patients (1.9%) met the Amsterdam criteria II. Of 56 endometrial cancer patients, 24 patients (42.9%) had a 5-10% risk of Lynch syndrome. The endometrial cancer patients with genetic risk of Lynch syndrome were younger (mean age: 47.79) at diagnosis compared to patients without a genetic risk of Lynch syndrome (mean age: 57.91). Conclusions: In this study, we were able to show that the newly designed questionnaire is a useful tool for evaluating cancer family history along with Society of Gynecologic Oncology criteria or Amsterdam criteria II. When considering the risk of Lynch syndrome for a patient with ovarian cancer, it is important to collect a second and third relative's family history.

DOI： 10.1093/jjco/hyx019

Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer. Reviewed International journal

Kenta Masuda, Akira Hirasawa, Haruko Irie-Kunitomi, Tomoko Akahane, Arisa Ueki, Yusuke Kobayashi, Wataru Yamagami, Hiroyuki Nomura, Fumio Kataoka, Eiichiro Tominaga, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

Japanese journal of clinical oncology 47 ( 5 ) 473 - 473 2017.5

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

This study shows that the newly designed self-administered questionnaire is a useful tool to assess the risk of hereditary cancer for patients with gynecologic cancer.A patient's medical history and familial cancer history are important information for assessing the risk of hereditary cancer. We have generated a self-administered questionnaire for patients with gynecologic cancer. This pilot study analyzed the usefulness of this questionnaire and the rates of patients that meet the Society of Gynecologic Oncology criteria in ovarian cancer and endometrial cancer patients.
Ovarian or endometrial cancer patients were recruited for this study. After informed consent was obtained, participants completed the questionnaire. Genetic risks were assessed from the data of each patient's questionnaire by Society of Gynecologic Oncology guideline. Clinical and pathological findings were compared between the genetic risk groups.
A total of 105 patients were identified with ovarian cancer and 56 patients with endometrial cancer eligible for this study. According to the Society of Gynecologic Oncology guideline, of the 105 ovarian cancer patients, 25 patients (23%) had a 20-25% risk and three patients (2.9%) had a 5-10% risk of hereditary breast and ovarian cancer syndrome. A further 22 patients (21%) had a 5-10% risk of Lynch syndrome. Two patients (1.9%) met the Amsterdam criteria II. Of 56 endometrial cancer patients, 24 patients (42.9%) had a 5-10% risk of Lynch syndrome. The endometrial cancer patients with genetic risk of Lynch syndrome were younger (mean age: 47.79) at diagnosis compared to patients without a genetic risk of Lynch syndrome (mean age: 57.91).
In this study, we were able to show that the newly designed questionnaire is a useful tool for evaluating cancer family history along with Society of Gynecologic Oncology criteria or Amsterdam criteria II. When considering the risk of Lynch syndrome for a patient with ovarian cancer, it is important to collect a second and third relative's family history.

DOI： 10.1093/jjco/hyx037

Carcinoma of the lower uterine segment diagnosed with Lynch syndrome based on MSH6 germline mutation: A case report. Reviewed International journal

Masataka Adachi, Kouji Banno, Kenta Masuda, Megumi Yanokura, Moito Iijima, Takashi Takeda, Haruko Kunitomi, Yusuke Kobayashi, Wataru Yamagami, Akira Hirasawa, Kaori Kameyama, Kokichi Sugano, Daisuke Aoki

The journal of obstetrics and gynaecology research 43 ( 2 ) 416 - 420 2017.2

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

Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

DOI： 10.1111/jog.13202

UGT1A1 polymorphism as a prognostic indicator of stage I ovarian clear cell carcinoma patients treated with irinotecan Reviewed International journal

Tomoko Yoshihama, Akira Hirasawa, Hiroyuki Nomura, Tomoko Akahane, Yoshiko Nanki, Wataru Yamagami, Fumio Kataoka, Eiichiro Tominaga, Nobuyuki Susumu, Taisei Mushiroda, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 ( 2 ) 170 - 174 2017.2

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

We investigated whether UGT1A1 polymorphisms are associated with the prognosis of ovarian cancer patients treated with irinotecan. UGT1A1 genotypes were analyzed in 11 stage I ovarian clear cell carcinoma patients who received irinotecan as first-line therapy. Progression-free survival, overall survival and adverse events were also assessed for each genotype. Three patients harbored UGT1A1*1/*6 while another three harbored UGT1A1*1/*28. Two patients with a wildtype genotype experienced recurrence and one died, whereas no recurrence or death was observed in patients with heterozygous genotypes. Adverse events tended to be more severe in patients with UGT1A1*6 and *28, although progression-free survival and overall survival rates tended to be better than in wild-type; the differences were not significant. We conclude that UGT1A1 polymorphisms have the potential to be a prognostic marker of irinotecan treatment.

DOI： 10.1093/jjco/hyw163

Carcinoma of the lower uterine segment diagnosed with Lynch syndrome based on MSH6 germline mutation: A case report Reviewed

Masataka Adachi, Kouji Banno, Kenta Masuda, Megumi Yanokura, Moito Iijima, Takashi Takeda, Haruko Kunitomi, Yusuke Kobayashi, Wataru Yamagami, Akira Hirasawa, Kaori Kameyama, Kokichi Sugano, Daisuke Aoki

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 43 ( 2 ) 416 - 420 2017.2

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

Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

DOI： 10.1111/jog.13202

遺伝性乳癌卵巣癌症候群と女性ヘルスケア Invited

平沢晃, 青木大輔

更年期と加齢のヘルスケア 16 ( 1 ) 42 - 45 2017

手術前禁忌薬（経口避妊薬,低用量エストロゲン-プロゲスチン配合薬）に関する医療安全対策 Reviewed

高柳裕子, 冨永英一郎, 小林佑介, 仲村勝, 片岡史夫, 平沢晃, 阪埜浩司, 田中守, 青木大輔

東京産科婦人科学会会誌 66 ( 3 ) 424 - 428 2017

一般病院における家族性腫瘍相談外来とハイリスク外来の開設 –一般病院み求められる家族性腫瘍診療の意義についての考察- . Invited Reviewed

植木有紗, 中田さくら, 安斎純子, 麻薙美香, 嶋田恭輔, 久保内光一, 三須久美子, 平沢晃, 阪埜浩司, 菅野康吉, 小崎健次郎, 青木大輔

家族性腫瘍 16 ( 2 ) 38 - 43 2017

BRCA1またはBRCA2遺伝子変異陽性女性へのHRT Invited

平沢晃, 高松潔, 青木大輔

産科と婦人科 84 ( 12 ) 1468 - 1471 2017

Consistency in drug response profiling. Reviewed International journal

John Patrick Mpindi, Bhagwan Yadav, Päivi Östling, Prson Gautam, Disha Malani, Astrid Murumägi, Akira Hirasawa, Sara Kangaspeska, Krister Wennerberg, Olli Kallioniemi, Tero Aittokallio

Nature 540 ( 7631 ) E5-E6 - E6 2016.11

Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis. Reviewed International journal

Takashi Takeda, Kouji Banno, Megumi Yanokura, Masataka Adachi, Moito Iijima, Haruko Kunitomi, Kanako Nakamura, Miho Iida, Yuya Nogami, Kiyoko Umene, Kenta Masuda, Yusuke Kobayashi, Wataru Yamagami, Akira Hirasawa, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

Genes 7 ( 10 ) e86 2016.10

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

Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)-1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

DOI： 10.3390/genes7100086

遺伝性腫瘍領域の新たな潮流

AOKI DAISUKE

実験医学 34 ( 16 ) 2671 - 2674 2016.10

婦人科悪性腫瘍に脳梗塞を合併したTrousseau症候群5例の検討

AOKI DAISUKE

日本婦人科腫瘍学会雑誌 34 ( 4 ) 620 - 625 2016.10

Symptoms and effects of physical factors in Japanese middle-aged women Reviewed

Megumi Yokota, Kazuya Makita, Akira Hirasawa, Takashi Iwata, Daisuke Aoki

MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY 23 ( 9 ) 974 - 983 2016.9

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

Objective:The aim of the study was to clarify the prevalence and severity rates of symptoms and investigate whether symptoms varied in relation to body mass index (BMI).Methods:The study group composed of 1,969 women, aged 40 to 60 years, who presented at our department from 1993 through 2014. The participation rate was 98%. The presence or absence of symptoms was evaluated by having the participants complete the Keio Questionnaire, a self-administered questionnaire. To allow the results to be compared according to ovarian function, serum levels of follicle-stimulating hormone and estradiol were measured. Participants were classified into three groups according to BMI: underweight, normal weight, and overweight. Symptoms were also compared among these subgroups.Results:The most common symptom was general fatigue. Vasomotor symptoms differed significantly between pre- and postmenopause status. When symptoms were analyzed according to BMI, the severity rates of the following symptoms were significantly higher in the overweight group than in the normal weight and underweight groups: hot flushes, sweats, joint pain, numbness, and incontinence. On the contrary, the underweight group had significantly higher severities of cold constitution, nervousness, and wrinkled skin than did the other groups. In addition, an increase in BMI was associated with an increased severity of vasomotor symptoms.Conclusions:The prevalence and severities of shoulder stiffness, considered a characteristic symptom in Japanese women, were high. Increased BMI was shown to be associated with a higher severity of vasomotor symptoms, joint pain, nervousness, and urinary symptoms.

DOI： 10.1097/GME.0000000000000660

Symptoms and effects of physical factors in Japanese middle-aged women. International journal

Megumi Yokota, Kazuya Makita, Akira Hirasawa, Takashi Iwata, Daisuke Aoki

Menopause (New York, N.Y.) 23 ( 9 ) 974 - 83 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Lippincott Williams and Wilkins

OBJECTIVE: The aim of the study was to clarify the prevalence and severity rates of symptoms and investigate whether symptoms varied in relation to body mass index (BMI). METHODS: The study group composed of 1,969 women, aged 40 to 60 years, who presented at our department from 1993 through 2014. The participation rate was 98%. The presence or absence of symptoms was evaluated by having the participants complete the Keio Questionnaire, a self-administered questionnaire. To allow the results to be compared according to ovarian function, serum levels of follicle-stimulating hormone and estradiol were measured. Participants were classified into three groups according to BMI: underweight, normal weight, and overweight. Symptoms were also compared among these subgroups. RESULTS: The most common symptom was general fatigue. Vasomotor symptoms differed significantly between pre- and postmenopause status. When symptoms were analyzed according to BMI, the severity rates of the following symptoms were significantly higher in the overweight group than in the normal weight and underweight groups: hot flushes, sweats, joint pain, numbness, and incontinence. On the contrary, the underweight group had significantly higher severities of cold constitution, nervousness, and wrinkled skin than did the other groups. In addition, an increase in BMI was associated with an increased severity of vasomotor symptoms. CONCLUSIONS: The prevalence and severities of shoulder stiffness, considered a characteristic symptom in Japanese women, were high. Increased BMI was shown to be associated with a higher severity of vasomotor symptoms, joint pain, nervousness, and urinary symptoms.

DOI： 10.1097/GME.0000000000000660

Retrospective Analysis on the Feasibility and Efficacy of Docetaxel-Cisplatin Therapy for Recurrent Endometrial Cancer. International journal

Tomomi Ninomiya, Wataru Yamagami, Nobuyuki Susumu, Takeshi Makabe, Kensuke Sakai, Michiko Wada, Aya Takigawa, Tatsuyuki Chiyoda, Hiroyuki Nomura, Fumio Kataoka, Akira Hirasawa, Kouji Banno, Daisuke Aoki

Anticancer research 36 ( 4 ) 1751 - 8 2016.4

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

AIM: There is poor evidence regarding effective treatment for recurrent endometrial cancer. We treated patients with recurrent endometrial cancer with docetaxel-cisplatin (DP) therapy as second-line or third-line chemotherapy. We aimed to evaluate the feasibility and efficacy of DP therapy for patients with recurrent endometrial cancer. PATIENT AND METHODS: We included 26 patients diagnosed with recurrent endometrial cancer, who underwent DP chemotherapy at our Institution. Docetaxel at 70 mg/m(2)and cisplatin at 60 mg/m(2)were administered by intravenous injection every 3 weeks. We retrospectively analyzed the clinicopathological factors associated with the response rate (RR) and prognosis. We also analyzed the adverse effects of DP therapy. RESULTS: Median follow-up was 33.8 months and the median number of therapy cycles was six. Grade 3 or 4 adverse effects included leukopenia (66%), neutropenia (81%), anemia (9%), diarrhea (12%), general fatigue (12%), liver dysfunction (4%), peripheral neuropathy (4%), and hyponatremia (4%). RR was 58% and the median progression-free survival (PFS) was 7.5 months. The group with a treatment-free interval of 6 months or more tended to have better PFS than that with less than 6 months (p=0.01). The group with a platinum-free interval of 6 months or more had significantly better PFS than that with less than 6 months (p=0.09). Although the history of taxane usage was not relevant to prognosis, a taxane-free interval of 12 months or more was associated with a tendency for better PFS (p=0.06). CONCLUSION: DP therapy was fully feasible and demonstrated efficacy for patients with recurrent endometrial cancer.

婦人科疾患における自覚症状としての「冷え」,疾患単位としての「冷え症」の合併頻度についての検討

WATANABE KENJI

日本産科婦人科学会雑誌 68 ( 2 ) 677 - 677 2016.2

遺伝性乳がん卵巣がんに対するリスク低減卵管卵巣摘出術と術後ヘルスケア

AOKI DAISUKE

更年期と加齢のヘルスケア 14 ( 2 ) 316 - 318 2016.2

Factors affecting pregnancy outcomes in young women treated with fertility-preserving therapy for well-differentiated endometrial cancer or atypical endometrial hyperplasia. Reviewed International journal

Osamu Inoue, Toshio Hamatani, Nobuyuki Susumu, Wataru Yamagami, Seiji Ogawa, Takashi Takemoto, Akira Hirasawa, Kouji Banno, Naoaki Kuji, Mamoru Tanaka, Daisuke Aoki

Reproductive biology and endocrinology : RB&E 14 ( 1 ) 2 - 2 2016.1

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

BACKGROUND: Patients hoping to preserve their fertility receive conservative treatment with high-dose medroxyprogesterone acetate (MPA) for well-differentiated endometrioid adenocarcinoma (EC) or atypical endometrial hyperplasia (AEH) . Such treatment generally involves frequent intrauterine operations, including dilation and curettage (D&C) and endometrial biopsy (EMB), which could result in endometritis, endometrial thinning, or intrauterine adhesion. In turn, any of these outcomes could adversely affect implantation and pregnancy development. The current study thus aimed to identify factors that might affect pregnancy following conservative treatment by MPA. METHODS: We compared a pregnancy group (45 patients) with a non-pregnancy group (53 patients) of MPA-treated patients to evaluate the factors affecting clinical pregnancy establishment. We undertook a multivariate logistic regression analysis based on factors shown by univariate analysis to be significantly different between the groups. Univariate analysis identified number of D&C, endometrial thickness, duration of MPA administration, age of pregnancy permission (the age at which a patient was first allowed to attempt pregnancy after disappearance of the lesion), period of disappearance of lesions, and recurrence as independent variables. RESULTS: The odds ratios (95 % confidence interval) of multivariate analysis for disease recurrence, endometrial thickness during ovulation, and age of pregnancy permission were 0.283 (0.102-0.785), 1.677 (1.251-2.248), and 0.889 (0.792-0.998), respectively. There was no significant difference in the other independent variables between groups. CONCLUSIONS: We identified three factors considered to affect pregnancy establishment following conservative treatment with MPA: recurrence, endometrial thickness during ovulation, and the age of the pregnancy permission. Introduction of infertility treatment including assisted reproductive technology (ART) soon after achieving tumor disappearance by MPA would therefore be beneficial for patients with disease recurrence, thin endometrium, or a higher age of pregnancy permission.

DOI： 10.1186/s12958-015-0136-7

Characterization of the STK11 splicing variant as a normal splicing isomer in a patient with Peutz-Jeghers syndrome harboring genomic deletion of the STK11 gene. Reviewed International journal

Kenta Masuda, Yusuke Kobayashi, Tokuhiro Kimura, Kiyoko Umene, Kumiko Misu, Hiroyuki Nomura, Akira Hirasawa, Kouji Banno, Kenjiro Kosaki, Daisuke Aoki, Kokichi Sugano

Human genome variation 3 16002 - 16002 2016

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

We report a STK11 splicing variant comprising a 131-bp insertion that is derived from intron 1, which has previously been reported to possess potent pathogenicity. The same variant was detected in a Peutz-Jeghers syndrome patient harboring a genomic deletion in the vicinity of exon 1 of the STK11 gene, which indicated that this variant was derived from the wild-type allele. We also found the same variant in other normal subjects. This variant corresponds to the predicted transcript variant of STK11 (XM_011528209), which is derived from the genomic sequence of Chr19 (NT_011295.12). Therefore, we concluded that the splicing variant was not pathogenic.

DOI： 10.1038/hgv.2016.2

Profiling of Epithelial Ovarian Cancer as BRCAness Status with MLPA Method. Reviewed

Hirasawa A, Akahane T, Masuda K, Ninomiya T, Yamagami W, Nomura H, Kataoka F, Banno K, Susumu N, Aoki D

Curr Oncol 23 ( 3 ) e305 2016

バイオリソースを用いた研究基盤整備に関する国内外の動き Invited Reviewed

平沢晃, 青木大輔

産科と婦人科 83 ( 1 ) 13 - 19 2016

遺伝性腫瘍 Invited Reviewed

平沢晃, 山上亘, 青木大輔

産婦人科の実際 65 ( 6 ) 653 - 659 2016

遺伝性乳がん卵巣がん; 遺伝性腫瘍-実地臨床での対応を目指して Invited

平沢晃, 青木大輔

日本医師会雑誌 145 ( 4 ) 705 - 709 2016

卵巣・卵管の良性腫瘍・類腫瘍 Invited

日本女性医学学会編

女性医学ガイドブック思春期・性成熟期編2016年度版 151 - 154 2016

両側卵巣摘出術を施行した婦人科がんサバイバーのQOL向上を目指した疫学因子および遺伝因子の解析. Invited Reviewed

平沢晃

日本女性医学学会雑誌 24 ( 1 ) 48 - 52 2016

子宮体部・卵巣同時発生重複癌40症例の臨床病理学的検討. Reviewed

小笠原淳, 小林佑介, 野村弘行, 山上亘, 片岡史夫, 平沢晃, 冨永英一郎, 鈴木淳, 阪埜浩司, 進伸幸, 田中守, 青木大輔

東京産科婦人科学会会誌 65 ( 3 ) 436 - 439 2016

[Free fatty acid receptors as therapeutic targets for metabolic disorders].

Akira Hirasawa, Masato Takeuchi, Ryouhei Shirai, Zao Chen, Shota Ishii, Keiko Iida

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 146 ( 6 ) 296 - 301 2015.12

EVALUATION OF PRE- OR INTRA-OPERATIVE DIAGNOSTIC METHOD FOR UTERINE CARCINOSARCOMA

T. Makabe, W. Yamagami, N. Susumu, K. Sakai, T. Yoshihama, N. Iwasa, N. Nakadaira, S. Hashimoto, T. Ninomiya, M. Wada, A. Takigawa, H. Nomura, F. Kataoka, A. Hirasawa, K. Banno, D. Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 25 ( 9 ) 1107 - 1107 2015.10

子宮体がんの予防とヘルスケア

AOKI DAISUKE

産婦人科の実際女性ヘルスケア集中講義！ 61 ( 10月臨時増刊号 ) 399 - 408 2015.10

若年子宮体癌、および子宮内膜異型増殖症に対して妊孕性温存治療を施行することによる精神的影響

横田めぐみ, 山上亘, 坂井健良, 真壁健, 二宮委美, 和田美智子, 野村弘行, 片岡史夫, 平澤晃, 牧田和也, 阪埜浩司, 進伸幸, 青木大輔, 白波瀬丈一郎

日本女性医学学会雑誌 23 ( Suppl. ) 140 - 140 2015.10

Intratumoral CD8(+) Lymphocyte Infiltration as a Prognostic Factor and Its Relationship With Cyclooxygenase 2 Expression and Microsatellite Instability in Endometrial Cancer Reviewed

Tomohiro Suemori, Nobuyuki Susumu, Takashi Iwata, Kouji Banno, Wataru Yamagami, Akira Hirasawa, Kokichi Sugano, Eri Matsumoto, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 25 ( 7 ) 1165 - 1172 2015.9

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

Objective Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer.
Methods The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8(+) T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses.
Results The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression.
Conclusions The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

DOI： 10.1097/IGC.0000000000000482

High Expression of p62 Protein Is Associated with Poor Prognosis and Aggressive Phenotypes in Endometrial Cancer. International journal

Reiko Iwadate, Jun Inoue, Hitoshi Tsuda, Masashi Takano, Kenichi Furuya, Akira Hirasawa, Daisuke Aoki, Johji Inazawa

The American journal of pathology 185 ( 9 ) 2523 - 33 2015.9

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

High expression of SQSTM1/p62 (p62) protein, which functions as a hub of oncogenic signaling pathways, has been detected in several human cancers. However, the clinicopathological and functional contribution of p62 expression is largely unknown in endometrial cancers (ECs). In this study, we assessed the expression status of p62 in primary ECs (n = 194) by immunohistochemistry and analyzed its clinical significance. Although p62 was expressed in the cytoplasm and/or nucleus in primary ECs, we observed that an expression subtype, high expression of cytoplasmic p62 but low expression of nuclear p62 (cytoplasm(High)/nucleus(Low)), significantly correlated with nonendometrioid types (P = 0.002), high grade (P < 0.001), deep myometrial invasion (P = 0.025), vascular invasion (P = 0.012), and poor prognosis (P < 0.001), and may be an independent prognostic marker of ECs (P = 0.011). Furthermore, RNA interference-mediated inhibition of p62 expression in the HEC-1A EC cell line led to the reduction of invasiveness and resistance to oxidative stress in vitro, as well as the suppression of in vivo tumor growth in an orthotopic mouse model of ECs. High expression of cytoplasmic p62 is a novel prognostic biomarker of ECs, and excess p62 expression may functionally contribute to the acquirement of malignant phenotypes in EC cells.

DOI： 10.1016/j.ajpath.2015.05.008

Intratumoral CD8+ Lymphocyte Infiltration as a Prognostic Factor and Its Relationship With Cyclooxygenase 2 Expression and Microsatellite Instability in Endometrial Cancer. International journal

Tomohiro Suemori, Nobuyuki Susumu, Takashi Iwata, Kouji Banno, Wataru Yamagami, Akira Hirasawa, Kokichi Sugano, Eri Matsumoto, Daisuke Aoki

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 25 ( 7 ) 1165 - 72 2015.9

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

OBJECTIVE: Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer. METHODS: The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8 T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses. RESULTS: The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression. CONCLUSIONS: The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

DOI： 10.1097/IGC.0000000000000482

Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women. Reviewed International journal

Megumi Yokota, Akira Hirasawa, Kazuya Makita, Tomoko Akahane, Kensuke Sakai, Takeshi Makabe, Yuko Horiba, Wataru Yamagami, Mariko Ogawa, Takashi Iwata, Shigehisa Yanamoto, Ryota Deshimaru, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

Przeglad menopauzalny = Menopause review 14 ( 3 ) 161 - 7 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Termedia Publishing House Ltd.

INTRODUCTION: Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life. MATERIAL AND METHODS: This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. RESULTS: No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations. CONCLUSIONS: These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

DOI： 10.5114/pm.2015.54339

一般病院における家族性腫瘍相談外来とハイリスク外来の開設

植木有紗, 安齋純子, 中田さくら, 麻薙美香, 嶋田恭輔, 久保内光一, 三須久美子, 平沢晃, 阪埜浩司, 菅野康吉, 小崎健次郎, 青木大輔

家族性腫瘍 15 ( 2 ) A96 - A96 2015.5

当科健康維持外来初診患者に認められた甲状腺機能異常の現状

AOKI DAISUKE

日本女性医学学会雑誌 22 ( 2 ) 133 - 137 2015.4

子宮体がんの予防とへするケア－妊孕性温存と術後のQOL改善を目指して－

AOKI DAISUKE

日本女性医学学会雑誌 22 ( 2 ) 282 - 104 2015.4

Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer. Reviewed International journal

Masataka Adachi, Kouji Banno, Megumi Yanokura, Miho Iida, Kanako Nakamura, Yuya Nogami, Kiyoko Umene, Kenta Masuda, Iori Kisu, Arisa Ueki, Akira Hirasawa, Eiichiro Tominaga, Daisuke Aoki

Molecular and clinical oncology 3 ( 2 ) 267 - 273 2015.3

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

Risk-reducing surgery (RRS) is defined as a prophylactic approach with removal of organs at high risk of developing cancer, which is performed in cases without lesions or absence of clinically significant lesions. Hereditary gynecological cancers for which RRS is performed include hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. For HBOC, RRS in the United States (US) is recommended for women with mutations in the breast cancer susceptibility (BRCA)1 and BRCA2 genes and bilateral salpingo-oophorectomy (BSO) is generally performed. This procedure may reduce the risk of breast, ovarian, Fallopian tube and primary peritoneal cancer, although ovarian deficiency symptoms occur postoperatively. For Lynch syndrome, RRS in the US is considered for postmenopausal women or for women who do not desire to bear children and BSO and hysterectomy are usually performed. This approach may reduce the risk of endometrial and ovarian cancer, although ovarian deficiency symptoms also occur. For RRS, there are several issues that must be addressed to reduce the risk of cancer development in patients with HBOC or Lynch syndrome. To the best of our knowledge, this is the first review to discuss RRS with a focus on hereditary gynecological cancer.

Clinicopathologic Analysis With Immunohistochemistry for DNA Mismatch Repair Protein Expression in Synchronous Primary Endometrial and Ovarian Cancers Reviewed

Yusuke Kobayashi, Kanako Nakamura, Hiroyuki Nomura, Kouji Banno, Haruko Irie, Masataka Adachi, Miho Iida, Kiyoko Umene, Yuya Nogami, Kenta Masuda, Iori Kisu, Arisa Ueki, Wataru Yamagami, Fumio Kataoka, Akira Hirasawa, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 25 ( 3 ) 440 - 446 2015.3

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

Objective: Synchronous primary endometrial and ovarian cancers have been an important topic in clinical medicine because it is sometimes difficult to distinguish whether there are 2 primary tumors or a single primary tumor and an associated metastasis. In addition, although these tumors are recommended for either immunohistochemistry for DNA mismatch repair (MMR) proteins or a microsatellite instability test in the Bethesda guidelines as Lynch syndrome-associated cancers, few studies have completed these analyses. In this study, we characterized the clinicopathologic features and the expression pattern of MMR proteins in synchronous primary endometrial and ovarian cancers.
Methods: Clinicopathologic features and the expression pattern of MMR proteins (MLH1, MSH2, and MSH6) were characterized and analyzed in 32 synchronous primary endometrial and ovarian cancers.
Results: Most synchronous cancers are endometrioid type (endometrioid/endometrioid) (n = 24, 75%), grade 1 (n = 19, 59.4%), and diagnosed as stage I (n = 15, 46.9%) in both endometrium and ovary. It is worth mentioning that 75% of the patients (n = 24) had endometriosis, which was more common (n = 21, 87.5%) in endometrioid/endometrioid cancers, whereas only 3 cases (37.5%) were of different histology (P = 0.018). Loss of expression of at least 1 MMR protein was observed in 17 (53.1%) of the endometrial tumors and in 10 (31.3%) of ovarian tumors. Only 4 cases (12.5%) that had specific MMR protein loss showed the same type of loss for both endometrial and ovarian tumors, in which 3 of the cases were losses in MLH1. One case showed concordant MSH6 protein loss, although the cases did not meet the Amsterdam criteria II.
Conclusions: These results suggest that most synchronous primary endometrial ovarian cancers are not hereditary cancers caused by germ line mutations but rather sporadic cancers.

DOI： 10.1097/IGC.0000000000000377

Clinicopathologic analysis with immunohistochemistry for DNA mismatch repair protein expression in synchronous primary endometrial and ovarian cancers. International journal

Yusuke Kobayashi, Kanako Nakamura, Hiroyuki Nomura, Kouji Banno, Haruko Irie, Masataka Adachi, Miho Iida, Kiyoko Umene, Yuya Nogami, Kenta Masuda, Iori Kisu, Arisa Ueki, Wataru Yamagami, Fumio Kataoka, Akira Hirasawa, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 25 ( 3 ) 440 - 6 2015.3

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

OBJECTIVE: Synchronous primary endometrial and ovarian cancers have been an important topic in clinical medicine because it is sometimes difficult to distinguish whether there are 2 primary tumors or a single primary tumor and an associated metastasis. In addition, although these tumors are recommended for either immunohistochemistry for DNA mismatch repair (MMR) proteins or a microsatellite instability test in the Bethesda guidelines as Lynch syndrome-associated cancers, few studies have completed these analyses. In this study, we characterized the clinicopathologic features and the expression pattern of MMR proteins in synchronous primary endometrial and ovarian cancers. METHODS: Clinicopathologic features and the expression pattern of MMR proteins (MLH1, MSH2, and MSH6) were characterized and analyzed in 32 synchronous primary endometrial and ovarian cancers. RESULTS: Most synchronous cancers are endometrioid type (endometrioid/endometrioid) (n = 24, 75%), grade 1 (n = 19, 59.4%), and diagnosed as stage I (n = 15, 46.9%) in both endometrium and ovary. It is worth mentioning that 75% of the patients (n = 24) had endometriosis, which was more common (n = 21, 87.5%) in endometrioid/endometrioid cancers, whereas only 3 cases (37.5%) were of different histology (P = 0.018). Loss of expression of at least 1 MMR protein was observed in 17 (53.1%) of the endometrial tumors and in 10 (31.3%) of ovarian tumors. Only 4 cases (12.5%) that had specific MMR protein loss showed the same type of loss for both endometrial and ovarian tumors, in which 3 of the cases were losses in MLH1. One case showed concordant MSH6 protein loss, although the cases did not meet the Amsterdam criteria II. CONCLUSIONS: These results suggest that most synchronous primary endometrial ovarian cancers are not hereditary cancers caused by germ line mutations but rather sporadic cancers.

DOI： 10.1097/IGC.0000000000000377

遺伝性乳癌・卵巣癌とLynch症候群のリスク低減手術

AOKI DAISUKE

産婦人科の実際 64 ( 3 ) 377 - 383 2015.3

Osteoporosis is less frequent in endometrial cancer survivors with hypertriglyceridemia. International journal

Akira Hirasawa, Kazuya Makita, Tomoko Akahane, Wataru Yamagami, Takeshi Makabe, Megumi Yokota, Yuko Horiba, Mariko Ogawa, Shigehisa Yanamoto, Rhota Deshimaru, Eiichiro Tominaga, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

Japanese journal of clinical oncology 45 ( 1 ) 127 - 31 2015.1

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

We previously reported an association between dyslipidemia and endometrial cancers. Osteoporosis is also reported to relate with some cancers. A common etiologic event has been proposed between dyslipidemia and osteoporosis. However, the pattern of interrelationships among dyslipidemia, osteoporosis and endometrial cancer is not well understood. To improve the quality of life of endometrial cancer survivors, these relationships should be determined. This study included 179 Japanese menopausal women who underwent bilateral salpingo-oophorectomy, including 114 women with incident endometrial cancer and 65 without endometrial cancer. The women were categorized according to dyslipidemia status. Bone mineral density was measured and compared between groups. Osteoporosis was statistically more frequent in women with hypertriglyceridemia who did not have endometrial cancer. In contrast, osteoporosis was statistically less frequent in women with hypertriglyceridemia who had endometrial cancer. In this cross-sectional study in a Japanese population, osteoporosis was associated with hypertriglyceridemia in post-menopausal women without endometrial cancer, but was less frequent in endometrial cancer survivors with hypertriglyceridemia.

DOI： 10.1093/jjco/hyu164

Osteoporosis is less frequent in endometrial cancer survivors with hypertriglyceridemia Reviewed

Akira Hirasawa, Kazuya Makita, Tomoko Akahane, Wataru Yamagami, Takeshi Makabe, Megumi Yokota, Yuko Horiba, Mariko Ogawa, Shigehisa Yanamoto, Rhota Deshimaru, Eiichiro Tominaga, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 1 ) 127 - 131 2015.1

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

We previously reported an association between dyslipidemia and endometrial cancers. Osteoporosis is also reported to relate with some cancers. A common etiologic event has been proposed between dyslipidemia and osteoporosis. However, the pattern of interrelationships among dyslipidemia, osteoporosis and endometrial cancer is not well understood. To improve the quality of life of endometrial cancer survivors, these relationships should be determined. This study included 179 Japanese menopausal women who underwent bilateral salpingo-oophorectomy, including 114 women with incident endometrial cancer and 65 without endometrial cancer. The women were categorized according to dyslipidemia status. Bone mineral density was measured and compared between groups. Osteoporosis was statistically more frequent in women with hypertriglyceridemia who did not have endometrial cancer. In contrast, osteoporosis was statistically less frequent in women with hypertriglyceridemia who had endometrial cancer. In this cross-sectional study in a Japanese population, osteoporosis was associated with hypertriglyceridemia in post-menopausal women without endometrial cancer, but was less frequent in endometrial cancer survivors with hypertriglyceridemia.

DOI： 10.1093/jjco/hyu164

Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women

Megumi Yokota, Akira Hirasawa, Kazuya Makita, Tomoko Akahane, Kensuke Sakai, Takeshi Makabe, Yuko Horiba, Wataru Yamagami, Mariko Ogawa, Takashi Iwata, Shigehisa Yanamoto, Ryota Deshimaru, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

MENOPAUSE REVIEW-PRZEGLAD MENOPAUZALNY 14 ( 3 ) 161 - 167 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：TERMEDIA PUBLISHING HOUSE LTD

Introduction: Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life.Material and methods: This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated.Results: No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations.Conclusions: These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

DOI： 10.5114/pm.2015.54339

臓器・領域別家族性腫瘍の臨床卵巣癌 Invited Reviewed

植木有紗, 増田健太, 平沢晃, 中田さくら, 青木大輔

日本臨床 73 ( 6 ) 462 - 466 2015

遺伝性乳癌卵巣癌 Invited Reviewed

平沢晃, 増田健太, 青木大輔

臨床画像 31 ( 10 ) 220 - 221 2015

子宮体癌の予防とヘルスケア Invited Reviewed

進伸幸, 平沢晃, 山上亘, 青木大輔

産婦人科の実際 64 ( 1 ) 1741 - 1750 2015

遺伝性乳癌卵巣癌の遺伝子検査 Reviewed

平沢晃, 増田健太, 青木大輔

産科と婦人科 82 ( Sup ) 202 - 205 2015

BRCA1/2遺伝子変異保持者に対するリスク低減卵管卵巣摘出術とサーベイランス Invited Reviewed

平沢晃, 増田健太, 青木大輔

産科と婦人科 82 ( 6 ) 639 - 643 2015

High Expression of p62 Protein Is Associated with Poor Prognosis and Aggressive Phenotypes in Endometrial Cancer. Reviewed

Iwadate R, Inoue J, Tsuda H, Takano M, Furuya K, Hirasawa A, Aoki D, Inazawa J

Am J Pathol 185 ( 9 ) 2523 - 2533 2015

Features of ovarian cancer in Lynch syndrome (Review). Reviewed International journal

Kanako Nakamura, Kouji Banno, Megumi Yanokura, Miho Iida, Masataka Adachi, Kenta Masuda, Arisa Ueki, Yusuke Kobayashi, Hiroyuki Nomura, Akira Hirasawa, Eiichiro Tominaga, Daisuke Aoki

Molecular and clinical oncology 2 ( 6 ) 909 - 916 2014.11

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

Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome.

Clinicopathological study on para-aortic lymph node metastasis without pelvic lymph node metastasis in endometrial cancer. Reviewed International journal

Shoko Tomisato, Wataru Yamagami, Nobuyuki Susumu, Michiko Kuwahata, Aya Takigawa, Hiroyuki Nomura, Fumio Kataoka, Akira Hirasawa, Kouji Banno, Daisuke Aoki

The journal of obstetrics and gynaecology research 40 ( 6 ) 1733 - 9 2014.6

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

AIM: One of the important risk factors for recurrence of endometrial cancer is lymph node metastasis. The regional lymph nodes are pelvic lymph nodes (PLN) and para-aortic lymph nodes (PAN). PAN metastasis was often detected in the cases with PLN metastasis. However, PAN metastasis not associated with PLN metastasis was identified in a few cases. We focused on nine cases with PAN metastasis and without PLN metastasis. MATERIAL AND METHODS: The subjects of this study were 260 cases that were diagnosed with endometrial cancer. The initial treatments were surgery, including pelvic and para-aortic lymphadenectomy. Nine of these cases had PAN metastasis but did not have PLN metastasis. We retrospectively analyzed the clinicopathological factors and prognosis in cases with PLN-PAN+ cases. RESULTS: A total of 91 (35%) cases were identified as positive for either PLN or PAN. PAN metastases were detected in 62.6% of the cases that had some regional lymph node metastases and 3.5% of all cases were PLN- and PAN+. In all PLN-PAN+ cases, PAN swelling was not detected by preoperative chest-abdominal computed tomography scan. There were no clear trends among risk factors of regional lymph node metastasis. The 5-year progression-free survival was 87.1% for PLN-PAN- cases, 67.5% for PLN+PAN- cases, 44.4% for PLN-PAN+ cases, and 33.2% for PLN+PAN+ cases. CONCLUSION: During diagnosis and treatment for endometrial cancer, PLN-PAN+ cases should also be considered because the prognosis in PLN-PAN+ cases tended to be lower than that in PLN-PAN- cases and PLN+PAN- cases.

DOI： 10.1111/jog.12399

Clinicopathological study on para-aortic lymph node metastasis without pelvic lymph node metastasis in endometrial cancer

Shoko Tomisato, Wataru Yamagami, Nobuyuki Susumu, Michiko Kuwahata, Aya Takigawa, Hiroyuki Nomura, Fumio Kataoka, Akira Hirasawa, Kouji Banno, Daisuke Aoki

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 40 ( 6 ) 1733 - 1739 2014.6

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

Aim One of the important risk factors for recurrence of endometrial cancer is lymph node metastasis. The regional lymph nodes are pelvic lymph nodes (PLN) and para-aortic lymph nodes (PAN). PAN metastasis was often detected in the cases with PLN metastasis. However, PAN metastasis not associated with PLN metastasis was identified in a few cases. We focused on nine cases with PAN metastasis and without PLN metastasis. Material and Methods The subjects of this study were 260 cases that were diagnosed with endometrial cancer. The initial treatments were surgery, including pelvic and para-aortic lymphadenectomy. Nine of these cases had PAN metastasis but did not have PLN metastasis. We retrospectively analyzed the clinicopathological factors and prognosis in cases with PLN-PAN+ cases. Results A total of 91 (35%) cases were identified as positive for either PLN or PAN. PAN metastases were detected in 62.6% of the cases that had some regional lymph node metastases and 3.5% of all cases were PLN- and PAN+. In all PLN-PAN+ cases, PAN swelling was not detected by preoperative chest-abdominal computed tomography scan. There were no clear trends among risk factors of regional lymph node metastasis. The 5-year progression-free survival was 87.1% for PLN-PAN- cases, 67.5% for PLN+PAN- cases, 44.4% for PLN-PAN+ cases, and 33.2% for PLN+PAN+ cases. Conclusion During diagnosis and treatment for endometrial cancer, PLN-PAN+ cases should also be considered because the prognosis in PLN-PAN+ cases tended to be lower than that in PLN-PAN- cases and PLN+PAN- cases.

DOI： 10.1111/jog.12399

A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region

Yusuke Kobayashi, Kenta Masuda, Tokuhiro Kimura, Hiroyuki Nomura, Akira Hirasawa, Kouji Banno, Nobuyuki Susumu, Kokichi Sugano, Daisuke Aoki

FUTURE ONCOLOGY 10 ( 2 ) 171 - 177 2014.2

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

Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma.

DOI： 10.2217/FON.13.180

A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region. Reviewed International journal

Yusuke Kobayashi, Kenta Masuda, Tokuhiro Kimura, Hiroyuki Nomura, Akira Hirasawa, Kouji Banno, Nobuyuki Susumu, Kokichi Sugano, Daisuke Aoki

Future oncology (London, England) 10 ( 2 ) 171 - 7 2014.2

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

Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma.

DOI： 10.2217/fon.13.180

Family History and BRCA1/BRCA2 Status Among Japanese Ovarian Cancer Patients and Occult Cancer in a BRCA1 Mutant Case Reviewed

Akira Hirasawa, Kenta Masuda, Tomoko Akahane, Arisa Ueki, Megumi Yokota, Tomohiko Tsuruta, Hiroyuki Nomura, Fumio Kataoka, Eiichiro Tominaga, Kouji Banno, Kazuya Makita, Nobuyuki Susumu, Kokichi Sugano, Kenjiro Kosaki, Kaori Kameyama, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 ( 1 ) 49 - 56 2014.1

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

This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer.
One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer.
Nine of 102 (8.8) families were regarded as having hereditary breastovarian cancer syndrome, two families (2.0) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case.
Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

DOI： 10.1093/jjco/hyt171

Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case. International journal

Akira Hirasawa, Kenta Masuda, Tomoko Akahane, Arisa Ueki, Megumi Yokota, Tomohiko Tsuruta, Hiroyuki Nomura, Fumio Kataoka, Eiichiro Tominaga, Kouji Banno, Kazuya Makita, Nobuyuki Susumu, Kokichi Sugano, Kenjiro Kosaki, Kaori Kameyama, Daisuke Aoki

Japanese journal of clinical oncology 44 ( 1 ) 49 - 56 2014.1

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

BACKGROUND: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer. METHODS: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer. RESULTS: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case. CONCLUSIONS: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

DOI： 10.1093/jjco/hyt171

遺伝性乳がん卵巣がん（HBOC）への対応 Reviewed

増田健太, 阪埜浩司, 植木有紗, 平沢晃, 青木大輔

産婦人科の実際 63 ( 7 ) 973 - 980 2014

High Expression of SQSTM1/p62 Protein Is Associated with Poor Prognosis in Epithelial Ovarian Cancer

Reiko Iwadate, Jun Inoue, Hitoshi Tsuda, Masashi Takano, Kenichi Furuya, Akira Hirasawa, Daisuke Aoki, Johji Inazawa

ACTA HISTOCHEMICA ET CYTOCHEMICA 47 ( 6 ) 295 - 301 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY

High expression of SQSTM1/p62 (p62) protein, which functions as a hub for various cellular signaling pathways, has been detected in several human cancers. However, the clinicopathological impact of high p62 expression is largely unknown in epithelial ovarian cancer (EOC). Here, the expression level of p62 in primary EOCs (n=266) was assessed by immunohistochemistry, and its clinical significance was analyzed. Univariate and multivariate analyses were used to determine the impact of p62 expression on overall survival. p62 was expressed in the cytoplasm (Cyto) and/or nucleus (Nuc) in primary E0Cs, and an expression subtype (Cyto(High)/Nuc(Low)), showing high expression in the cytoplasm but low expression in the nucleus, was significantly correlated with serous carcinoma (P<0.001), advanced stage (P=0.005), presence of residual tumor (P<0.001), and low overall survival rate (P=0.013). Furthermore, in serous carcinomas (n=107), the p62 Cyto(High)/Nuc(Low) subtype was significantly correlated with low overall survival rate (P=0.019) as an independent factor (P=0.044). Thus, our findings suggest that high expression of cytoplasmic p62 may be a novel prognostic biomarker in EOC, particularly in serous carcinoma.

DOI： 10.1267/ahc.14048

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients. International journal

Akira Hirasawa, Takeru Zama, Tomoko Akahane, Hiroyuki Nomura, Fumio Kataoka, Koichiro Saito, Keisuke Okubo, Eiichiro Tominaga, Kazuya Makita, Nobuyuki Susumu, Kenjiro Kosaki, Yusuke Tanigawara, Daisuke Aoki

Journal of human genetics 58 ( 12 ) 794 - 8 2013.12

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

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.

DOI： 10.1038/jhg.2013.105

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients

Akira Hirasawa, Takeru Zama, Tomoko Akahane, Hiroyuki Nomura, Fumio Kataoka, Koichiro Saito, Keisuke Okubo, Eiichiro Tominaga, Kazuya Makita, Nobuyuki Susumu, Kenjiro Kosaki, Yusuke Tanigawara, Daisuke Aoki

Journal of Human Genetics 58 ( 12 ) 794 - 798 2013.12

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

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers
however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients. © 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13.

DOI： 10.1038/jhg.2013.105

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients Reviewed

Akira Hirasawa, Takeru Zama, Tomoko Akahane, Hiroyuki Nomura, Fumio Kataoka, Koichiro Saito, Keisuke Okubo, Eiichiro Tominaga, Kazuya Makita, Nobuyuki Susumu, Kenjiro Kosaki, Yusuke Tanigawara, Daisuke Aoki

Journal of Human Genetics 58 ( 12 ) 794 - 798 2013.12

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

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers
however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients. © 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13.

DOI： 10.1038/jhg.2013.105

Hereditary gynecological tumors associated with Peutz-Jeghers syndrome Reviewed

Kouji Banno, Iori Kisu, Megumi Yanokura, Kenta Masuda, Arisa Ueki, Yusuke Kobayashi, Akira Hirasawa, Daisuke Aoki

ONCOLOGY LETTERS 6 ( 5 ) 1184 - 1188 2013.11

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

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

DOI： 10.3892/ol.2013.1527

Hypertriglyceridemia is Frequent in Endometrial Cancer Survivors

Akira Hirasawa, Kazuya Makita, Tomoko Akahane, Megumi Yokota, Wataru Yamagami, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 43 ( 11 ) 1087 - 1092 2013.11

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

Objective: Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic.
Methods: This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed.
Results: Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls.
Conclusions: Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors.

DOI： 10.1093/jjco/hyt125

Hereditary gynecological tumors associated with Peutz-Jeghers syndrome (Review). International journal

Kouji Banno, Iori Kisu, Megumi Yanokura, Kenta Masuda, Arisa Ueki, Yusuke Kobayashi, Akira Hirasawa, Daisuke Aoki

Oncology letters 6 ( 5 ) 1184 - 1188 2013.11

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

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

DOI： 10.3892/ol.2013.1527

Hereditary gynecological tumors associated with Peutz-Jeghers syndrome

Kouji Banno, Iori Kisu, Megumi Yanokura, Kenta Masuda, Arisa Ueki, Yusuke Kobayashi, Akira Hirasawa, Daisuke Aoki

ONCOLOGY LETTERS 6 ( 5 ) 1184 - 1188 2013.11

Language：English Publisher：SPANDIDOS PUBL LTD

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

DOI： 10.3892/ol.2013.1527

Hypertriglyceridemia is frequent in endometrial cancer survivors. Reviewed International journal

Akira Hirasawa, Kazuya Makita, Tomoko Akahane, Megumi Yokota, Wataru Yamagami, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

Japanese journal of clinical oncology 43 ( 11 ) 1087 - 92 2013.11

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

OBJECTIVE: Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic. METHODS: This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed. RESULTS: Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls. CONCLUSIONS: Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors.

DOI： 10.1093/jjco/hyt125

Distinguishing between lymphangioleiomyomatosis and carcinomatous peritonitis in a patient with ovarian cancer. International journal

Akira Hirasawa, Takashi Sato, Mari Ueno, Tomoko Akahane, Nobuyuki Susumu, Tomoko Betsuyaku, Daisuke Aoki

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31 ( 28 ) e427-9 - E429 2013.10

Distinguishing Between Lymphangioleiomyomatosis and Carcinomatous Peritonitis in a Patient With Ovarian Cancer

Akira Hirasawa, Takashi Sato, Mari Ueno, Tomoko Akahane, Nobuyuki Susumu, Tomoko Betsuyaku, Daisuke Aoki

JOURNAL OF CLINICAL ONCOLOGY 31 ( 28 ) E427 - E429 2013.10

Distinguishing Between Lymphangioleiomyomatosis and Carcinomatous Peritonitis in a Patient With Ovarian Cancer Reviewed

Akira Hirasawa, Takashi Sato, Mari Ueno, Tomoko Akahane, Nobuyuki Susumu, Tomoko Betsuyaku, Daisuke Aoki

JOURNAL OF CLINICAL ONCOLOGY 31 ( 28 ) E427 - E429 2013.10

MicroRNA-196a Is a Putative Diagnostic Biomarker and Therapeutic Target for Laryngeal Cancer

Koichiro Saito, Koji Inagaki, Takahiro Kamimoto, Yoko Ito, Toshiaki Sugita, Satoko Nakajo, Akira Hirasawa, Arifumi Iwamaru, Takashi Ishikura, Hideki Hanaoka, Keisuke Okubo, Tokio Onozaki, Takeru Zama

PLOS ONE 8 ( 8 ) 2013.8

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

Background: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue-or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary.
Methodology/Principal Findings: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model.
Conclusions/Significance: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

DOI： 10.1371/journal.pone.0071480

beta-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation

M. Villacorte, K. Suzuki, A. Hirasawa, Y. Ohkawa, M. Suyama, T. Maruyama, D. Aoki, Y. Ogino, S. Miyagawa, T. Terabayashi, Y. Tomooka, N. Nakagata, G. Yamada

ONCOGENE 32 ( 29 ) 3477 - 3482 2013.7

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

The Wnt/beta-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated beta-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/beta-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of beta-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that beta-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that beta-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that beta-catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of beta-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia.

DOI： 10.1038/onc.2012.376

beta-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation Reviewed

M. Villacorte, K. Suzuki, A. Hirasawa, Y. Ohkawa, M. Suyama, T. Maruyama, D. Aoki, Y. Ogino, S. Miyagawa, T. Terabayashi, Y. Tomooka, N. Nakagata, G. Yamada

ONCOGENE 32 ( 29 ) 3477 - 3482 2013.7

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

The Wnt/beta-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated beta-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/beta-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of beta-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that beta-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that beta-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that beta-catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of beta-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia.

DOI： 10.1038/onc.2012.376

Experience of risk-reducing salpingo-oophorectomy for a BRCA1 mutation carrier and establishment of a system performing a preventive surgery for hereditary breast and ovarian cancer syndrome in Japan: our challenges for the future. International journal

Akira Hirasawa, Kenta Masuda, Tomoko Akahane, Tomohiko Tsuruta, Kouji Banno, Kazuya Makita, Nobuyuki Susumu, Hiromitsu Jinno, Yuko Kitagawa, Kokichi Sugano, Kenjiro Kosaki, Daisuke Aoki

Japanese journal of clinical oncology 43 ( 5 ) 515 - 9 2013.5

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

BACKGROUND: Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan. METHODS: We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008. RESULTS: The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan. CONCLUSIONS: Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

DOI： 10.1093/jjco/hyt036

Experience of Risk-reducing Salpingo-oophorectomy for a BRCA1 Mutation Carrier and Establishment of a System Performing a Preventive Surgery for Hereditary Breast and Ovarian Cancer Syndrome in Japan: Our Challenges for the Future

Akira Hirasawa, Kenta Masuda, Tomoko Akahane, Tomohiko Tsuruta, Kouji Banno, Kazuya Makita, Nobuyuki Susumu, Hiromitsu Jinno, Yuko Kitagawa, Kokichi Sugano, Kenjiro Kosaki, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 43 ( 5 ) 515 - 519 2013.5

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

Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan.
We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008.
The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan.
Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

DOI： 10.1093/jjco/hyt036

高用量黄体ホルモン療法後に妊娠に至った若年性子宮体癌および複雑型子宮内膜異型増殖症43例の妊娠予後と分娩後のサーベイランス Reviewed

山上亘, 進伸幸, 市川義一, 桑波田美智子, 野村弘行, 平沢晃, 峰岸一宏, 冨永英一郎, 宮越敬, 阪埜浩司, 青木大輔, 吉村泰典

日本産科婦人科学会雑誌 65 ( 2 ) 574 - 574 2013.2

The origin of stroma surrounding epithelial ovarian cancer cells. International journal

Tomoko Akahane, Akira Hirasawa, Hiroshi Tsuda, Fumio Kataoka, Sadako Nishimura, Hideo Tanaka, Eiichiro Tominaga, Hiroyuki Nomura, Tatsuyuki Chiyoda, Yoko Iguchi, Wataru Yamagami, Nobuyuki Susumu, Daisuke Aoki

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 32 ( 1 ) 26 - 30 2013.1

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

Cancer stroma is thought to play an important role in tumor behavior, including invasion or metastasis and response to therapy. Cancer stroma is generally thought either to be non-neoplastic cells, including tissue-marrow or bone-marrow-derived fibroblasts, or to originate in epithelial mesenchymal transition of cancer cells. In this study, we evaluated the status of the p53 gene in both the cancer cells and the cancer stroma in epithelial ovarian cancer (EOC) to elucidate the origin of the stroma. Samples from 16 EOC patients were included in this study. Tumor cells and adjacent nontumor stromal cells were microdissected and DNA was extracted separately. We analyzed p53 sequences (exons 5-8) of both cancer and stromal tissues in all cases. Furthermore, we examined p53 protein expression in all cases. Mutations in p53 were detected in 9 of the 16 EOCs: in 8 of these cases, the mutations were detected only in cancer cells. In 1 case, the same mutation (R248Q) was detected in both cancer and stromal tissues, and p53 protein expression was detected in both the cancer cells and the cancer stroma. Most cancer stroma in EOC is thought to originate from non-neoplastic cells, but some parts of the cancer stroma might originate from cancer cells.

DOI： 10.1097/PGP.0b013e3182518533

MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer. Reviewed International journal

Koichiro Saito, Koji Inagaki, Takahiro Kamimoto, Yoko Ito, Toshiaki Sugita, Satoko Nakajo, Akira Hirasawa, Arifumi Iwamaru, Takashi Ishikura, Hideki Hanaoka, Keisuke Okubo, Tokio Onozaki, Takeru Zama

PloS one 8 ( 8 ) e71480 2013

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

BACKGROUND: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary. METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model. CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

DOI： 10.1371/journal.pone.0071480

Establishment of a system for performing risk-reducing salpingo-oophorectomy for BRCA1 or BRCA2 mutation carriers in Japan: Our challenges for the future. Reviewed

Hirasawa A, Masuda K, Akahane T, Tsuruta T, Banno K, Makita K, Susumu N, Sugano K, Kosaki K, Aoki D

Jpn J Clin Oncol 43 ( 5 ) 515-519 2013

遺伝性乳癌・卵巣癌に対する婦人科の取り組み Invited

平沢晃, 青木大輔

化療ニュース 22 ( 2 ) 13 - 19 2013

子宮体がんとエストロゲン Invited Reviewed

進伸幸, 山上亘, 二宮委美, 桑波田美智子, 片岡史夫, 平沢晃, 阪埜浩司, 青木大輔

産婦人科の実際 62 ( 9 ) 1181 - 1187 2013

ホルモンによるがんの化学予防 Invited Reviewed

平沢晃, 鶴田智彦, 青木大輔

産科と婦人科 80 ( Sup ) 164 - 168 2013

遺伝性乳癌・卵巣癌女性への遺伝カウンセリング Invited Reviewed

平沢晃, 青木大輔

産科と婦人科 80 ( 11 ) 1465 - 1472 2013

当科健康維持外来患者からみためまいの現状 Invited

牧田和也, 橫田めぐみ, 堀場裕子, 平沢晃, 小川真里子, 弟子丸亮太, 柳本茂久, 高松潔, 青木大輔, 吉村泰典

日本女性医学学会雑誌 21 ( 1 ) 54 - 59 2013

子宮峡部癌の臨床病理学的特徴とLynch症候群との関連 Invited Reviewed

増田健太, 阪埜浩司, 矢野倉恵, 小林佑介, 辻浩介, 木須伊織, 植木有紗, 野村弘行, 平沢晃, 進伸幸, 青木大輔

家族性腫瘍 13 ( 1 ) 1 - 5 2013

Lobular endocervical glandular hyperplasia and peritoneal pigmentation associated with Peutz-Jeghers syndrome due to a germline mutation of STK11

A. Hirasawa, T. Akahane, T. Tsuruta, Y. Kobayashi, K. Masuda, K. Banno, T. Fujii, N. Susumu, T. Itsubo, K. Kameyama, K. Sugano, D. Aoki

ANNALS OF ONCOLOGY 23 ( 11 ) 2990 - 2992 2012.11

Relationship of lower uterine segment cancer with Lynch syndrome: a novel case with an hMLH1 germline mutation. Reviewed International journal

Kenta Masuda, Kouji Banno, Akira Hirasawa, Megumi Yanokura, Kosuke Tsuji, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Hiroyuki Nomura, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

Oncology reports 28 ( 5 ) 1537 - 43 2012.11

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

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) had cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

DOI： 10.3892/or.2012.2008

Relationship of lower uterine segment cancer with Lynch syndrome: A novel case with an hMLH1 germline mutation

Kenta Masuda, Kouji Banno, Akira Hirasawa, Megumi Yanokura, Kosuke Tsuji, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Hiroyuki Nomura, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

ONCOLOGY REPORTS 28 ( 5 ) 1537 - 1543 2012.11

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

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) :lad cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

DOI： 10.3892/or.2012.2008

Lobular endocervical glandular hyperplasia and peritoneal pigmentation associated with Peutz-Jeghers syndrome due to a germline mutation of STK11 Reviewed

A. Hirasawa, T. Akahane, T. Tsuruta, Y. Kobayashi, K. Masuda, K. Banno, T. Fujii, N. Susumu, T. Itsubo, K. Kameyama, K. Sugano, D. Aoki

ANNALS OF ONCOLOGY 23 ( 11 ) 2990 - 2992 2012.11

Blood-direct InvaderPlus® as a new method for genetic testing. International journal

Akira Hirasawa, Tomoko Akahane, Yusuke Tanigawara, Daisuke Aoki

Personalized medicine 9 ( 6 ) 657 - 663 2012.8

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

AIM: This study compared the efficiency of Blood-direct InvaderPlus® with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. MATERIALS & METHODS: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. RESULTS: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A1*6, *27, *28, *60, VKORC1 -1639G>A, VKORC1 1173T>C and CYP2C9 *2 and *3 much faster than the conventional methods. CONCLUSION: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms.

DOI： 10.2217/pme.12.71

Blood-direct InvaderPlus (R) as a new method for genetic testing Reviewed

Akira Hirasawa, Tomoko Akahane, Yusuke Tanigawara, Daisuke Aoki

PERSONALIZED MEDICINE 9 ( 6 ) 657 - 663 2012.8

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

Aim: This study compared the efficiency of Blood-direct InvaderPlus (R) with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials & methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A1*6, *2Z *28, *60, VKORC1 -1639G>A, VKORC1 1173T>C and CYP2C9 *2 and *3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms.

DOI： 10.2217/PME.12.71

Blood-direct InvaderPlus (R) as a new method for genetic testing

Akira Hirasawa, Tomoko Akahane, Yusuke Tanigawara, Daisuke Aoki

PERSONALIZED MEDICINE 9 ( 6 ) 657 - 663 2012.8

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

Aim: This study compared the efficiency of Blood-direct InvaderPlus (R) with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials & methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A1*6, *2Z *28, *60, VKORC1 -1639G>A, VKORC1 1173T>C and CYP2C9 *2 and *3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms.

DOI： 10.2217/PME.12.71

当科健康維持外来受診者における大腿骨近位部骨密度の検討

AOKI DAISUKE

Osteoporosis Japan 20 ( 3 ) 489 - 491 2012.7

子宮体癌の家族発生と遺伝子診断

AOKI DAISUKE

日本臨床婦人科がん－最新の研究動向－ 70 ( 増刊号4 ) 292-296 - 296 2012.6

[Hereditary endometrial cancer and genetic testing].

Akira Hirasawa, Tomohiko Tsuruta, Kouji Banno, Nobuyuki Susumu, Daisuke Aoki

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 4 292 - 6 2012.6

[Hereditary endometrial cancer and genetic testing].

Hirasawa Akira, Tsuruta Tomohiko, Banno Kouji, Susumu Nobuyuki, Aoki Daisuke

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 4 292 - 296 2012.6

EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy

Fumio Kataoka, Hiroshi Tsuda, Tokuzo Arao, Sadako Nishimura, Hideo Tanaka, Hiroyuki Nomura, Tatsuyuki Chiyoda, Akira Hirasawa, Tomoko Akahane, Hiroshi Nishio, Kazuto Nishio, Daisuke Aoki

GENES CHROMOSOMES & CANCER 51 ( 3 ) 300 - 312 2012.3

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

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and a-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC. (c) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/gcc.21916

EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy Reviewed

Fumio Kataoka, Hiroshi Tsuda, Tokuzo Arao, Sadako Nishimura, Hideo Tanaka, Hiroyuki Nomura, Tatsuyuki Chiyoda, Akira Hirasawa, Tomoko Akahane, Hiroshi Nishio, Kazuto Nishio, Daisuke Aoki

GENES CHROMOSOMES & CANCER 51 ( 3 ) 300 - 312 2012.3

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

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and a-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC. (c) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/gcc.21916

発現解析による子宮体部癌肉腫の生物学的特性の解明.

千代田達幸, 津田浩史, 片岡史夫, 野村弘行, 田中英雄, 平沢晃, 進伸幸, 佐谷秀行, 青木大輔

日本分子腫瘍マーカー研究会誌 27 23-34 - 24 2012

Aberrant DNA Methylation in Endometrial Cancer

Kenta Masuda, Kouji Banno, Megumi Yanokura, Kosuke Tsuji, Iori Kisu, Arisa Ueki, Yusuke Kobayashi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Epigenetics in Human Disease 471 - 480 2012

遺伝性乳癌卵巣癌 Invited Reviewed

平沢晃, 青木大輔

日本産科婦人科学会雑誌 64 ( 4 ) 292 - 296 2012

発現解析による子宮体癌再発予測モデルの開発.

津田浩史, 井口蓉子, 片岡史夫, 野村弘行, 田中英雄, 千代田達幸, 平沢晃, 進伸幸, 青木大輔

日本分子腫瘍マーカー研究会誌 27 45-46 - 46 2012

子宮体がんの術後補助療法

AOKI DAISUKE

腫瘍内科 8 ( 6 ) 563-571 - 571 2011.12

Immunofluorescence-Detected Infiltration of CD4(+)FOXP3(+) Regulatory T Cells is Relevant to the Prognosis of Patients With Endometrial Cancer Reviewed

Wataru Yamagami, Nobuyuki Susumu, Hideo Tanaka, Akira Hirasawa, Kouji Banno, Nao Suzuki, Hiroshi Tsuda, Katsumi Tsukazaki, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 21 ( 9 ) 1628 - 1634 2011.12

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

Objective: Host antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8(+) cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients.
Methods: The study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4(+) FOXP3(+) cells were identified as Tregs in this study. The numbers of CD8(+) cells, CD4(+) cells, and Tregs as well as the Treg/CD8(+) and Treg/CD4(+) ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis.
Results: Of the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8(+) and CD4(+) cell counts, Treg count, and Treg/CD8(+) and Treg/CD4(+) ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8(+) ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8(+) ratios (P < 0.05).
Conclusions: The Treg count and Treg/CD8(+) ratio may be new prognostic factors for endometrial cancer.

DOI： 10.1097/IGC.0b013e31822c271f

Immunofluorescence-Detected Infiltration of CD4(+)FOXP3(+) Regulatory T Cells is Relevant to the Prognosis of Patients With Endometrial Cancer

Wataru Yamagami, Nobuyuki Susumu, Hideo Tanaka, Akira Hirasawa, Kouji Banno, Nao Suzuki, Hiroshi Tsuda, Katsumi Tsukazaki, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 21 ( 9 ) 1628 - 1634 2011.12

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

Objective: Host antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8(+) cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients.Methods: The study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4(+) FOXP3(+) cells were identified as Tregs in this study. The numbers of CD8(+) cells, CD4(+) cells, and Tregs as well as the Treg/CD8(+) and Treg/CD4(+) ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis.Results: Of the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8(+) and CD4(+) cell counts, Treg count, and Treg/CD8(+) and Treg/CD4(+) ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8(+) ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8(+) ratios (P < 0.05).Conclusions: The Treg count and Treg/CD8(+) ratio may be new prognostic factors for endometrial cancer.

DOI： 10.1097/IGC.0b013e31822c271f

Immunofluorescence-detected infiltration of CD4+FOXP3+ regulatory T cells is relevant to the prognosis of patients with endometrial cancer. International journal

Wataru Yamagami, Nobuyuki Susumu, Hideo Tanaka, Akira Hirasawa, Kouji Banno, Nao Suzuki, Hiroshi Tsuda, Katsumi Tsukazaki, Daisuke Aoki

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 21 ( 9 ) 1628 - 34 2011.12

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

OBJECTIVE: Host antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8 cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients. METHODS: The study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4FOXP3 cells were identified as Tregs in this study. The numbers of CD8 cells, CD4 cells, and Tregs as well as the Treg/CD8 and Treg/CD4 ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis. RESULTS: Of the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8 and CD4 cell counts, Treg count, and Treg/CD8 and Treg/CD4 ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8 ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8 ratios (P < 0.05). CONCLUSIONS: The Treg count and Treg/CD8 ratio may be new prognostic factors for endometrial cancer.

DOI： 10.1097/IGC.0b013e31822c271f

Narrow band imaging hysteroscopy: A comparative study using randomized video images Reviewed

Iori Kisu, Kouji Banno, Yusuke Kobayashi, Asuka Ono, Kenta Masuda, Arisa Ueki, Hiroyuki Nomura, Akira Hirasawa, Takayuki Abe, Keisuke Kouyama, Nobuyuki Susumu, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 39 ( 5 ) 1057 - 1062 2011.11

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

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of A EH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P<0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.1131

Narrow band imaging hysteroscopy: A comparative study using randomized video images

Iori Kisu, Kouji Banno, Yusuke Kobayashi, Asuka Ono, Kenta Masuda, Arisa Ueki, Hiroyuki Nomura, Akira Hirasawa, Takayuki Abe, Keisuke Kouyama, Nobuyuki Susumu, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 39 ( 5 ) 1057 - 1062 2011.11

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

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of A EH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P<0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.1131

Narrow band imaging hysteroscopy: a comparative study using randomized video images. International journal

Iori Kisu, Kouji Banno, Yusuke Kobayashi, Asuka Ono, Kenta Masuda, Arisa Ueki, Hiroyuki Nomura, Akira Hirasawa, Takayuki Abe, Keisuke Kouyama, Nobuyuki Susumu, Daisuke Aoki

International journal of oncology 39 ( 5 ) 1057 - 62 2011.11

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

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of AEH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P<0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.1131

miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. International journal

Tomohiko Tsuruta, Ken-Ichi Kozaki, Atsushi Uesugi, Mayuko Furuta, Akira Hirasawa, Issei Imoto, Nobuyuki Susumu, Daisuke Aoki, Johji Inazawa

Cancer research 71 ( 20 ) 6450 - 62 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer.

DOI： 10.1158/0008-5472.CAN-11-0364

miR-152 Is a Tumor Suppressor microRNA That Is Silenced by DNA Hypermethylation in Endometrial Cancer

Tomohiko Tsuruta, Ken-ichi Kozaki, Atsushi Uesugi, Mayuko Furuta, Akira Hirasawa, Issei Imoto, Nobuyuki Susumu, Daisuke Aoki, Johji Inazawa

CANCER RESEARCH 71 ( 20 ) 6450 - 6462 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450-62. (C) 2011 AACR.

DOI： 10.1158/0008-5472.CAN-11-0364

妊産婦への向精神薬の投与

AOKI DAISUKE

産婦人科治療 103 ( 4 ) 417-421 - 421 2011.10

Magnifying hysteroscopy with narrow-band imaging for visualization of endometrial lesions

Kisu I, Banno K, Kobayashi Y, Ono A, Masuda K, Ueki A, Nomura H, Hirasawa A, Abe T, Kouyama K, Susumu N, Aoki D

Int J Gynaecol Obstet 115 ( 1 ) 74-75 2011.10

miR-152 Is a Tumor Suppressor microRNA That Is Silenced by DNA Hypermethylation in Endometrial Cancer Reviewed

Tomohiko Tsuruta, Ken-ichi Kozaki, Atsushi Uesugi, Mayuko Furuta, Akira Hirasawa, Issei Imoto, Nobuyuki Susumu, Daisuke Aoki, Johji Inazawa

CANCER RESEARCH 71 ( 20 ) 6450 - 6462 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450-62. (C) 2011 AACR.

DOI： 10.1158/0008-5472.CAN-11-0364

遺伝性乳癌・卵巣がんの取扱いとリスク低減卵管卵巣摘出術

AOKI DAISUKE

産科と婦人科 78 ( 9 ) 1064-1068 - 1068 2011.9

婦人科疾患と遺伝カウンセリング

AOKI DAISUKE

産婦人科の実際 60 ( 9 ) 1331-1338 - 1338 2011.9

遺伝性腫瘍の基礎知識と遺伝子診断および予防法～遺伝性乳がん・卵巣がんに着目して～．

AOKI DAISUKE

がん看護 16 ( 6 ) 631-635 - 635 2011.9

発現解析による子宮体癌の再発予測モデルの開発

津田浩史, 井口蓉子, 片岡史夫, 野村弘行, 田中英雄, 千代田達幸, 平沢晃, 進伸幸, 青木大輔

日本分子腫瘍マーカー研究会プログラム・講演抄録 31回 68 - 69 2011.9

発現解析による子宮体部癌肉腫の生物学的特性の解明

千代田達幸, 津田浩史, 片岡史夫, 野村弘行, 田中英雄, 平沢晃, 進伸幸, 佐谷秀行, 青木大輔

日本分子腫瘍マーカー研究会プログラム・講演抄録 31回 46 - 47 2011.9

家系内の遺伝子検査が契機となり早期介入を行ったLynch症候群の1例

AOKI DAISUKE

東京産科婦人科学会会誌 60 ( 2 ) 293-297 - 297 2011.6

産婦人科臨床における遺伝性乳癌卵巣癌の位置づけ

AOKI DAISUKE

家族性腫瘍 11 ( 2 ) 48-51 - 51 2011.5

老人性腟炎

AOKI DAISUKE

臨床婦人科産科 65 ( 4(増大号) ) 568-571 2011.4

Flexible hysteroscopy with narrow band imaging (NBI) for endoscopic diagnosis of malignant endometrial lesions

Iori Kisu, Kouji Banno, Yusuke Kobayashi, Asuka Ono, Kenta Masuda, Arisa Ueki, Hiroyuki Nomura, Akira Hirasawa, Takayuki Abe, Keisuke Kouyama, Nobuyuki Susumu, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 38 ( 3 ) 613 - 618 2011.3

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

Narrow band imaging (NBI) for detection of blood vessels and microstructures on the mucosal surface is used in gastrointestinal endoscopy since it can improve qualitative diagnosis and detection of lesion. However, there are no studies on flexible hysteroscopy using NBI. We performed flexible hysteroscopy with NBI for outpatients to investigate the sensitivity and specificity of endoscopic diagnosis of malignant endometrial lesions. Of patients who attended our hospital for suspected lesions in the uterine cavity between April 2009 and May 2010, 104 subjects underwent hysteroscopy with NBI, in addition to white light. Using the pathological diagnosis as the gold-standard, we evaluated the sensitivity and specificity of NBI hysteroscopy for detecting atypical endometrial hyperplasia (AEH) or carcinoma. The results were also compared with historical data (n=209) for conventional hysteroscopy using white light only in 2008. The sensitivities were 97.2% [95% confidence interval (95% CI): 90.3-99.7%] and 82.6% (95% Cl: 74.4-89.0%) for NBI hysteroscopy and conventional hysteroscopy, respectively. The 95% CIs for the two methods did not overlap and the sensitivity of lesion detection was higher with NB! hysteroscopy. Specificities were comparable, 90.6% (95% CI: 75.0-98.0%) and 85.1% (95% CI: 76.3-91.6%) between the methods. NBI hysteroscopy has increased sensitivity for detection of atypical endometrial hyperplasia (AEH) or carcinoma. A comparison with historical data suggested that NBI may be useful for diagnosis of malignant endometrial lesions. As far as we are aware, this is the first evaluation of flexible hysteroscopy with NBI for diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.903

Flexible hysteroscopy with narrow band imaging (NBI) for endoscopic diagnosis of malignant endometrial lesions. International journal

Iori Kisu, Kouji Banno, Yusuke Kobayashi, Asuka Ono, Kenta Masuda, Arisa Ueki, Hiroyuki Nomura, Akira Hirasawa, Takayuki Abe, Keisuke Kouyama, Nobuyuki Susumu, Daisuke Aoki

International journal of oncology 38 ( 3 ) 613 - 8 2011.3

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

Narrow band imaging (NBI) for detection of blood vessels and microstructures on the mucosal surface is used in gastrointestinal endoscopy since it can improve qualitative diagnosis and detection of lesion. However, there are no studies on flexible hysteroscopy using NBI. We performed flexible hysteroscopy with NBI for outpatients to investigate the sensitivity and specificity of endoscopic diagnosis of malignant endometrial lesions. Of patients who attended our hospital for suspected lesions in the uterine cavity between April 2009 and May 2010, 104 subjects underwent hysteroscopy with NBI, in addition to white light. Using the pathological diagnosis as the gold-standard, we evaluated the sensitivity and specificity of NBI hysteroscopy for detecting atypical endometrial hyperplasia (AEH) or carcinoma. The results were also compared with historical data (n=209) for conventional hysteroscopy using white light only in 2008. The sensitivities were 97.2% [95% confidence interval (95% CI): 90.3-99.7%] and 82.6% (95% CI: 74.4-89.0%) for NBI hysteroscopy and conventional hysteroscopy, respectively. The 95% CIs for the two methods did not overlap and the sensitivity of lesion detection was higher with NBI hysteroscopy. Specificities were comparable, 90.6% (95% CI: 75.0-98.0%) and 85.1% (95% CI: 76.3-91.6%) between the methods. NBI hysteroscopy has increased sensitivity for detection of atypical endometrial hyperplasia (AEH) or carcinoma. A comparison with historical data suggested that NBI may be useful for diagnosis of malignant endometrial lesions. As far as we are aware, this is the first evaluation of flexible hysteroscopy with NBI for diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.903

Carcinoma of the Lower Uterine Segment (LUS): Clinicopathological Characteristics and Association with Lynch Syndrome

Kenta Masuda, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Asuka Ono, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

CURRENT GENOMICS 12 ( 1 ) 25 - 29 2011.3

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

Endometrial cancer arises from the uterine body and fundus in many cases, but can also originate from the lower region of the uterine body through the upper region of the cervix. Such tumors are referred to as carcinoma of the lower uterine segment (LUS) or isthmus, and account for 3-6.3% of all cases of endometrial cancer. This relatively low incidence has permitted performance of only small-scale studies, but the clinical and pathological characteristics of carcinoma of the LUS in all these reports have differed from those of other endometrial cancers. Generally, endometrial cancer is classified into estrogen-dependent endometrioid adenocarcinoma (designated as type I), and non-endometrioid types that are less associated with estrogen and include poorly differentiated adenocarcinoma (type II). In some reports, carcinoma of the LUS has been found to have type II characteristics. Carcinoma of the LUS has also been associated with Lynch syndrome, a hereditary disease with frequent development of colorectal, endometrial, and ovarian cancers. Lynch syndrome is thought to be induced by mismatch repair gene mutation. The frequency of Lynch syndrome in cases of general endometrial cancer is 1-2%. In contrast, the frequency in patients with carcinoma of the LUS is much higher, with up to 29% of cases diagnosable with Lynch syndrome and a high frequency of hMSH2 mutation found in one study. This suggests that further investigation of the clinical and pathological characteristics of carcinoma of the LUS and the association with Lynch syndrome is required through performance of a large-scale survey.

DOI： 10.2174/138920211794520169

Carcinoma of the Lower Uterine Segment (LUS): Clinicopathological Characteristics and Association with Lynch Syndrome. International journal

Kenta Masuda, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Asuka Ono, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Current genomics 12 ( 1 ) 25 - 9 2011.3

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

Endometrial cancer arises from the uterine body and fundus in many cases, but can also originate from the lower region of the uterine body through the upper region of the cervix. Such tumors are referred to as carcinoma of the lower uterine segment (LUS) or isthmus, and account for 3-6.3% of all cases of endometrial cancer. This relatively low incidence has permitted performance of only small-scale studies, but the clinical and pathological characteristics of carcinoma of the LUS in all these reports have differed from those of other endometrial cancers. Generally, endometrial cancer is classified into estrogen-dependent endometrioid adenocarcinoma (designated as type I), and non-endometrioid types that are less associated with estrogen and include poorly differentiated adenocarcinoma (type II). In some reports, carcinoma of the LUS has been found to have type II characteristics. Carcinoma of the LUS has also been associated with Lynch syndrome, a hereditary disease with frequent development of colorectal, endometrial, and ovarian cancers. Lynch syndrome is thought to be induced by mismatch repair gene mutation. The frequency of Lynch syndrome in cases of general endometrial cancer is 1-2%. In contrast, the frequency in patients with carcinoma of the LUS is much higher, with up to 29% of cases diagnosable with Lynch syndrome and a high frequency of hMSH2 mutation found in one study. This suggests that further investigation of the clinical and pathological characteristics of carcinoma of the LUS and the association with Lynch syndrome is required through performance of a large-scale survey.

DOI： 10.2174/138920211794520169

腫瘍間質の遺伝子発現解析を用いた進行上皮性卵巣癌に対する新規バイオマーカーの探索

AOKI DAISUKE

日本分子腫瘍マーカー研究会誌 26 32-33 - 33 2011.1

ホルモン補充療法が腰椎骨密度に及ぼす長期的な効果の検討 -当科健康維持外来における10年継続投与例からの検証- .

牧田和也, 松村聡子, 堀場裕子, 平沢晃, 小川真里子, 弟子丸亮太, 柳本茂久, 高松潔, 青木大輔

Osteoporosis Japan 18 ( 3 ) 83-85 - 539 2011

MicroRNA in endometrial cancer Reviewed

Yanokura M, Banno K, Kisu I, Masuda K, Ueki A, Kobayashi Y, Tsuji K, Yamagami W, Nomura H, Hirasawa A, Susumu N, Aoki D

Trends in Cancer Research 7 49-55 2011

Relationship between DNA Mismatch Repair Deficiency and Endometrial Cancer. Reviewed International journal

Kenta Masuda, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Asuka Ono, Nana Asahara, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Molecular biology international 2011 256063 - 256063 2011

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

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Lynch syndrome is thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene. An aberration in the MMR gene prevents accurate repair of base mismatches produced during DNA replication. This phenomenon can lead to an increased frequency of errors in target genes involved in carcinogenesis, resulting in cancerization of the cell. On the other hand, aberrant DNA methylation is thought to play a key role in sporadic endometrial carcinogenesis. Hypermethylation of unmethylated CpG islands in the promoter regions of cancer-related genes associated with DNA repair leads to the cell becoming cancerous. Thus, both genetic and epigenetic changes are intricately involved in the process through which cells become cancerous. In this review, we introduce the latest findings on the DNA mismatch repair pathway in endometrial cancer.

DOI： 10.4061/2011/256063

Visual Analogue Scale（VAS）を用いた呉茱萸湯の片頭痛に対する治療効果の検討.

堀場裕子, 牧田和也, 松村聡子, 平沢晃, 青木大輔, 吉村泰典

産婦人科漢方研究のあゆみ 28 ( 28 ) 80-83 - 83 2011

当科｢健康維持外来｣におけるホルモン補充療法施行症例についての検証.

牧田和也, 松村聡子, 堀場裕子, 平沢晃, 小川真里子, 弟子丸亮太, 柳本茂久, 高松潔, 青木大輔, 吉村泰典

日本女性医学学会雑誌 19 ( 1 ) 18-23 - 24 2011

家系内の遺伝子検査が契機となり早期介入に至ったリンチ症候群の1例.

中村加奈子, 平沢晃, 赤羽智子, 鶴田智彦, 冨永英一郎, 阪埜浩司, 藤井多久磨, 進伸幸, 青木大輔, 吉村泰典

日本産科婦人科学会東京地方部会会誌 60 ( 2 ) 293-297 2011

大腿骨頸部骨密度測定は腰椎骨骨密度測定の代用となり得るか？—当科健康維持外来受診者からの比較検討—

牧田和也, 松村聡子, 堀場裕子, 平沢晃, 小川真里子, 弟子丸亮太, 柳本茂久, 青木大輔

Osteoporosis Japan 19 ( 3 ) 481-483 - 483 2011

Atypical Polypoid Adenomyoma (APAM) of the Uterine: Relationship with Endometrial Cancer Reviewed

Kisu I, Banno K, Yanokura M, Kobayashi Y, Ueki A, Ono A, Masuda K, Yamagami W, Nomura H, HIRASAWA AKIRA, Susumu N, Aoki D

Journal of Cancer Therapy 2 ( 4 ) 458-462 2011

Gynecological tumors in patients with Peutz-Jeghers syndrome (PJS). Reviewed

Ueki A, Kisu I, Banno K, Yanokura M, Masuda K, Kobayashi Y, HIRASAWA AKIRA, Aoki D

Open Journal of Genetics 1 ( 3 ) 65-69 2011

ASSOCIATION BETWEEN COPY NUMBER VARIATIONS OF ESTROGEN MATABOLISM-RELATED GENE AND BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN OF JANANESE Reviewed

A. Hirasawa, K. Makita, T. Akahane, K. Banno, N. Susumu, D. Aoki

OSTEOPOROSIS INTERNATIONAL 21 ( 5 ) S722 - S723 2010.12

遺伝性乳癌卵巣癌－婦人科の観点より－

平沢晃, 野村弘行, 青木大輔

乳癌の臨床 25 ( 5 ) 523-527 - 527 2010.11

MicroRNA and endometrial cancer: Roles of small RNAs in human tumors and clinical applications (Review). Reviewed International journal

Megumi Yanokura, Kouji Banno, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Asuka Ono, Kennta Masuda, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Oncology letters 1 ( 6 ) 935 - 940 2010.11

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

MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 base pairs that regulate the expression of genes by targeting messenger RNA with complementarity with the miRNA base sequence. Regulation of gene expression by miRNAs is crucial in cellular development and differentiation, and recent studies suggest a relationship between human diseases and the breakdown of gene silencing mechanisms induced by miRNA abnormalities. In particular, abnormal miRNA expression has been detected in various types of cancer and the target genes have been identified. These results indicate that miRNAs act in a manner equivalent to oncogenes or tumor suppressors. miRNAs may also serve as diagnostic biomarkers and therapeutic targets. In this review, we introduce the latest findings on miRNAs in human endometrial cancer, a common malignancy, and discuss the potential of miRNAs as biomarkers and targets for molecular therapy.

DOI： 10.3892/ol.2010.173

MicroRNA and endometrial cancer: Roles of small RNAs in human tumors and clinical applications

Megumi Yanokura, Kouji Banno, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Asuka Ono, Kennta Masuda, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

ONCOLOGY LETTERS 1 ( 6 ) 935 - 940 2010.11

Language：English Publisher：SPANDIDOS PUBL LTD

MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 base pairs that regulate the expression of genes by targeting messenger RNA with complementarity with the miRNA base sequence. Regulation of gene expression by miRNAs is crucial in cellular development and differentiation, and recent studies suggest a relationship between human diseases and the breakdown of gene silencing mechanisms induced by miRNA abnormalities. In particular, abnormal miRNA expression has been detected in various types of cancer and the target genes have been identified. These results indicate that miRNAs act in a manner equivalent to oncogenes or tumor suppressors. miRNAs may also serve as diagnostic biomarkers and therapeutic targets. In this review, we introduce the latest findings on miRNAs in human endometrial cancer, a common malignancy, and discuss the potential of miRNAs as biomarkers and targets for molecular therapy.

DOI： 10.3892/ol.2010.173

腫瘍間質の遺伝子発現解析を用いた進行上皮性卵巣癌に対する新規バイオマーカーの探索

片岡史夫, 津田浩史, 野村弘行, 千代田達幸, 平沢晃, 冨永英一郎, 鈴木淳, 進伸幸, 青木大輔

日本分子腫瘍マーカー研究会プログラム・講演抄録 30回 52 - 53 2010.9

女性の片頭痛

AOKI DAISUKE

産婦人科治療 101 ( 2 ) 135-139 - 139 2010.8

Amplification of GNAS may be an independent, qualitative, and reproducible biomarker to predict progression-free survival in epithelial ovarian cancer. International journal

Ei-ichiro Tominaga, Hiroshi Tsuda, Tokuzo Arao, Sadako Nishimura, Masashi Takano, Fumio Kataoka, Hiroyuki Nomura, Akira Hirasawa, Daisuke Aoki, Kazuto Nishio

Gynecologic oncology 118 ( 2 ) 160 - 6 2010.8

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

OBJECTIVES: The purpose of this study was to identify genes that predict progression-free survival (PFS) in advanced epithelial ovarian cancer (aEOC) receiving standard therapy. METHODS: We performed microarray analysis on laser microdissected aEOC cells. All cases received staging laparotomy and adjuvant chemotherapy (carboplatin+paclitaxel) as primary therapy. RESULTS: Microarray analysis identified 50 genes differentially expressed between tumors of patients with no evidence of disease (NED) or evidence of disease (ED) (p<0.001). Six genes (13%) were located at 8q24, and 9 genes (19.6%), at 20q11-13. The ratio of selected gene set/analyzed gene set in chromosomes 8 and 20 are significantly higher than that in other chromosome regions (6/606 vs. 32/13656, p=0.01) and (12/383 vs. 32/13656, p=1.3 x 10(-)(16)). We speculate that the abnormal chromosomal distribution is due to genomic alteration and that these genes may play an important role in aEOC and choose GNAS (GNAS complex locus, NM_000516) on 20q13 based on the p value and fold change. Genomic PCR of aEOC cells also showed that amplification of GNAS was significantly correlated with unfavorable PFS (p=0.011). Real-time quantitative RT-PCR analysis of independent samples revealed that high mRNA expression levels of the GNAS genes, located at chromosome 20q13, was significantly unfavorable indicators of progression-free survival (PFS). Finally, GNAS amplification was an independent prognostic factor for PFS. CONCLUSIONS: Our results suggest that GNAS gene amplification may be an independent, qualitative, and reproducible biomarker of PFS in aEOC.

DOI： 10.1016/j.ygyno.2010.03.010

無結紮手術（BiClamp，Ligasure，ハーモニック）－広汎子宮全摘出術におけるBiClamp使用の実際

AOKI DAISUKE

産婦人科の実際 59 ( 8 ) 1195-1200 - 1200 2010.8

A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Reviewed International journal

Satoko Uno, Hitoshi Zembutsu, Akira Hirasawa, Atsushi Takahashi, Michiaki Kubo, Tomoko Akahane, Daisuke Aoki, Naoyuki Kamatani, Koichi Hirata, Yusuke Nakamura

Nature genetics 42 ( 8 ) 707 - 10 2010.8

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

Although the pathogenesis of endometriosis is not well understood, genetic factors have been considered to have critical roles in its etiology. Through a genome-wide association study and a replication study using a total of 1,907 Japanese individuals with endometriosis (cases) and 5,292 controls, we identified a significant association of endometriosis with rs10965235 (P = 5.57 x 10(-12), odds ratio = 1.44), which is located in CDKN2BAS on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA. By fine mapping, the SNP showing the strongest association was located in intron 16 of CDKN2BAS and was implicated in regulating the expression of p15, p16 and p14. A SNP, rs16826658, in the LD block including WNT4 on chromosome 1p36, which is considered to play an important role in the development of the female genital tract, revealed a possible association with endometriosis (P = 1.66 x 10(-6), odds ratio = 1.20). Our findings suggest that these regions are new susceptibility loci for endometriosis.

DOI： 10.1038/ng.612

A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese

Satoko Uno, Hitoshi Zembutsu, Akira Hirasawa, Atsushi Takahashi, Michiaki Kubo, Tomoko Akahane, Daisuke Aoki, Naoyuki Kamatani, Koichi Hirata, Yusuke Nakamura

NATURE GENETICS 42 ( 8 ) 707 - U88 2010.8

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

Although the pathogenesis of endometriosis is not well understood, genetic factors have been considered to have critical roles in its etiology. Through a genome-wide association study and a replication study using a total of 1,907 Japanese individuals with endometriosis (cases) and 5,292 controls, we identified a significant association of endometriosis with rs10965235 (P = 5.57 x 10(-12), odds ratio = 1.44), which is located in CDKN2BAS on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA. By fine mapping, the SNP showing the strongest association was located in intron 16 of CDKN2BAS and was implicated in regulating the expression of p15, p16 and p14. A SNP, rs16826658, in the LD block including WNT4 on chromosome 1p36, which is considered to play an important role in the development of the female genital tract, revealed a possible association with endometriosis (P = 1.66 x 10(-6), odds ratio = 1.20). Our findings suggest that these regions are new susceptibility loci for endometriosis.

DOI： 10.1038/ng.612

Amplification of GNAS may be an independent, qualitative, and reproducible biomarker to predict progression-free survival in epithelial ovarian cancer Reviewed

Ei-ichiro Tominaga, Hiroshi Tsuda, Tokuzo Arao, Sadako Nishimura, Masashi Takano, Fumio Kataoka, Hiroyuki Nomura, Akira Hirasawa, Daisuke Aoki, Kazuto Nishio

GYNECOLOGIC ONCOLOGY 118 ( 2 ) 160 - 166 2010.8

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

Objectives. The purpose of this study was to identify genes that predict progression-free survival (PFS) in advanced epithelial ovarian cancer (aEOC) receiving standard therapy.Methods. We performed microarray analysis on laser microdissected aEOC cells. All cases received staging laparotomy and adjuvant chemotherapy (carboplatin + paclitaxel) as primary therapy.Results. Microarray analysis identified 50 genes differentially expressed between tumors of patients with no evidence of disease (NED) or evidence of disease (ED) (p<0.001). Six genes (13%) were located at 8q24, and 9 genes (19.6%), at 20q11-13. The ratio of selected gene set/analyzed gene set in chromosomes 8 and 20 are significantly higher than that in other chromosome regions (6/606 vs. 32/13656, p 0.01) and (12/383 vs. 32/13656, p = 1.3 x 10(-16)). We speculate that the abnormal chromosomal distribution is due to genomic alteration and that these genes may play an important role in aEOC and choose GNAS (GNAS complex locus, NM__000516) on 20q13 based on the p value and fold change. Genomic PCR of aEOC cells also showed that amplification of GNAS was significantly correlated with unfavorable PFS (p = 0.011). Real-time quantitative RT-PCR analysis of independent samples revealed that high mRNA expression levels of the GNAS genes, located at chromosome 20q13, was significantly unfavorable indicators of progression-free survival (PFS). Finally, GNAS amplification was an independent prognostic factor for PFS.Conclusions. Our results suggest that GNAS gene amplification may be an independent, qualitative, and reproducible biomarker of PFS in aEOC. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ygyno.2010.03.010

Amplification of GNAS may be an independent, qualitative, and reproducible biomarker to predict progression-free survival in epithelial ovarian cancer

Ei-ichiro Tominaga, Hiroshi Tsuda, Tokuzo Arao, Sadako Nishimura, Masashi Takano, Fumio Kataoka, Hiroyuki Nomura, Akira Hirasawa, Daisuke Aoki, Kazuto Nishio

GYNECOLOGIC ONCOLOGY 118 ( 2 ) 160 - 166 2010.8

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

Objectives. The purpose of this study was to identify genes that predict progression-free survival (PFS) in advanced epithelial ovarian cancer (aEOC) receiving standard therapy.
Methods. We performed microarray analysis on laser microdissected aEOC cells. All cases received staging laparotomy and adjuvant chemotherapy (carboplatin + paclitaxel) as primary therapy.
Results. Microarray analysis identified 50 genes differentially expressed between tumors of patients with no evidence of disease (NED) or evidence of disease (ED) (p<0.001). Six genes (13%) were located at 8q24, and 9 genes (19.6%), at 20q11-13. The ratio of selected gene set/analyzed gene set in chromosomes 8 and 20 are significantly higher than that in other chromosome regions (6/606 vs. 32/13656, p 0.01) and (12/383 vs. 32/13656, p = 1.3 x 10(-16)). We speculate that the abnormal chromosomal distribution is due to genomic alteration and that these genes may play an important role in aEOC and choose GNAS (GNAS complex locus, NM__000516) on 20q13 based on the p value and fold change. Genomic PCR of aEOC cells also showed that amplification of GNAS was significantly correlated with unfavorable PFS (p = 0.011). Real-time quantitative RT-PCR analysis of independent samples revealed that high mRNA expression levels of the GNAS genes, located at chromosome 20q13, was significantly unfavorable indicators of progression-free survival (PFS). Finally, GNAS amplification was an independent prognostic factor for PFS.
Conclusions. Our results suggest that GNAS gene amplification may be an independent, qualitative, and reproducible biomarker of PFS in aEOC. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ygyno.2010.03.010

Relationship Between ABCF2 Expression and Response to Chemotherapy or Prognosis in Clear Cell Adenocarcinoma of the Ovary Reviewed

Hiroshi Tsuda, Kiyoshi Ito, Nobuo Yaegashi, Akira Hirasawa, Tamotsu Sudo, Tsunekazu Kita, Yoshito Terai, Junzo Kigawa, Toru Sugiyama, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 20 ( 5 ) 794 - 797 2010.7

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

Objectives: The purpose of this study was to evaluate the association of ABCF2 (adenosine triphosphate-binding cassette superfamily F2) protein expression with response to chemotherapy and prognosis in patients with clear cell adenocarcinoma (CCC) of the ovary.Methods: One hundred sixty-five patients with CCC were studied, and cytoplasmic ABCF2 expression was detected by immunohistochemical staining. All patients underwent platinum-based primary chemotherapy followed by primary surgery.Results: Adenosine triphosphate-binding cassette superfamily F2 expression was detected in 118 (71.5%) of 165 patients and was not related to age or clinical stage. The response rate to chemotherapy in 38 patients with measurable disease was 47.3% (18/38). The response rate tended to be higher in patients without ABCF2 expression than in those with ABCF2 expression; however, this difference was not significant (66.7% vs 34.8%, P = 0.096). There was no significant difference in overall survival between ABCF2-positive and ABCF2-negative cases (median survival time, 1175 vs 1257 days; P = 0.24).Conclusions: Adenosine triphosphate-binding cassette superfamily F2 protein was highly expressed in CCC of the ovary, but expression was not related to age, clinical stage, chemoresponse, or prognosis.

DOI： 10.1111/IGC.0b013e3181a835fc

Relationship between ABCF2 expression and response to chemotherapy or prognosis in clear cell adenocarcinoma of the ovary. International journal

Hiroshi Tsuda, Kiyoshi Ito, Nobuo Yaegashi, Akira Hirasawa, Tamotsu Sudo, Tsunekazu Kita, Yoshito Terai, Junzo Kigawa, Toru Sugiyama, Daisuke Aoki

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 20 ( 5 ) 794 - 7 2010.7

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

OBJECTIVES: The purpose of this study was to evaluate the association of ABCF2 (adenosine triphosphate-binding cassette superfamily F2) protein expression with response to chemotherapy and prognosis in patients with clear cell adenocarcinoma (CCC) of the ovary. METHODS: One hundred sixty-five patients with CCC were studied, and cytoplasmic ABCF2 expression was detected by immunohistochemical staining. All patients underwent platinum-based primary chemotherapy followed by primary surgery. RESULTS: Adenosine triphosphate-binding cassette superfamily F2 expression was detected in 118 (71.5%) of 165 patients and was not related to age or clinical stage. The response rate to chemotherapy in 38 patients with measurable disease was 47.3% (18/38). The response rate tended to be higher in patients without ABCF2 expression than in those with ABCF2 expression; however, this difference was not significant (66.7% vs 34.8%, P = 0.096). There was no significant difference in overall survival between ABCF2-positive and ABCF2-negative cases (median survival time, 1175 vs 1257 days; P = 0.24). CONCLUSIONS: Adenosine triphosphate-binding cassette superfamily F2 protein was highly expressed in CCC of the ovary, but expression was not related to age, clinical stage, chemoresponse, or prognosis.

DOI： 10.1111/IGC.0b013e3181a835fc

Relationship Between ABCF2 Expression and Response to Chemotherapy or Prognosis in Clear Cell Adenocarcinoma of the Ovary

Hiroshi Tsuda, Kiyoshi Ito, Nobuo Yaegashi, Akira Hirasawa, Tamotsu Sudo, Tsunekazu Kita, Yoshito Terai, Junzo Kigawa, Toru Sugiyama, Daisuke Aoki

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 20 ( 5 ) 794 - 797 2010.7

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

Objectives: The purpose of this study was to evaluate the association of ABCF2 (adenosine triphosphate-binding cassette superfamily F2) protein expression with response to chemotherapy and prognosis in patients with clear cell adenocarcinoma (CCC) of the ovary.
Methods: One hundred sixty-five patients with CCC were studied, and cytoplasmic ABCF2 expression was detected by immunohistochemical staining. All patients underwent platinum-based primary chemotherapy followed by primary surgery.
Results: Adenosine triphosphate-binding cassette superfamily F2 expression was detected in 118 (71.5%) of 165 patients and was not related to age or clinical stage. The response rate to chemotherapy in 38 patients with measurable disease was 47.3% (18/38). The response rate tended to be higher in patients without ABCF2 expression than in those with ABCF2 expression; however, this difference was not significant (66.7% vs 34.8%, P = 0.096). There was no significant difference in overall survival between ABCF2-positive and ABCF2-negative cases (median survival time, 1175 vs 1257 days; P = 0.24).
Conclusions: Adenosine triphosphate-binding cassette superfamily F2 protein was highly expressed in CCC of the ovary, but expression was not related to age, clinical stage, chemoresponse, or prognosis.

DOI： 10.1111/IGC.0b013e3181a835fc

家族性乳癌・遺伝性乳癌の現状と課題遺伝相談外来を受診したBRCA1/2遺伝子変異を有する遺伝性乳がん卵巣がん家系の臨床遺伝学的特徴

菅野康吉, 牧島恵子, 友田茉莉, 安藤二郎, 矢崎久妙子, 武田祐子, 平澤晃, 神野浩光, 北川雄光, 和泉秀子, 古賀範子, 木下貴之

日本乳癌学会総会プログラム抄録集 18回 260 - 260 2010.5

月経関連片頭痛に対する呉茱萸湯の周期的投与の試み.

牧田和也, 堀場裕子, 平沢晃, 青木大輔, 吉村泰典

産婦人科漢方研究のあゆみ 27 ( 27 ) 73-75 - 75 2010

ファーマコゲノミクスの臨床応用を目指した簡易迅速な遺伝子多型診断システムの開発.

平沢晃

臨床薬理 41 ( 3 ) 109-110 - 110S 2010

両側卵巣摘出術施行例における骨代謝関連遺伝子多型の探索-性ホルモン代謝関連酵素遺伝子におけるコピー数多型の検索を中心として-

平沢晃, 赤羽智子, 牧田和也, 青木大輔

Osteoporosis Japan 18 ( 3 ) 406-408 - 408 2010

閉経前両側卵巣摘出例における骨密度とFRAXの特徴に関する検討.

堀場裕子, 平沢晃, 牧田和也, 松村聡子, 小川真里子, 岩田卓, 弟子丸亮太, 柳本茂久, 青木大輔

Osteoporosis Japan 18 ( 3 ) 461-465 - 465 2010

ゲノム薬理学の最近の親展とUGT1A1遺伝子多型診断について

AOKI DAISUKE

産婦人科の実際 58 ( 12 ) 2005-2011 - 2011 2009.11

私はこうしている：私の主張週1回のビスフォスフォネート製剤の投与

AOKI DAISUKE

産婦人科治療 99 ( 5 ) 509-511 - 511 2009.11

Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer

Makiko Kawaguchi, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Arisa Kishimi, Seiji Ogawa, Iori Kisu, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 35 ( 5 ) 977 - 982 2009.11

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

Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MST in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MST mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.

DOI： 10.3892/ijo_00000411

Epigenetic DNA hypermethylation: Clinical applications in endometrial cancer (Review) Reviewed

Yuriko Muraki, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

ONCOLOGY REPORTS 22 ( 5 ) 967 - 972 2009.11

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

Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation.

DOI： 10.3892/or_00000523

Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer Reviewed

Makiko Kawaguchi, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Arisa Kishimi, Seiji Ogawa, Iori Kisu, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 35 ( 5 ) 977 - 982 2009.11

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

Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MST in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MST mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.

DOI： 10.3892/ijo_00000411

Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer. International journal

Makiko Kawaguchi, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Arisa Kishimi, Seiji Ogawa, Iori Kisu, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

International journal of oncology 35 ( 5 ) 977 - 82 2009.11

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

Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MSI in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MSI mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.

DOI： 10.3892/ijo_00000411

Epigenetic DNA hypermethylation: Clinical applications in endometrial cancer (Review)

Yuriko Muraki, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

ONCOLOGY REPORTS 22 ( 5 ) 967 - 972 2009.11

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

Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation.

DOI： 10.3892/or_00000523

Epigenetic DNA hypermethylation: clinical applications in endometrial cancer (Review). International journal

Yuriko Muraki, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Oncology reports 22 ( 5 ) 967 - 72 2009.11

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

Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1 expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation.

DOI： 10.3892/or_00000523

ファーマコゲノミクスの現状と課題ファーマコゲノミクスの臨床応用を目指した簡易迅速な遺伝子多型診断システムの開発

平沢晃, 松村聡子, 鶴田智彦, 赤羽智子, 野村弘行, 青木大輔, 谷川原祐介, 杉田哲佳, 緒方是嗣, 花房信博

臨床薬理 40 ( Suppl. ) S138 - S138 2009.11

当科更年期外来受診患者における動脈硬化性疾患の危険因子に関する検討

柳本茂久, 牧田和也, 堀場裕子, 平沢晃, 田島博人, 金田佳史, 伊藤仁彦, 高松潔, 青木大輔

日本更年期医学会雑誌 17 ( Suppl. ) 113 - 113 2009.10

子宮傍結合織炎

AOKI DAISUKE

日本臨床（子宮疾患・子宮内膜症の臨床－基礎・臨床研究のアップデート） 67 ( 増刊号5 ) 327-330 2009.8

イリノテカン

AOKI DAISUKE

小児科 50 ( 7 ) 1227-1232 2009.6

中高年女性と片頭痛

AOKI DAISUKE

産婦人科治療 98 ( 6 ) 971-975 - 975 2009.6

Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer. International journal

Makiko Kawaguchi, Megumi Yanokura, Kouji Banno, Yusuke Kobayashi, Yoshiko Kuwabara, Maya Kobayashi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

International journal of oncology 34 ( 6 ) 1541 - 7 2009.6

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

Point mutations of KRAS and BRAF genes are thought to be important in carcinogenesis of colon cancer. In particular, gene instability caused by decreased expression of the hMLH1 gene, a DNA mismatch repair (MMR) gene, may be linked to the activating BRAF V600E point mutation in sporadic colon cancer. However, a consensus has not been established regarding the correlation between point mutations of KRAS or BRAF and carcinogenesis in patients with endometrial cancer, which is closely related to colon cancer. Therefore, we analyzed aberrant hypermethylation of the hMLH1 gene, microsatellite instability (MSI), and point mutations of KRAS and BRAF in 44 samples of sporadic endo-metrial cancer, with the aim of examining the mechanism of carcinogenesis in patients with endometrial cancer. Aberrant hMLH1 hypermethylation was found in 17 of the 44 cases (38.6%) and showed a significant positive correlation with MSI (p=0.02). This suggests that an abnormal MMR mechanism plays an important role in carcinogenesis of sporadic endometrial cancer. Point mutation of KRAS was found in 6 of the 44 cases (13.6%), but no BRAF V600E mutation was detected. These data suggest that the BRAF V600E mutation is not the target gene for abnormal MMR in carcinogenesis in patients with sporadic endometrial cancer, unlike in colon cancer. This is supported by the relatively few previous reports indicating a correlation between endometrial cancer and the BRAF V600E mutation. Identification of new candidates for the target gene for abnormal MMR in endometrial cancer requires further work.

DOI： 10.3892/ijo_00000283

Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer

Makiko Kawaguchi, Megumi Yanokura, Kouji Banno, Yusuke Kobayashi, Yoshiko Kuwabara, Maya Kobayashi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Datsuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 34 ( 6 ) 1541 - 1547 2009.6

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

Point mutations of KRAS and BRAF genes are thought to be important in carcinogenesis of colon cancer. In particular, gene instability caused by decreased expression of the hMLH1 gene, a DNA mismatch repair (MMR) gene, may be linked to the activating BRAF V600E point mutation in sporadic colon cancer. However, a consensus has not been established regarding the correlation between point mutations of KRAS or BRAF and carcinogenesis in patients with endometrial cancer, which is closely related to colon cancer. Therefore, we analyzed aberrant hypermethylation of the hMLH1 gene, microsatellite instability (MSI), and point mutations of KRAS and BRAF in 44 samples of sporadic endometrial cancer, with the aim of examining the mechanism of carcinogenesis in patients with endometrial cancer. Aberrant hMLH1 hypermethylation was found in 17 of the 44 cases (38.6%) and showed a significant positive correlation with MSI (p=0.02). This suggests that an abnormal MMR mechanism plays an important role in carcinogenesis of sporadic endometrial cancer. Point mutation of KRAS was found in 6 of the 44 cases (13.6%), but no BRAF V600E mutation was detected. These data suggest that the BRAF V600E mutation is not the target gene for abnormal MMR in carcinogenesis in patients with sporadic endometrial cancer, unlike in colon cancer. This is supported by the relatively few previous reports indicating a correlation between endometrial cancer and the BRAF V600E mutation. Identification of new candidates for the target gene for abnormal MMR in endometrial cancer requires further work.

DOI： 10.3892/ijo_00000283

Endometrial cancer as HNPCC associated tumor

Kouji Banno, Yusuke Kobayashi, Megumi Yanokura, Arisa Kishimi, Seiji Ogawa, Iori Kisu, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

家族性腫瘍 9 ( 2 ) 64-68 2009.5

Endometrial Cancer as a Familial Tumor: Pathology and Molecular Carcinogenesis (Review) Reviewed

Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

CURRENT GENOMICS 10 ( 2 ) 127 - 132 2009.4

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

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.

DOI： 10.2174/138920209787847069

結合型エストロゲン製剤を用いたホルモン補充療法の腰椎骨密度に対する長期的な効果の検討～当科更年期外来における継続投与10年例の結果から～

AOKI DAISUKE

Osteoporosis Japan 17 ( 2 ) 329-330 - 330 2009.4

Endometrial cancer as a familial tumor: pathology and molecular carcinogenesis (review). International journal

Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Current genomics 10 ( 2 ) 127 - 32 2009.4

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

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.

DOI： 10.2174/138920209787847069

当科更年期外来における更年期不定愁訴に対する漢方薬の使用状況について-8年前の調査結果との比較検討-.

牧田和也, 堀場裕子, 平沢晃, 岩田卓, 片岡史夫, 冨永英一郎, 堀口文, 青木大輔, 吉村泰典

産婦人科漢方研究のあゆみ 26 ( 26 ) 44-47 - 47 2009

更年期外来受診患者における動脈硬化性疾患の危険因子に関する検討.

柳本茂久, 牧田和也, 堀場裕子, 平沢晃, 高松潔, 堀口文, 青木大輔

日本更年期医学会雑誌 17 ( 2 ) 171-178 - 178 2009

Endometrial cancer as a familial tumor: Pathology and molecular carcinogenesis (review)

Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

Current Genomics 10 ( 2 ) 127 - 132 2009

Language：English

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor. © 2009 Bentham Science Publishers Ltd.

DOI： 10.2174/138920209787847069

閉経後骨粗鬆症に対する予防的治療を行う際の薬剤選択に関する再検証.

牧田和也, 平沢晃, 堀場裕子, 弟子丸亮太, 柳本茂久, 堀口文, 青木大輔

Osteoporosis Japan 17 ( 3 ) 447-449 - 449 2009

子宮体がん例におけるFRAXを用いた骨折リスク評価.

平沢晃, 牧田和也, 堀場裕子, 弟子丸亮太, 柳本茂久, 阪埜浩司, 進伸幸, 青木大輔

Osteoporosis Japan 17 ( 3 ) 492-495 - 495 2009

当科更年期外来における塩酸ラロキシフェン治療の現況-子宮体癌術後症例を中心に-.

牧田和也, 堀場裕子, 岩田卓, 平沢晃, 片岡史夫, 富永英一郎, 堀口文, 青木大輔

SERM 7 106-107 2009

Can ABCF2 protein expression predict the prognosis of uterine cancer? Reviewed

S. Nishimura, H. Tsuda, Y. Miyagi, A. Hirasawa, A. Suzuki, F. Kataoka, H. Nomura, T. Chiyoda, K. Banno, T. Fujii, N. Susumu, D. Aoki

BRITISH JOURNAL OF CANCER 99 ( 10 ) 1651 - 1655 2008.11

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

Uterine cervical and endometrial cancers are common malignant solid neoplasms for which there are no useful prognostic markers. In this study, we evaluate the relationship between ATP-binding cassette superfamily F2 (ABCF2) expression and clinical factors including clinical stage, histologic type, grade and prognosis in uterine cervical and endometrial cancer. Two hundred and sixty seven cervical and 103 endometrial cancers were studied. ATP-binding cassette superfamily F2 cytoplasmic expression was detected by immunohistochemical staining and scored as positive or negative. Among cervical cancer cases, 149 (55.8%) expressed ABCF2. The overall survival was longer in ABCF2-negative than ABCF2-positive cases (P=0.0069). Statistically significant prognostic factors for survival were ABCF2 positivity ( risk ratio (rr) = 1.437), old age (rr = 1.550) and advanced stage (rr = 2.577). ATP-binding cassette superfamily F2 positivity was an independent prognostic factor by multivariate proportional hazard test (P=0.0002). Among endometrial cancer cases, 72 (69.9%) were cytoplasmic ABCF2 positive. However, there was no significant relationship between ABCF2 expression and age, clinical stage, histologic type, histologic grade, oestrogen receptor status or prognosis. ATP-binding cassette superfamily F2 expression may be a useful prognostic marker in cervical but not endometrial cancer. The role of ABCF2 protein may differ depending on the type of cancer.

DOI： 10.1038/sj.bjc.6604734

Can ABCF2 protein expression predict the prognosis of uterine cancer?

S. Nishimura, H. Tsuda, Y. Miyagi, A. Hirasawa, A. Suzuki, F. Kataoka, H. Nomura, T. Chiyoda, K. Banno, T. Fujii, N. Susumu, D. Aoki

BRITISH JOURNAL OF CANCER 99 ( 10 ) 1651 - 1655 2008.11

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

Uterine cervical and endometrial cancers are common malignant solid neoplasms for which there are no useful prognostic markers. In this study, we evaluate the relationship between ATP-binding cassette superfamily F2 (ABCF2) expression and clinical factors including clinical stage, histologic type, grade and prognosis in uterine cervical and endometrial cancer. Two hundred and sixty seven cervical and 103 endometrial cancers were studied. ATP-binding cassette superfamily F2 cytoplasmic expression was detected by immunohistochemical staining and scored as positive or negative. Among cervical cancer cases, 149 (55.8%) expressed ABCF2. The overall survival was longer in ABCF2-negative than ABCF2-positive cases (P=0.0069). Statistically significant prognostic factors for survival were ABCF2 positivity ( risk ratio (rr) = 1.437), old age (rr = 1.550) and advanced stage (rr = 2.577). ATP-binding cassette superfamily F2 positivity was an independent prognostic factor by multivariate proportional hazard test (P=0.0002). Among endometrial cancer cases, 72 (69.9%) were cytoplasmic ABCF2 positive. However, there was no significant relationship between ABCF2 expression and age, clinical stage, histologic type, histologic grade, oestrogen receptor status or prognosis. ATP-binding cassette superfamily F2 expression may be a useful prognostic marker in cervical but not endometrial cancer. The role of ABCF2 protein may differ depending on the type of cancer.

DOI： 10.1038/sj.bjc.6604734

子宮がん患者へのインフォームドコンセント（IC）

AOKI DAISUKE

臨床腫瘍プラクティス 4 ( 4 ) 313-319 - 319 2008.11

Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer. Reviewed International journal

Kokichi Sugano, Seigo Nakamura, Jiro Ando, Shin Takayama, Hiroyuki Kamata, Isao Sekiguchi, Megumi Ubukata, Tetsuro Kodama, Masami Arai, Fujio Kasumi, Yasuo Hirai, Tadashi Ikeda, Hiromitsu Jinno, Masaki Kitajima, Daisuke Aoki, Akira Hirasawa, Yuko Takeda, Kumiko Yazaki, Takashi Fukutomi, Takayuki Kinoshita, Ryuichiro Tsunematsu, Teruhiko Yoshida, Masako Izumi, Shino Umezawa, Hiroshi Yagata, Hiroko Komatsu, Naoko Arimori, Noriko Matoba, Nobuhisa Gondo, Shiro Yokoyama, Yoshio Miki

Cancer science 99 ( 10 ) 1967 - 76 2008.10

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

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165-7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25-6.64).

DOI： 10.1111/j.1349-7006.2008.00944.x

Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

Kokichi Sugano, Seigo Nakamura, Jiro Ando, Shin Takayama, Hiroyuki Kamata, Isao Sekiguchi, Megumi Ubukata, Tetsuro Kodama, Masami Arai, Fujio Kasumi, Yasuo Hirai, Tadashi Ikeda, Hiromitsu Jinno, Masaki Kitajima, Daisuke Aoki, Akira Hirasawa, Yuko Takeda, Kumiko Yazaki, Takashi Fukutomi, Takayuki Kinoshita, Ryuichiro Tsunematsu, Teruhiko Yoshida, Masako Izumi, Shino Umezawa, Hiroshi Yagata, Hiroko Komatsu, Naoko Arimori, Noriko Matoba, Nobuhisa Gondo, Shiro Yokoyama, Yoshio Miki

CANCER SCIENCE 99 ( 10 ) 1967 - 1976 2008.10

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

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165-7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25-6.64). (Cancer Sci 2008; 99: 1967-1976).

DOI： 10.1111/j.1349-7006.2008.00944.x

子宮体がん術後患者における骨密度の特徴に関する検討.

平沢晃, 牧田和也, 堀場裕子, 弟子丸亮太, 柳本茂久, 野村弘行, 片岡史夫, 岩田卓, 冨永英一郎, 阪埜浩司, 進伸幸, 堀口文, 青木大輔

Osteoporosis Japan 16 ( 3 ) 429-431 2008

子宮体がん術後患者における骨密度の特徴に関する検討

HIRASAWA AKIRA

Osteoporosis Japan 16 ( 3 ) 429-431 - 431 2008

当科更年期外来にて診断し得た骨粗鬆症/骨量減少症における低エストロゲン血症以外の危険因子の検討

HIRASAWA AKIRA

Osteoporosis Japan 16 ( 2 ) 308 2008

更年期外来でのアンケート調査結果からみた本邦中高年婦人の「night sweats」の実態とホルモン療法の有用性に関する一考察.

牧田和也, 柳本茂久, 張簡珮怡, 平沢晃, 冨永英一郎, 高松潔, 堀口文, 青木大輔

日本更年期医学会雑誌 16 ( 2 ) 246-251 - 251 2008

季節による漢方製剤の切り替えが片頭痛発作の軽減に有効であった1例

HIRASAWA AKIRA

産婦人科漢方研究のあゆみ 25 115-118 2008

季節による漢方製剤の切り替えが片頭痛発作の軽減に有効であった1例.

牧田和也, 平沢晃, 冨永英一郎, 堀口文, 青木大輔, 吉村泰典

産婦人科漢方研究のあゆみ 25 ( 25 ) 115-118 - 118 2008

当科更年期外来にて診断し得た骨粗鬆症/骨量減少症における低エストロゲン血症以外の危険因子の検討.

牧田和也, 冨永英一郎, 平沢晃, 堀口文, 青木大輔

Osteoporosis Japan 16 ( 2 ) 308 - 308 2008

当科更年期外来受診者におけるアレンドロネート製剤のweekly投与への切り替えの現状.

牧田和也, 平沢晃, 冨永英一郎, 堀口文, 青木大輔

Osteoporosis Japan 16 ( 3 ) 268-269 - 469 2008

Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes

Kouji Banno, Megumi Yanokura, Makiko Kawaguchi, Yoshiko Kuwabara, Jyunko Akiyoshi, Yusuke Kobayashi, Takashi Iwata, Akira Hirasawa, Takuma Fujii, Nobuyuki Susumu, Kastumi Tsukazaki, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 31 ( 4 ) 713 - 720 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes Reviewed

Kouji Banno, Megumi Yanokura, Makiko Kawaguchi, Yoshiko Kuwabara, Jyunko Akiyoshi, Yusuke Kobayashi, Takashi Iwata, Akira Hirasawa, Takuma Fujii, Nobuyuki Susumu, Kastumi Tsukazaki, Daisuke Aoki

INTERNATIONAL JOURNAL OF ONCOLOGY 31 ( 4 ) 713 - 720 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes. International journal

Kouji Banno, Megumi Yanokura, Makiko Kawaguchi, Yoshiko Kuwabara, Jyunko Akiyoshi, Yusuke Kobayashi, Takashi Iwata, Akira Hirasawa, Takuma Fujii, Nobuyuki Susumu, Kastumi Tsukazaki, Daisuke Aoki

International journal of oncology 31 ( 4 ) 713 - 20 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

進行子宮体癌の再発・予後因子としてのCOX-2とCD8陽性リンパ球についての検討

末盛友浩, 進伸幸, 鶴田智彦, 市川義一, 野村弘行, 片岡史夫, 平澤晃, 冨永英一郎, 阪埜浩司, 鈴木淳, 青木大輔

日本癌治療学会誌 42 ( 2 ) 508 - 508 2007.9

ヒトモノクローナル抗体HMMC-1の子宮体癌細胞に対する増殖抑制効果の検討

笈川文子, 鈴木淳, 冨永英一郎, 末盛友浩, 市川義一, 野村弘行, 片岡史夫, 平澤晃, 進伸幸, 青木大輔

日本臨床細胞学会雑誌 46 ( Suppl.2 ) 448 - 448 2007.9

卵巣明細胞腺癌におけるシアリダーゼ発現の多寡が腹膜播種形成に及ぼす影響の検討

AOKI DAISUKE

日本分子腫瘍マーカー研究会誌 22 39429 - 13 2007.4

卵巣癌の各組織型特異的バイオマーカーに基づく診断用マイクロアレイDNAチップ作成

鈴木淳, 杉田哲佳, 東口敦史, 末盛友浩, 市川義一, 野村弘行, 平澤晃, 玉田裕, 進伸幸, 佐藤孝明, 青木大輔, 吉村泰典

日本産科婦人科学会雑誌 59 ( 2 ) 409 - 409 2007.2

Relationship of aberrant DNA hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer Reviewed

Megumi Yanokura, Kouji Banno, Makiko Kawaguchi, Nobumaru Hirao, Akira Hirasawa, Nobuyuki Susumu, Katsumi Tsukazaki, Daisuke Aoki

ONCOLOGY REPORTS 17 ( 1 ) 41 - 48 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

The relationship of aberrant DNA hypermethylation of cell cycle checkpoint genes with the sensitivity of cancer cells to anticancer drugs is a question of current interest. In this study, we investigated the relationship between aberrant hypermethylation of the CHFR (checkpoint with forkhead-associated and ring finger) mitotic checkpoint gene and sensitivity to taxanes in endometrial cancer. Methylation-specific PCR (MSP) indicated aberrant hypermethylation of CHFR in 12.0% (6/50) of endometrial cancer specimens, and suggested that aberrant hypermethylation is significantly more frequent in poorly differentiated adenocarcinoma (G3) (p < 0.05). Of six culture cell lines, SNG-II and HEC108 cells showed aberrant hypermethylation and reduced expression of CHFR. These cells had high sensitivity to taxanes but became resistant after demethylation. Cancer specimens with aberrant hypermethylation of CHFR also exhibited high sensitivity to taxanes. To our knowledge, this study is the first to examine aberrant hypermethylation of CHFR in endometrial cancer, and our results suggest that the methylation status of CHFR may be a new molecular index that will allow design of personalized treatment in endometrial cancer. This may be particularly important in poorly differentiated adenocarcinoma (G3), which is known to have a poor prognosis.

Relationship of aberrant DNA hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer

Megumi Yanokura, Kouji Banno, Makiko Kawaguchi, Nobumaru Hirao, Akira Hirasawa, Nobuyuki Susumu, Katsumi Tsukazaki, Daisuke Aoki

ONCOLOGY REPORTS 17 ( 1 ) 41 - 48 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

The relationship of aberrant DNA hypermethylation of cell cycle checkpoint genes with the sensitivity of cancer cells to anticancer drugs is a question of current interest. In this study, we investigated the relationship between aberrant hypermethylation of the CHFR (checkpoint with forkhead-associated and ring finger) mitotic checkpoint gene and sensitivity to taxanes in endometrial cancer. Methylation-specific PCR (MSP) indicated aberrant hypermethylation of CHFR in 12.0% (6/50) of endometrial cancer specimens, and suggested that aberrant hypermethylation is significantly more frequent in poorly differentiated adenocarcinoma (G3) (p < 0.05). Of six culture cell lines, SNG-II and HEC108 cells showed aberrant hypermethylation and reduced expression of CHFR. These cells had high sensitivity to taxanes but became resistant after demethylation. Cancer specimens with aberrant hypermethylation of CHFR also exhibited high sensitivity to taxanes. To our knowledge, this study is the first to examine aberrant hypermethylation of CHFR in endometrial cancer, and our results suggest that the methylation status of CHFR may be a new molecular index that will allow design of personalized treatment in endometrial cancer. This may be particularly important in poorly differentiated adenocarcinoma (G3), which is known to have a poor prognosis.

Relationship of aberrant DNA hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer. International journal

Megumi Yanokura, Kouji Banno, Makiko Kawaguchi, Nobumaru Hirao, Akira Hirasawa, Nobuyuki Susumu, Katsumi Tsukazaki, Daisuke Aoki

Oncology reports 17 ( 1 ) 41 - 8 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

The relationship of aberrant DNA hypermethylation of cell cycle checkpoint genes with the sensitivity of cancer cells to anticancer drugs is a question of current interest. In this study, we investigated the relationship between aberrant hypermethylation of the CHFR (checkpoint with forkhead-associated and ring finger) mitotic checkpoint gene and sensitivity to taxanes in endometrial cancer. Methylation-specific PCR (MSP) indicated aberrant hypermethylation of CHFR in 12.0% (6/50) of endometrial cancer specimens, and suggested that aberrant hypermethylation is significantly more frequent in poorly differentiated adenocarcinoma (G3) (p<0.05). Of six culture cell lines, SNG-II and HEC108 cells showed aberrant hypermethylation and reduced expression of CHFR. These cells had high sensitivity to taxanes but became resistant after demethylation. Cancer specimens with aberrant hypermethylation of CHFR also exhibited high sensitivity to taxanes. To our knowledge, this study is the first to examine aberrant hypermethylation of CHFR in endometrial cancer, and our results suggest that the methylation status of CHFR may be a new molecular index that will allow design of personalized treatment in endometrial cancer. This may be particularly important in poorly differentiated adenocarcinoma (G3), which is known to have a poor prognosis.

家族内癌集積性を有する子宮体癌症例におけるMMR遺伝子の生殖細胞変異解析

HIRASAWA AKIRA

家族性腫瘍 7 ( 1 ) 15-18 - 18 2007

妊娠に伴い増悪した片頭痛に対して呉茱萸湯が著効した１例―妊娠期間中の片頭痛治療に関する考察も含めて―

HIRASAWA AKIRA

産婦人科漢方研究のあゆみ 24 ( 24 ) 98-101 - 101 2007

当院更年期外来にて診断された閉経後骨粗鬆症/骨量減少症における血清脂質動態の検討

HIRASAWA AKIRA

Osteoporosis Japan 15 ( 2 ) 158 2007

骨粗鬆症治療薬の服薬コンプライアンス向上に必要な要因の検討

HIRASAWA AKIRA

Osteoporosis Japan 15 ( 3 ) 142-144 - 486 2007

明細胞腺癌

AOKI DAISUKE

産婦人科の実際 55 ( 13 ) 2185-2193 2006.12

Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer. Reviewed International journal

Kouji Banno, Megumi Yanokura, Nobuyuki Susumu, Makiko Kawaguchi, Nobumaru Hirao, Akira Hirasawa, Katsumi Tsukazaki, Daisuke Aoki

Oncology reports 16 ( 6 ) 1189 - 96 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Epigenetic abnormalities including the aberrant DNA hypermethylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis. To identify the genes associated with aberrant DNA hypermethylation in endometrial carcinogenesis, we studied the hypermethylation of the promoter regions of five genes: hMLH1, APC, E-cadherin, RAR-beta and p16. The frequencies of aberrant hypermethylation were 40.4% (21/52) in hMLH1, 22% (11/50) in APC, 14% (7/50) in E-cadherin, and 2.3% (1/44) in RAR-beta in endometrial cancer specimens. No aberrant DNA methylation was found in p16. In atypical endometrial hyperplasia, the frequencies of aberrant methylation were 14.3% (2/14) in hMLH1 and 7.3% (1/14) in APC, whereas normal endometrial cells showed no aberrant hypermethylation of any of the five genes. The high frequencies of the aberrant DNA hypermethylation of hMLH1, APC and E-cadherin suggest that the methylation of the DNA mismatch repair and Wnt signal-related genes may be associated with endometrial carcinogenesis.

Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer

Kouji Banno, Megumi Yanokura, Nobuyuki Susumu, Makiko Kawaguchi, Nobumaru Hirao, Akira Hirasawa, Katsumi Tsukazaki, Daisuke Aoki

ONCOLOGY REPORTS 16 ( 6 ) 1189 - 1196 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Epigenetic abnormalities including the aberrant DNA hypermethylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis. To identify the genes associated with aberrant DNA hypermethylation in endometrial carcinogenesis, we studied the. hypermethylation of the promoter regions of five genes: hMLH1, APC, E-cadherin, RAR-beta and p16. The frequencies of aberrant hypermethylation were 40.4% (21/52) in hMLH1, 22% (11/50) in APC, 14% (7/50) in E-cadherin, and 2.3% (1/44) in RAR-beta in endometrial cancer specimens. No aberrant DNA methylation was found in p16. In atypical endometrial hyperplasia, the frequencies of aberrant methylation were 14.3% (2/14) in hMLH1 and 7.3% (1/14) in APC, whereas normal endometrial cells showed no aberrant hypermethylation of any of the five genes. The high frequencies of the aberrant DNA hypermethylation of hMLH1, APC and E-cadherin suggest that the methylation of the DNA mismatch repair and Wnt signal-related genes may be associated with endometrial carcinogenesis.

Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer Reviewed

Kouji Banno, Megumi Yanokura, Nobuyuki Susumu, Makiko Kawaguchi, Nobumaru Hirao, Akira Hirasawa, Katsumi Tsukazaki, Daisuke Aoki

ONCOLOGY REPORTS 16 ( 6 ) 1189 - 1196 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Epigenetic abnormalities including the aberrant DNA hypermethylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis. To identify the genes associated with aberrant DNA hypermethylation in endometrial carcinogenesis, we studied the. hypermethylation of the promoter regions of five genes: hMLH1, APC, E-cadherin, RAR-beta and p16. The frequencies of aberrant hypermethylation were 40.4% (21/52) in hMLH1, 22% (11/50) in APC, 14% (7/50) in E-cadherin, and 2.3% (1/44) in RAR-beta in endometrial cancer specimens. No aberrant DNA methylation was found in p16. In atypical endometrial hyperplasia, the frequencies of aberrant methylation were 14.3% (2/14) in hMLH1 and 7.3% (1/14) in APC, whereas normal endometrial cells showed no aberrant hypermethylation of any of the five genes. The high frequencies of the aberrant DNA hypermethylation of hMLH1, APC and E-cadherin suggest that the methylation of the DNA mismatch repair and Wnt signal-related genes may be associated with endometrial carcinogenesis.

卵巣明細胞腺癌におけるシアリダーゼ発現の多寡が腹膜播種形成に及ぼす影響の検討

野村弘行, 玉田裕, 鈴木淳, 平沢晃, 進伸幸, 宮城妙子, 入村達郎, 青木大輔

日本分子腫瘍マーカー研究会プログラム・講演抄録 26回 28 - 29 2006.9

子宮体癌における腫瘍マーカーの意義

AOKI DAISUKE

産婦人科の実際 55 ( 5 ) 753-762 - 762 2006.5

コルポスコピー、コルポ下狙い生検

AOKI DAISUKE

臨床婦人科産科 60 ( 4 ) 369-375 - 375 2006.4

Clinicopathologic manifestations of early-onset endometrial cancer in Japanese women with a familial predisposition to cancer. International journal

Wataru Yamagami, Nobuyuki Susumu, Kouji Banno, Takeshi Hirao, Fumio Kataoka, Akira Hirasawa, Nao Suzuki, Daisuke Aoki, Shiro Nozawa

The journal of obstetrics and gynaecology research 31 ( 5 ) 444 - 51 2005.10

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

AIM: The number of patients under 40 years of age with early-onset endometrial cancer is on the rise in Japan. Preservation of fertility in younger patients is a critical issue. In order to examine the clinical and pathological characteristics of these patients, cases of early-onset endometrial cancer at a single hospital were analyzed. METHODS: Seventy-four patients were diagnosed with endometrial cancer before age 40 and included in this study after obtaining informed consent. RESULTS: The clinical characteristics included a significantly higher prevalence of complications such as nulligravidity and nulliparity (P < 0.001). Pathologically, well-differentiated endometrial carcinoma was significantly more frequent (P = 0.011). The 5-year survival rate was high (98.7%). In regards to the relationship between clinicopathological features and grade of differentiation, the prevalence of G2 and G3 carcinoma was not significantly lower (P = 0.24) in patients with obesity. Although the frequency of G2 and G3 carcinoma was significantly higher in patients with a family history of cancer (P = 0.02), their 5-year survival rate was not significantly lower (100%). CONCLUSION: This study found that these two types of early-onset endometrial cancer are clinicopathologically different. In patients with a family history of cancer, their body mass index was lower, and the frequency of G2 and G3 carcinoma was significantly higher, but their 5-year disease-free survival rate was not significantly lower.

DOI： 10.1111/j.1447-0756.2005.00318.x

実地臨床応用が期待される新たな腫瘍マーカー−バイオマーカーとしてのゲノム変化を中心に−

AOKI DAISUKE

臨床婦人科産科 59 ( 10 ) 1383-1387 - 1387 2005.10

[Diagnostic significance of tumor markers for gynecologic malignancies].

Daisuke Aoki, Akira Hirasawa, Nobuyuki Susumu

Gan to kagaku ryoho. Cancer & chemotherapy 32 ( 3 ) 411 - 6 2005.3

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

Gynecologic malignancies include ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms. With ovarian tumors, due to their location within the abdominal cavity, it is difficult to make a preoperative pathological diagnosis of cancer without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA 125, in addition to diagnostic imaging are useful in the diagnosis of ovarian cancer. SCC antigen, a marker for squamous cell carcinoma, is clinically useful in the management of advanced cervical cancer. At present, there are no useful tumor markers for endometrial cancer that exhibit both high sensitivity and specificity, although CA 125 is often used in clinical practice. Finally, human chorionic gonadotropin (hCG) serves as an ideal tumor marker for trophoblastic disease; however, the incidence of trophoblastic neoplasms has decreased dramatically with the incorporation of strict clinical management of post-molar disease as well as with the overall decrease in the number of pregnancies.

婦人科腫瘍

AOKI DAISUKE

癌と化学療法 32 ( 33 ) 411-416 2005.3

Diagnostic significance of tumor markers for gynecologic malignancies

Aoki Daisuke, Hirasawa Akira, Susumu Nobuyuki

Gan to kagaku ryoho. Cancer & chemotherapy 32 ( 3 ) 411 - 416 2005.3

Language：English

<p>Gynecologic malignancies include ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms. With ovarian tumors, due to their location within the abdominal cavity, it is difficult to make a preoperative pathological diagnosis of cancer without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA 125, in addition to diagnostic imaging are useful in the diagnosis of ovarian cancer. SCC antigen, a marker for squamous cell carcinoma, is clinically useful in the management of advanced cervical cancer. At present, there are no useful tumor markers for endometrial cancer that exhibit both high sensitivity and specificity, although CA 125 is often used in clinical practice. Finally, human chorionic gonadotropin (hCG) serves as an ideal tumor marker for trophoblastic disease; however, the incidence of trophoblastic neoplasms has decreased dramatically with the incorporation of strict clinical management of post-molar disease as well as with the overall decrease in the number of pregnancies.</p>

子宮体癌手術症例における傍大動脈リンパ節廓清の検討.

HIRASAWA AKIRA

日本産科婦人科学会東京地方部会会誌 54 ( 2 ) 219-222 - 222 2005

Clinicopathologic manifestations of early-onset endometrial cancer in Japanese women with a familial predisposition to cancer

W Yamagami, N Susumu, K Banno, T Hirao, F Kataoka, A Hirasawa, N Suzuki, D Aoki, S Nozawa

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 31 ( 5 ) 444 - 451 2005

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

Aim: The number of patients under 40 years of age with early-onset endometrial cancer is on the rise in Japan. Preservation of fertility in younger patients is a critical issue. In order to examine the clinical and pathological characteristics of these patients, cases of early-onset endometrial cancer at a single hospital were analyzed.
Methods: Seventy-four patients were diagnosed with endometrial cancer before age 40 and included in this study after obtaining informed consent.
Results: The clinical characteristics included a significantly higher prevalence of complications such as nulligravidity and nulliparity (P < 0.001). Pathologically, well-differentiated endometrial carcinoma was significantly more frequent (P = 0.011). The 5-year survival rate was high (98.7%). In regards to the relationship between clinicopathological features and grade of differentiation, the prevalence of G2 and G3 carcinoma was not significantly lower (P = 0.24) in patients with obesity. Although the frequency of G2 and G3 carcinoma was significantly higher in patients with a family history of cancer (P = 0.02), their 5-year survival rate was not significantly lower (100%).
Conclusion: This study found that these two types of early-onset endometrial cancer are clinicopathologically different. In patients with a family history of cancer, their body mass index was lower, and the frequency of G2 and G3 carcinoma was significantly higher, but their 5-year disease-free survival rate was not significantly lower.

DOI： 10.1111/j.1447-0756.2005.00318.x

Clinicopathologic manifestations of early-onset endometrial cancer in Japanese women with a familial predisposition to cancer Reviewed

W Yamagami, N Susumu, K Banno, T Hirao, F Kataoka, A Hirasawa, N Suzuki, D Aoki, S Nozawa

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 31 ( 5 ) 444 - 451 2005

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

Aim: The number of patients under 40 years of age with early-onset endometrial cancer is on the rise in Japan. Preservation of fertility in younger patients is a critical issue. In order to examine the clinical and pathological characteristics of these patients, cases of early-onset endometrial cancer at a single hospital were analyzed.
Methods: Seventy-four patients were diagnosed with endometrial cancer before age 40 and included in this study after obtaining informed consent.
Results: The clinical characteristics included a significantly higher prevalence of complications such as nulligravidity and nulliparity (P < 0.001). Pathologically, well-differentiated endometrial carcinoma was significantly more frequent (P = 0.011). The 5-year survival rate was high (98.7%). In regards to the relationship between clinicopathological features and grade of differentiation, the prevalence of G2 and G3 carcinoma was not significantly lower (P = 0.24) in patients with obesity. Although the frequency of G2 and G3 carcinoma was significantly higher in patients with a family history of cancer (P = 0.02), their 5-year survival rate was not significantly lower (100%).
Conclusion: This study found that these two types of early-onset endometrial cancer are clinicopathologically different. In patients with a family history of cancer, their body mass index was lower, and the frequency of G2 and G3 carcinoma was significantly higher, but their 5-year disease-free survival rate was not significantly lower.

DOI： 10.1111/j.1447-0756.2005.00318.x

Involvement of overexpressed wild-type BRAF in the growth of malignant melanoma cell lines. Reviewed International journal

Hideaki Tanami, Issei Imoto, Akira Hirasawa, Yasuhiro Yuki, Itaru Sonoda, Jun Inoue, Kohichiro Yasui, Akiko Misawa-Furihata, Yutaka Kawakami, Johji Inazawa

Oncogene 23 ( 54 ) 8796 - 804 2004.11

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

Comparative genomic hybridization (CGH) using 40 cell lines derived from malignant melanomas (MMs) revealed frequent amplification at 7q33-q34 containing BRAF gene, which often is mutated in MM. We found this gene to be amplified to a remarkable degree in the MM cell lines that exhibited high-level gains at 7q33-q34 in CGH. Among 40 cell lines, the eight lines that revealed neither BRAF nor NRAS mutations showed even higher levels of BRAF mRNA expression than the 32 mutated lines, although DNA amplification at 7q33-q34 was not detected in every lines overexpressing BRAF. MM cells that carried wild-type BRAF and NRAS showed constitutive overexpression of B-Raf protein and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), even after serum starvation. Not only downregulation of the endogenously overexpressed wild-type B-Raf by antisense oligonucleotide but also a treatment with an inhibitor of mitogen-activated protein kinase kinase (MAPKK, MEK) reduced phosphorylated ERK1/2 and cell growth, whereas the exogenously expressed wild-type B-Raf promoted cell growth in MM cells. Our results provide the evidence that overexpression of wild-type B-Raf, in part but not always as a result of gene amplification, is one of the mechanisms underlying constitutive activation of the MAPK pathway that stimulates growth of MM cells.

DOI： 10.1038/sj.onc.1208152

Involvement of overexpressed wild-type BRAF in the growth of malignant melanoma cell lines

H Tanami, Imoto, I, A Hirasawa, Y Yuki, Sonoda, I, J Inoue, K Yasui, A Misawa-Furihata, Y Kawakami, J Inazawa

ONCOGENE 23 ( 54 ) 8796 - 8804 2004.11

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

Comparative genomic hybridization (CGH) using 40 cell lines derived from malignant melanomas (MMs) revealed frequent amplification at 7q33-q34 containing BRAF gene, which often is mutated in MM. We found this gene to be amplified to a remarkable degree in the MM cell lines that exhibited high-level gains at 7q33-q34 in CGH. Among 40 cell lines, the eight lines that revealed neither BRAF nor NRAS mutations showed even higher levels of BRAF mRNA expression than the 32 mutated lines, although DNA amplification at 7q33-q34 was not detected in every lines overexpressing BRAF. MM cells that carried wild-type BRAF and NRAS showed constitutive overexpression of B-Raf protein and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), even after serum starvation. Not only downregulation of the endogenously overexpressed wild-type B-Raf by antisense oligonucleotide but also a treatment with an inhibitor of mitogen-activated protein kinase kinase (MAPKK, MEK) reduced phosphorylated ERK1/2 and cell growth, whereas the exogenously expressed wild-type B-Raf promoted cell growth in MM cells. Our results provide the evidence that overexpression of wild-type B-Raf, in part but not always as a result of gene amplification, is one of the mechanisms underlying constitutive activation of the MAPK pathway that stimulates growth of MM cells.

DOI： 10.1038/sj.onc.1208152

[Outline of treatment for endometrial cancer].

Daisuke Aoki, Akira Hirasawa, Nobuyuki Susumu, Shiro Nozawa

Nihon rinsho. Japanese journal of clinical medicine 62 Suppl 10 324 - 8 2004.10

子宮体癌の治療治療概論

青木大輔, 平沢晃, 進伸幸, 野澤志朗

日本臨床 62 ( 増刊 ) 324-328 - 328 2004.10

Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II Reviewed

K Banno, N Susumu, T Hirao, M Yanokura, A Hirasawa, D Aoki, Y Udagawa, K Sugano, S Nozawa

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 30 ( 4 ) 287 - 292 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6.
Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.

DOI： 10.1111/j.1447-0756.2004.00195.x

Association of HNPCC and endometrial cancers.

Kouji Banno, Nobuyuki Susumu, Megumi Yanokura, Takeshi Hirao, Takashi Iwata, Akira Hirasawa, Daisuke Aoki, Kokichi Sugano, Shiro Nozawa

International journal of clinical oncology 9 ( 4 ) 262 - 9 2004.8

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

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

DOI： 10.1007/s10147-004-0402-8

Association of HNPCC and endometrial cancers

Kouji Banno, Nobuyuld Susumu, Megumi Yanokura, Takeshi Hirao, Takashi Iwata, Akira Hirasawa, Daisuke Aoki, Kokichi Sugano, Shiro Nozawa

International Journal of Clinical Oncology 9 ( 4 ) 262 - 269 2004.8

Language：English

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

DOI： 10.1007/s10147-004-0402-8

Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II. International journal

Kouji Banno, Nobuyuki Susumu, Takeshi Hirao, Megumi Yanokura, Akira Hirasawa, Daisuke Aoki, Yasuhiro Udagawa, Kokichi Sugano, Shiro Nozawa

The journal of obstetrics and gynaecology research 30 ( 4 ) 287 - 92 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6. Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.

DOI： 10.1111/j.1447-0756.2004.00195.x

Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II

K Banno, N Susumu, T Hirao, M Yanokura, A Hirasawa, D Aoki, Y Udagawa, K Sugano, S Nozawa

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 30 ( 4 ) 287 - 292 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6.
Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.

DOI： 10.1111/j.1447-0756.2004.00195.x

Association of HNPCC and endometrial cancers Reviewed

Kouji Banno, Nobuyuld Susumu, Megumi Yanokura, Takeshi Hirao, Takashi Iwata, Akira Hirasawa, Daisuke Aoki, Kokichi Sugano, Shiro Nozawa

International Journal of Clinical Oncology 9 ( 4 ) 262 - 269 2004.8

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

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

DOI： 10.1007/s10147-004-0402-8

Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. Reviewed International journal

Jun Inoue, Takemi Otsuki, Akira Hirasawa, Issei Imoto, Yoshinobu Matsuo, Shiroh Shimizu, Masafumi Taniwaki, Johji Inazawa

The American journal of pathology 165 ( 1 ) 71 - 81 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

We investigated DNA copy number aberrations in 37 cell lines derived from multiple myelomas (MMs) using comparative genomic hybridization, and 11 (29.7%) showed high-level gain indicative of gene amplification at 1q12-q22. A corresponding transcriptional mapping using oligonucleotide arrays extracted three up-regulated genes (IRTA2, PDZK1, and S100A6) within the smallest region of overlapping in amplifications. Among them PDZK1 showed amplification and consequent overexpression in the MM cell lines. Amplification of PDZK1 was observed in primary cases of MM as well. MM cell lines with amplification of PDZK1 exhibited the resistance to melphalan-, cis-platin-, and vincristin-induced cell death compared with MM cell lines without its amplifications. Furthermore, down-regulation of PDZK1 with an anti-sense oligonucleotide sensitized a cell line KMS-11 to melphalan, cis-platin, and vincristin. Taken together, our results indicate that PDZK1 is likely to be one of targets for 1q12-q22 amplification in MM and may be associated with the malignant phenotype, including drug resistance, in this type of tumor.

Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug resistance phenotype in multiple myeloma

J Inoue, T Otsuki, A Hirasawa, Imoto, I, Y Matsuo, S Shimizu, M Taniwaki, J Inazawa

AMERICAN JOURNAL OF PATHOLOGY 165 ( 1 ) 71 - 81 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

We investigated DNA copy number aberrations in 37 cell lines derived from multiple myelomas (MMs) using comparative genomic hybridization, and 11 (29.7%) showed high-level gain indicative of gene amplification at 1q12-q22. A corresponding transcriptional mapping using oligonucleotide arrays extracted three up-regulated genes (IRTA2, PDZK1, and S100A6) within the smallest region of overlapping in amplifications. Among them PDZK1 showed amplification and consequent overexpression in the MM cell lines. Amplification of PDZK1 was observed in primary cases of MM as well. MM cell lines with amplification of PDZK1 exhibited the resistance to melphalan-, cis-platin-, and vincristin-induced cell death compared with MM cell lines without its amplifications. Furthermore, down-regulation of PDZK1 with an anti-sense oligonucleotide sensitized a cell line KMS-11 to melphalan, cis-platin, and vincristin. Taken together, our results indicate that PDZK1 is likely to be one of targets for 1q12-q22 amplification in MM and may be associated with the malignant phenotype, including drug resistance, in this type of tumor.

子宮体癌に対する新たな治療戦略

平沢晃, 青木大輔, 野澤志朗

産科と婦人科 71 ( 2 ) 201-207 - 207 2004.2

術前細胞診にて癌腫成分のみを示した子宮体部異所性癌肉腫の一例

HIRASAWA AKIRA

日本婦人科腫瘍学会雑誌 22 ( 4 ) 393-398 2004

Outline of treatment for endometrial cancer

Aoki Daisuke, Hirasawa Akira, Susumu Nobuyuki, Nozawa Shiro

Nippon rinsho. Japanese journal of clinical medicine 62 Suppl 10 324 - 328 2004

腹腔内出血を繰り返した卵巣顆粒細胞腫晩期再発の一例.

HIRASAWA AKIRA

日本産科婦人科学会東京地方部会会誌 53 ( 3 ) 362-366 - 366 2004

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer. International journal

Akira Hirasawa, Daisuke Aoki, Jun Inoue, Issei Imoto, Nobuyuki Susumu, Kokichi Sugano, Shiro Nozawa, Johji Inazawa

Clinical cancer research : an official journal of the American Association for Cancer Research 9 ( 15 ) 5675 - 82 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

PURPOSE: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis. EXPERIMENTAL DESIGN: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization and 11 microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors. RESULTS: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC. CONCLUSIONS: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer Reviewed

A Hirasawa, D Aoki, J Inoue, Imoto, I, N Susumu, K Sugano, S Nozawa, J Inazawa

CLINICAL CANCER RESEARCH 9 ( 15 ) 5675 - 5682 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis.
Experimental Design: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization And It microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors.
Results: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC.
Conclusions: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer

A Hirasawa, D Aoki, J Inoue, Imoto, I, N Susumu, K Sugano, S Nozawa, J Inazawa

CLINICAL CANCER RESEARCH 9 ( 15 ) 5675 - 5682 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis.
Experimental Design: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization And It microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors.
Results: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC.
Conclusions: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer. Reviewed International journal

Kouji Banno, Nobuyuki Susumu, Takeshi Hirao, Megumi Yanokura, Akira Hirasawa, Daisuke Aoki, Yasuhiro Udagawa, Kokichi Sugano, Shiro Nozawa

Cancer genetics and cytogenetics 146 ( 1 ) 58 - 65 2003.10

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

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG-->ATA, Met-->Ile) and 2) a missense mutation at codon 390 (CTT-->TTT, Leu-->Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled.

DOI： 10.1016/S0165-4608(03)00157-2

Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer

K Banno, N Susumu, T Hirao, M Yanokura, A Hirasawa, D Aoki, Y Udagawa, K Sugano, S Nozawa

CANCER GENETICS AND CYTOGENETICS 146 ( 1 ) 58 - 65 2003.10

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

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG-->ATA, Met-->Ile) and 2) a missense mutation at codon 390 (CTT-->TTT, Leu-->Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0165-4608(03)00157-2

遺伝性子宮内膜癌とは −特にDNAミスマッチ修復遺伝子について

阪埜浩司, 進伸幸, 矢野倉恵, 平尾健, 岩田卓, 平沢晃, 青木大輔, 野澤志朗

産婦人科の世界 55 ( 8 ) 863-870 - 870 2003.8

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets

A Hirasawa, F Saito-Ohara, J Inoue, D Aoki, N Susumu, T Yokoyama, S Nozawa, J Inazawa, Imoto, I

CLINICAL CANCER RESEARCH 9 ( 6 ) 1995 - 2004 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Although tumor stage is considered a prognostic feature for ovarian clear cell adenocarcinomas (OC- CAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease.
Experimental Design: We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes.
Results: We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons).
Conclusions: Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets Reviewed

A Hirasawa, F Saito-Ohara, J Inoue, D Aoki, N Susumu, T Yokoyama, S Nozawa, J Inazawa, Imoto, I

CLINICAL CANCER RESEARCH 9 ( 6 ) 1995 - 2004 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Although tumor stage is considered a prognostic feature for ovarian clear cell adenocarcinomas (OC- CAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease.
Experimental Design: We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes.
Results: We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons).
Conclusions: Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. International journal

Akira Hirasawa, Fumiko Saito-Ohara, Jun Inoue, Daisuke Aoki, Nobuyuki Susumu, Tetsuji Yokoyama, Shiro Nozawa, Johji Inazawa, Issei Imoto

Clinical cancer research : an official journal of the American Association for Cancer Research 9 ( 6 ) 1995 - 2004 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

PURPOSE: Although tumor stage is considered a prognosticfeature for ovarian clear cell adenocarcinomas (OCCAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease. EXPERIMENTAL DESIGN: We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes. RESULTS: We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons). CONCLUSIONS: Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.

HNPCCの診療と研究遺伝性非腺腫症性大腸癌(HNPCC)と子宮内膜癌

阪埜浩司, 進伸幸, 平尾健, 岩田卓, 平沢晃, 青木大輔, 野澤志朗

家族性腫瘍 3 ( 2 ) 62-67 - 67 2003.5

子宮体癌におけるMicrosatellite Instability(MSI)の検出に免疫組織化学は有用か?

進, 伸幸, 青木, 大輔, 阪埜, 浩司, 平尾, 健, 平沢, 晃, 岩田, 卓, 鈴木, 直, 菅野, 康吉, 向井, 万起男, 野澤, 志朗

日本婦人科腫瘍学会雑誌 21 ( 3 ) 208 - 208 2003

Differentially regulated genes as putative targets of amplifications at 20q in ovarian cancers Reviewed

Watanabe T, Imoto I, Katahira T, Hirasawa A, Ishiwata I, Emi M, Takayama M, Sato A, Inazawa J

Jpn J Cancer Res 93 ( 10 ) 1114-1122 2003

子宮体癌におけるMicrosatellite Instabilityと薬剤感受性試験によるcisplatin感受性との関連

進, 伸幸, 青木, 大輔, 阪埜, 浩司, 平尾, 健, 岩田, 卓, 平沢, 晃, 金杉, 優, 鈴木, 直, 菅野, 康吉, 宇田川, 康博, 吉村, 泰典, 野澤, 志朗

日本産科婦人科学会雑誌 55 ( 2 ) 186 - 186 2003

Differentially regulated genes as putative targets of amplifications at 20q in ovarian cancers.

Takafumi Watanabe, Issei Imoto, Tomoyuki Katahira, Akira Hirasawa, Isamu Ishiwata, Mitsuru Emi, Masaomi Takayama, Akira Sato, Johji Inazawa

Japanese journal of cancer research : Gann 93 ( 10 ) 1114 - 22 2002.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BUSINESS CENTER ACADEMIC SOCIETIES JAPAN

Frequent amplification of DNA at 20q or part of 20q has been demonstrated by comparative genomic hybridization in ovarian cancer (OC), but the genetic target(s) of these amplification events remain unknown. We examined copy-number changes with respect to six candidate genes, E2F1 (20q11.2), TGIF2 (20q11.2), AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and BTAK (20q13), and then measured transcription levels of each candidate in 18 OC cell lines. Three distinct cores of amplification were identified: 20q11.2, harboring E2F1 and TGIF2 (region I; 1 of 18 cell lines, 5.6%); 20q13.1, harboring PTPN1 (region II; 5 lines, 27.8%); and 20q13.2, harboring ZNF217 and BTAK (region III; 6 lines, 33.3%). Among the six genes examined, expression levels of PTPN1 and ZNF217 were significantly correlated with absolute copy-number, and those of PTPN1 and TGIF2 were significantly correlated with copy-number relative to the centromere of chromosome 20 (20cen). Among 19 primary OCs examined, moreover, we observed amplification of TGIF2, PTPN1 and ZNF217 in five (26.3%), ten (52.6%), and twelve (63.2%) tumors, respectively. Expression levels of PTPN1 and ZNF217 were significantly correlated with their copy-numbers in those primary OCs. Our results suggest that 20q amplifications in OCs can be extensive and complex, probably due to synergistic or non-synergistic amplification of separate regions of 20q, involving multiple, independently amplified targets.

婦人科癌とDNAミスマッチ修復遺伝子―HNPCCに関する婦人科癌を中心として―

Aoki Daisuke, Hirasawa Akira, Susumu Nobuyuki, Nozawa Shirou

産婦人科の実際 51 ( 10 ) 1361-1368 - 1368 2002.10

Differentially regulated genes as putative targets of amplifications at 20q in ovarian cancers

T Watanabe, Imoto, I, T Katahira, A Hirasawa, Ishiwata, I, M Emi, M Takayama, A Sato, J Inazawa

JAPANESE JOURNAL OF CANCER RESEARCH 93 ( 10 ) 1114 - 1122 2002.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BUSINESS CENTER ACADEMIC SOCIETIES JAPAN

Frequent amplification of DNA at 20q or part of 20q has been demonstrated by comparative genomic hybridization in ovarian cancer (OC), but the genetic target(s) of these amplification events remain unknown. We examined copy-number changes with respect to six candidate genes, E2F1 (20q11.2), TGIF2 (20q11.2), AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and BTAK (20q13), and then measured transcription levels of each candidate in 18 OC cell lines. Three distinct cores of amplification were identified: 20q11.2, harboring E2F1 and TGIF2 (region I; I of 18 cell lines, 5.6%); 20q13.1, harboring PTPN1 (region H; 5 lines, 27.8%); and 20q13.2, harboring ZNF217 and BTAK (region 111; 6 lines, 33.3%). Among the six genes examined, expression levels of PTPN1 and ZNF217 were significantly correlated with absolute copy-number, and those of PTPN1 and TGIF2 were significantly correlated with copy-number relative to the centromere of chromosome 20 (20cen). Among 19 primary OCs examined, moreover, we observed amplification of TGIF2, PTPN1 and ZNF217 in five (26.3%), ten (52.6%), and twelve (63.2%) tumors, respectively. Expression levels of PTPN1 and ZNF217 were significantly correlated with their copy-numbers in those primary OCs. Our results suggest that 20q amplifications in OCs can be extensive and complex, probably due to synergistic or non-synergistic amplification of separate regions of 20q, involving multiple, independently amplified targets.

Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy. Reviewed International journal

Issei Imoto, Hitoshi Tsuda, Akira Hirasawa, Masahiko Miura, Masaru Sakamoto, Setsuo Hirohashi, Johji Inazawa

Cancer research 62 ( 17 ) 4860 - 6 2002.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Inhibition of, or increased resistance to, apoptosis is a common property of cancer cells. This means that a constitutive activation of antiapoptotic molecules via genetic or epigenetic mechanisms, including gene amplification, may well be involved in carcinogenesis. Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas and is associated with resistance of esophageal squamous cell carcinomas to drug-induced apoptosis (I. Imoto et al. Cancer Res., 61: 6629-6634, 2001). Because amplification of 11q22 has been implicated in other malignancies also, including cervical squamous cell carcinomas (CSCCs), we attempted to correlate amplification and overexpression of cIAP1 with radiation sensitivity in CSCC-derived cell lines and primary CSCC tumors. In the nine cell lines we examined, two showed amplification and consistent overexpression of cIAP1, as well as significant resistance to radiation-induced cell death as compared with lines showing no cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC. These findings demonstrate that cIAP1 may play an important role in the development/progression of this disease and that cIAP1 could be a novel predictive marker for resistance to radiotherapy in individual CSCC patients.

Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy

Imoto, I, H Tsuda, A Hirasawa, M Miura, M Sakamoto, S Hirohashi, J Inazawa

CANCER RESEARCH 62 ( 17 ) 4860 - 4866 2002.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Inhibition of, or increased resistance to, apoptosis is a common property of cancer cells. This means that a constitutive activation of antiapoptotic molecules via genetic or epigenetic mechanisms, including gene amplification, may well be involved in carcinogenesis. Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas and is associated with resistance of esophageal squamous cell carcinomas to drug-induced apoptosis (I. Imoto et al. Cancer Res., 67: 6629-6634, 2001). Because amplification of 11q22 has been implicated in other malignancies also, including cervical squamous cell carcinomas (CSCCs), we attempted to correlate amplification and overexpression of cIAP1 with radiation sensitivity in CSCC-derived cell lines and primary CSCC tumors. In the nine cell lines we examined, two showed amplification and consistent overexpression of cIAP1, as well as significant resistance to radiation-induced cell death as compared with lines showing no cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC. These findings demonstrate that cIAP1 may play an important role in the development/progression of this disease and that cIAP1 could be a novel predictive marker for resistance to radiotherapy in individual CSCC patients.

子宮体癌に対する手術療法

HIRASAWA AKIRA

日本婦人科腫瘍学会雑誌 20 ( 1 ) 26-32 - 32 2002

子宮内膜癌におけるマイクロサテライト不安定性とhMLH1蛋白発現低下との関連

阪埜, 浩司, 進, 伸幸, 平沢, 晃, 金杉, 優, 岩田, 卓, 青木, 大輔, 菅野, 康吉, 野澤, 志朗

家族性腫瘍 2 ( 2 ) A43 - A43 2002

子宮内膜癌におけるマイクロサテライト不安定性とhMLH1蛋白発現低下との関連

阪埜, 浩司, 進, 伸幸, 平沢, 晃, 金杉, 優, 岩田, 卓, 鈴木, 直, 青木, 大輔, 菅野, 康吉, 吉村, 泰典, 野澤, 志朗

日本産科婦人科学会雑誌 54 ( 2 ) 325 - 325 2002

遺伝性非腺腫性大腸癌(HNPCC)と婦人科癌

Banno Kouji, Nikata Masanobu, Hirasawa Akira, Susumu Nobuyuki, Aoki Daisuke, Udagawa Yasuhiro, Nozawa Shirou

産婦人科の実際 50 ( 12 ) 1819-1826 - 1826 2001.11

卵巣明細胞腺癌におけるPAI-1発現の生物学的意義

Komiyama Shinichi, Aoki Daisuke, Kanasugi Masaru, Hirasawa Akira, Susumu Nobuyuki, Nozawa Shirou

日本分子腫瘍マーカー研究会誌 16 48-49 2001.9

最近当科で経験したadenoma malignumの3例

HIRASAWA AKIRA

日本産婦人科学会東京地方部会誌 50 94-98 2001

わが教室における腫瘍マーカー検査

Hirasawa Akira, Aoki Daisuke, Udagawa Yasuhiro, Nozawa Shiro

産婦人科治療 79 ( 6 ) 680-685 - 685 1999.12

Genetic analysis of chromosome 17 and 1 in cervical cancers using fluorescencein situ hybridization and RFLP-Southern Blot

Susumu Nobuyuki, Tsuda Hitoshi, Aoki Daisuke, Udagawa Yasuhiro, Hirasawa A, Kanasugi Masaru, Nozawa Shiro

International Journal of Gynecological Cancer 9 ( Suppl 1 ) 101-102 1999.9

The relationship between MSN-1-reactive carbohydrate antigens and α-1,2 fucosyltransferase genes expressed in endometrial adenocarcinoma

Tominaga Eiichiro, Aoki Daisuke, Hirasawa Akira, Setoh Eri, Susumu Nobuyuki, Udagawa Yasuhiro, Nozawa Shiro

International Journal of Gynecological Cancer 9 ( Suppl 1 ) 68-69 1999.9

Two soluble forms of beta 1,4-galactosyltransferase released from ovarian cancer cells and from COS-1 cells transfected with its cDNA

D Aoki, E Saitoh, Y Matsumoto, E Tominaga, A Hirasawa, N Susumu, Y Udagawa, S Nozawa

ACTA HISTOCHEMICA ET CYTOCHEMICA 32 ( 3 ) 209 - 214 1999

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY

Employing RMG-1 cells derived from human ovarian adenocarcinoma and COS-1 cells transfected with cDNA for beta 1,4-galactosyltransferase, we first investigated the intracellular localization of this enzyme anal secondly assayed separately the two types of soluble forms of it (designated as normal GalT and GAT) in their culture supernatants. As results, the binding of anti-beta 1,4-galactosyltransferase monoclonal antibody was strongly positive at the Golgi area surrounding nuclei and the staining pattern was the same between RMG-1 cells and COS-1 transformants. These data demonstrated that the cells were producing beta 1,4-galactosyltransferase and had the ability to release it into the culture medium. As for the two soluble farms released from the cells, they were simultaneously detected in the culture medium by Western blotting and enzyme immunoassay using monoclonal antibodies, i.e., Mab8628 reactive to both GAT and normal-GalT and Mab8513 specific for GAT, indicating that both were derived from RMG-1 and from the cDNA introduced into COS-1 cells. Since serum-GAT clinically reflects tumor growth more accurately or specifically than normal GalT does, RMG-1 and COS-1 cells having cDNA for beta 1,4-galactosyltransferase would be promising as sources of these enzymes in order to investigate the differences in the behaviors of normal GalT and GAT associated with ovarian malignant tumors.

DOI： 10.1267/ahc.32.209

Two soluble forms of beta 1,4-galactosyltransferase released from ovarian cancer cells and from COS-1 cells transfected with its cDNA

D Aoki, E Saitoh, Y Matsumoto, E Tominaga, A Hirasawa, N Susumu, Y Udagawa, S Nozawa

ACTA HISTOCHEMICA ET CYTOCHEMICA 32 ( 3 ) 209 - 214 1999

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY

Employing RMG-1 cells derived from human ovarian adenocarcinoma and COS-1 cells transfected with cDNA for beta 1,4-galactosyltransferase, we first investigated the intracellular localization of this enzyme anal secondly assayed separately the two types of soluble forms of it (designated as normal GalT and GAT) in their culture supernatants. As results, the binding of anti-beta 1,4-galactosyltransferase monoclonal antibody was strongly positive at the Golgi area surrounding nuclei and the staining pattern was the same between RMG-1 cells and COS-1 transformants. These data demonstrated that the cells were producing beta 1,4-galactosyltransferase and had the ability to release it into the culture medium. As for the two soluble farms released from the cells, they were simultaneously detected in the culture medium by Western blotting and enzyme immunoassay using monoclonal antibodies, i.e., Mab8628 reactive to both GAT and normal-GalT and Mab8513 specific for GAT, indicating that both were derived from RMG-1 and from the cDNA introduced into COS-1 cells. Since serum-GAT clinically reflects tumor growth more accurately or specifically than normal GalT does, RMG-1 and COS-1 cells having cDNA for beta 1,4-galactosyltransferase would be promising as sources of these enzymes in order to investigate the differences in the behaviors of normal GalT and GAT associated with ovarian malignant tumors.

DOI： 10.1267/ahc.32.209

子宮肉腫の2症例

HIRASAWA AKIRA

栃木県産婦人科医報 25 ( 1 ) 40-42 - 42 1998

診断に苦慮した子宮頸部原発絨毛癌の1例

HIRASAWA AKIRA

栃木県産婦人科医報 25 ( 2 ) 113-116 - 116 1998

子宮体部に発生した癌肉腫の2例

HIRASAWA AKIRA

日本産科婦人科学会埼玉地方部会会誌 28 76-80 1998

当院における最近６年間の子宮体癌症例の予後因子について

HIRASAWA AKIRA

日本産科婦人科学会埼玉地方部会会誌 27 18-22 - 22 1997

産褥期MRSAによる敗血症ショックを来した２症例.

HIRASAWA AKIRA

日本産科婦人科学会埼玉地方部会会誌 27 42-46 1997

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