既成概念を打破する血清網羅的糖ペプチド解析による卵巣癌早期診断・予後診断法の開発

2018 Fiscal Year Annual Research Report

• Project/Area Number: 17H04340
• Research Institution: Tokai University
• Principal Investigator: 三上 幹男 東海大学, 医学部, 教授 (30190606)
• Co-Investigator(Kenkyū-buntansha): 信田 政子 東海大学, 医学部, 講師 (10338717) ; 池田 仁惠 東海大学, 医学部, 講師 (20365993) ; 柴田 健雄 東海大学, 健康学部, 講師 (30366033) ; 宮澤 昌樹 東海大学, 医学部, 客員講師 (30624572) ; 平澤 猛 東海大学, 医学部, 講師 (70307289)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 卵巣癌 / 血清バイオマーカー / 糖ペプチド / 質量分析 / 人工知能 / 深層学習 / リキッドバイオプシー

Outline of Annual Research Achievements

卵巣癌例39例、婦人科良性疾患例45例の血清の網羅的血清糖ペプチドスペクトラ解析にて得た糖ペプチドピークを用いてOPLS-DA (Orthogonal partial least squares Discriminant Analysis )法及びHeat MAP分析を行い、有効に両群を分離することが可能であった結果について論文投稿を行い、現在Revised Version査読中である。
2018年度はさらに進めて、同様の分析をTraining set (I期卵巣癌59例X非癌166例)、Test set (I期卵巣癌29例X非卵巣癌82例）、合計I期卵巣癌88例X非癌248例を用いて、OPLS-DA法にて両群を判別することを試みた。結果、本方法によって血清のみを用いて非癌患者と初期卵巣癌患者を分離することが可能であった。またこの結果は現在卵巣癌マーカーとして汎用されているCA125とHE4よりも高いAUCを示し非癌患者と初期卵巣癌患者を有意に分離することが可能であった。
同様に両群の糖ペプチドピークを2次元バーコードのように画像化してDeep learning（Mathworks 社MATLAB）にて分離を試みたところ、Training setでは100％、Test setでは93％、のAUCで分離が可能であった。
我々が用いている網羅的血清糖ペプチドスペクトラ解析にて得た糖ペプチドピークA2160（Gynecol Oncol. 2015 Dec;139(3):520-8. 有意に初期卵巣明細胞癌と子宮内膜症性嚢胞を分離する）に関して抗体作成を同時に進行している。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究はすでに方法論はほぼ確立していることから、その診断精度を上げるために多くの患者血液（卵巣癌、子宮内膜症性嚢胞、良性卵巣腫瘍、健常人）を必要とする。そこで本年度は日本中の血液バイオバンクより血清の収集を行う。

Strategy for Future Research Activity

卵巣癌は、前癌病変が分かっているタイプI型と de novo発生のタイプII型があり、健常人、前癌病変患者、卵巣癌各タイプ型・各進行期（I-II期XIII-IV期）患者の血液の組み合わせを変えることで、それぞれのカテゴリを選別する判別法としての確率（新たな腫瘍マーカーの概念：単一分子のマーカー値でない）が計算される（例、子宮内膜症性嚢胞の経過観察に有用な子宮内膜症性嚢胞例X卵巣明細胞腺癌I-II期例の組み合わせ、卵巣癌検診に生かすための卵巣癌I-II期X健常人の組み合わせ、など）。多数例を用いた検討で、各組み合わせの判別のためのAUSが99%を超えるようになるまでの診断システムの向上を目標に症例数の追加、分析、検討を重ね、そこが可能になることを確認の上、全国規模の臨床試験に進みたい。あるいは海外機関との共同研究に持ち込みたい。

Research Products

• [Journal Article] Multidisciplinary perspectives on newly revised 2018 FIGO staging of cancer of the cervix uteri (2019)
  • Author(s): Berek Jonathan S.、Matsuo Koji、Grubbs Brendan H.、Gaffney David K.、Lee Susanna I.、Kilcoyne Aoife、Cheon Gi Jeong、Yoo Chong Woo、Li Lu、Shao Yifeng、Chen Tianhui、Kim Miseon、Mikami Mikio
  • Journal Title: Journal of Gynecologic Oncology Volume: 30 Pages: e40
  • DOI: 10.3802/jgo.2019.30.e40
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asian Society of Gynecologic Oncology International Workshop 2018 (2019)
  • Author(s): Kong Tae-Wook、Ryu Hee-Sug、Kim Seung Cheol、Enomoto Takayuki、Li Jin、Kim Kenneth H.、Shim Seung-Hyuk、Wang Peng-Hui、Therasakvichya Suwanit、Kobayashi Yusuke、Lee Maria、Shi Tingyan、Lee Shin-Wha、Mikami Mikio、Nagase Satoru、et al
  • Journal Title: Journal of Gynecologic Oncology Volume: 30 Pages: e39
  • DOI: 10.3802/jgo.2019.30.e39
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neoadjuvant Chemotherapy with Taxane and Platinum Followed by Radical Hysterectomy for Stage IB2-IIB Cervical Cancer: Impact of Histology Type on Survival (2019)
  • Author(s): Matsuo Koji、Shimada Muneaki、Yamaguchi Satoshi、Kigawa Junzo、Tokunaga Hideki、Tabata Tsutomu、Kodama Junichi、Kawana Kei、Mikami Mikio、Sugiyama Toru
  • Journal Title: Journal of Clinical Medicine Volume: 8 Pages: 156～156
  • DOI: 10.3390/jcm8020156
  • Peer Reviewed / Open Access
• [Journal Article] Association of statins, aspirin, and venous thromboembolism in women with endometrial cancer (2019)
  • Author(s): Matsuo Koji、Hom Marianne S.、Yabuno Akira、Shida Masako、Kakuda Mamoru、Adachi Sosuke、Mandelbaum Rachel S.、Ueda Yutaka、Hasegawa Kosei、Enomoto Takayuki、Mikami Mikio、Roman Lynda D.
  • Journal Title: Gynecologic Oncology Volume: 152 Pages: 605～611
  • DOI: 10.1016/j.ygyno.2018.12.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Profile of treatment-related complications in women with clinical stage IB-IIB cervical cancer: A nationwide cohort study in Japan (2019)
  • Author(s): Machida Hiroko、Matsuo Koji、Furusawa Akiko、Kita Tsunekazu、Kitagawa Ryo、Mikami Mikio
  • Journal Title: PLOS ONE Volume: 14 Pages: e0210125
  • DOI: 10.1371/journal.pone.0210125
  • Peer Reviewed / Open Access
• [Journal Article] Validation of the 2018 FIGO cervical cancer staging system (2019)
  • Author(s): Matsuo Koji、Machida Hiroko、Mandelbaum Rachel S.、Konishi Ikuo、Mikami Mikio
  • Journal Title: Gynecologic Oncology Volume: 152 Pages: 87～93
  • DOI: 10.1016/j.ygyno.2018.10.026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer (2018)
  • Author(s): Ebina Yasuhiko、Mikami Mikio、Nagase Satoru、Tabata Tsutomu、Kaneuchi Masanori、Tashiro Hironori、Mandai Masaki、Enomoto Takayuki、Kobayashi Yoichi、Katabuchi Hidetaka、Yaegashi Nobuo、Udagawa Yasuhiro、Aoki Daisuke
  • Journal Title: International Journal of Clinical Oncology Volume: 24 Pages: 1～19
  • DOI: 10.1007/s10147-018-1351-y
  • Peer Reviewed
• [Journal Article] Trachelectomy for stage IB1 cervical cancer with tumor size >2 cm: trends and characteristics in the United States (2018)
  • Author(s): Matsuo Koji、Machida Hiroko、Mandelbaum Rachel S.、Mikami Mikio、Enomoto Takayuki、Roman Lynda D.、Wright Jason D.
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e85
  • DOI: 10.3802/jgo.2018.29.e85
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quality indicators for cervical cancer care in Japan (2018)
  • Author(s): Watanabe Tomone、Mikami Mikio、Katabuchi Hidetaka、Kato Shingo、Kaneuchi Masanori、Takahashi Masahiro、Nakai Hidekatsu、Nagase Satoru、Niikura Hitoshi、Mandai Masaki、Hirashima Yasuyuki、Yanai Hiroyuki、Yamagami Wataru、Kamitani Satoru、Higashi Takahiro
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e83
  • DOI: 10.3802/jgo.2018.29.e83
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics and outcomes of reproductive-aged women with early-stage cervical cancer: trachelectomy vs hysterectomy (2018)
  • Author(s): Machida Hiroko、Mandelbaum Rachel S.、Mikami Mikio、Enomoto Takayuki、Sonoda Yukio、Grubbs Brendan H.、Paulson Richard J.、Roman Lynda D.、Wright Jason D.、Matsuo Koji
  • Journal Title: American Journal of Obstetrics and Gynecology Volume: 219 Pages: 461.e1～461.e18
  • DOI: 10.1016/j.ajog.2018.08.020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Clinical Features of Recurrent Endometrial Cancer in Japan: Chemotherapy Instead of Radiotherapy as Postoperative Adjuvant Treatment (2018)
  • Author(s): Iwase Haruko、Furukawa Seigi、Hirasawa Takeshi、Asai Satoshi、Ohara Tatsuru、Hosonuma Shinji、Endo Shinichi、Tazo Yuki、Sato Hidetaka、Takada Toshio、Arai Masahide、Ikeda Masae、Shida Masako、Yoshioka Norihito、Tozawa-Ono Akiko、Suzuki Nao、Mikami Mikio、Onda Takashi
  • Journal Title: International Journal of Gynecologic Cancer Volume: 28 Pages: 1616～1623
  • DOI: 10.1097/IGC.0000000000001346
  • Peer Reviewed
• [Journal Article] Postoperative chemotherapy for node-positive cervical cancer: Results of a multicenter phase II trial (JGOG1067) (2018)
  • Author(s): Matoda Maki、Takeshima Nobuhiro、Michimae Hirofumi、Iwata Takashi、Yokota Harushige、Torii Yutaka、Yamamoto Yorito、Takehara Kazuhiro、Nishio Shin、Takano Hirokuni、Mizuno Mika、Takahashi Yoshiyuki、Takei Yuji、Hasegawa Tetsuya、Mikami Mikio、Enomoto Takayuki、Aoki Daisuke、Sugiyama Toru
  • Journal Title: Gynecologic Oncology Volume: 149 Pages: 513～519
  • DOI: 10.1016/j.ygyno.2018.04.009
  • Peer Reviewed
• [Journal Article] Significance of abnormal peritoneal cytology on survival of women with stage I?II endometrioid endometrial cancer (2018)
  • Author(s): Matsuo Koji、Yabuno Akira、Hom Marianne S.、Shida Masako、Kakuda Mamoru、Adachi Sosuke、Mandelbaum Rachel S.、Ueda Yutaka、Hasegawa Kosei、Enomoto Takayuki、Mikami Mikio、Roman Lynda D.
  • Journal Title: Gynecologic Oncology Volume: 149 Pages: 301～309
  • DOI: 10.1016/j.ygyno.2018.02.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The use of conization to identify and treat severe lesions among prediagnosed CIN1 and 2 patients in Japan (2018)
  • Author(s): Mikami Mikio、Ikeda Masae、Sato Hidetaka、Iwase Haruko、Enomoto Takayuki、Kobayashi Yoichi、Katabuchi Hidetaka
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e46
  • DOI: 10.3802/jgo.2018.29.e46
  • Peer Reviewed / Open Access
• [Journal Article] Impact of institutional accreditation by the Japan Society of Gynecologic Oncology on the treatment and survival of women with cervical cancer (2018)
  • Author(s): Mikami Mikio、Shida Masako、Shibata Takeo、Katabuchi Hidetaka、Kigawa Junzo、Aoki Daisuke、Yaegashi Nobuo
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e23
  • DOI: 10.3802/jgo.2018.29.e23
  • Peer Reviewed / Open Access
• [Journal Article] Fully sialylated alpha-chain of complement 4-binding protein (A2160): a novel prognostic marker for epithelial ovarian carcinoma (2018)
  • Author(s): Matsuo Koji、Tanabe Kazuhiro、Ikeda Masae、Shibata Takeo、Kajiwara Hiroshi、Miyazawa Masaki、Miyazawa Mariko、Hayashi Masaru、Shida Masako、Hirasawa Takeshi、Roman Lynda D.、Mikami Mikio
  • Journal Title: Archives of Gynecology and Obstetrics Volume: 297 Pages: 749～756
  • DOI: 10.1007/s00404-018-4658-z
  • Peer Reviewed
• [Journal Article] Multicenter Clinicopathological Study of High-Grade Serous Carcinoma Presenting as Primary Peritoneal Carcinoma (2018)
  • Author(s): Komiyama Shinichi、Nishijima Yoshihiro、Kondo Haruhiro、Nomura Hiroyuki、Yamaguchi Satoshi、Futagami Masayuki、Arai Hiroharu、Yokoyama Yoshihito、Suzuki Nao、Mikami Mikio、Kubushiro Kaneyuki、Aoki Daisuke、Udagawa Yasuhiro、Nishimura Ryuichiro
  • Journal Title: International Journal of Gynecologic Cancer Volume: 28 Pages: 657～665
  • DOI: 10.1097/IGC.0000000000001167
  • Peer Reviewed
• [Journal Article] Intrauterine Manipulator Use During Minimally Invasive Hysterectomy and Risk of Lymphovascular Space Invasion in Endometrial Cancer (2018)
  • Author(s): Machida Hiroko、Hom Marianne S.、Adams Crystal L.、Eckhardt Sarah E.、Garcia-Sayre Jocelyn、Mikami Mikio、Matsuo Koji
  • Journal Title: International Journal of Gynecological Cancer Volume: 28 Pages: 208～219
  • DOI: 10.1097/IGC.0000000000001181
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Trends in single women with malignancy of the uterine cervix in United States (2018)
  • Author(s): Machida Hiroko、Blake Erin A.、Eckhardt Sarah E.、Takiuchi Tsuyoshi、Grubbs Brendan H.、Mikami Mikio、Roman Lynda D.、Matsuo Koji
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e24
  • DOI: 10.3802/jgo.2018.29.e24
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] UPLC-MS/MS based diagnostics for epithelial ovarian cancer using fully sialylated C4-binding protein (2018)
  • Author(s): Tanabe Kazuhiro、Matsuo Koji、Miyazawa Masaki、Hayashi Masaru、Ikeda Masae、Shida Masako、Hirasawa Takeshi、Sho Ryuichiro、Mikami Mikio
  • Journal Title: Biomedical Chromatography Volume: 32 Pages: e4180
  • DOI: 10.1002/bmc.4180
  • Peer Reviewed
• [Journal Article] Risk stratification models for para-aortic lymph node metastasis and recurrence in stage IB?IIB cervical cancer (2018)
  • Author(s): Matsuo Koji、Shimada Muneaki、Saito Tsuyoshi、Takehara Kazuhiro、Tokunaga Hideki、Watanabe Yoh、Todo Yukiharu、Morishige Ken-ichirou、Mikami Mikio、Sugiyama Toru
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e11
  • DOI: 10.3802/jgo.2018.29.e11
  • Peer Reviewed / Open Access
• [Journal Article] Quality and quantity metrics of pelvic lymph node metastasis and risk of para-aortic lymph node metastasis in stage IB?IIB cervical cancer (2018)
  • Author(s): Matsuo Koji、Grubbs Brendan H.、Mikami Mikio
  • Journal Title: Journal of Gynecologic Oncology Volume: 29 Pages: e10
  • DOI: 10.3802/jgo.2018.29.e10
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Concurrent chemoradiotherapy for adenocarcinoma of the uterine cervix: Japanese Gynecologic Oncology Group (JGOG)multicenter retrospective study (2019)
  • Author(s): Y Nagai, M Takekuma, R Kitagawa, E Kobayashi, A Tozawa, S Nagao, S Hishio, T Toita, M Mikio,T Sugiyama
  • Organizer: SGO 50th Annual Meeting on Women's Cancer
  • Int'l Joint Research
• [Presentation] Trends and characteristics of epithelial ovarian cancer in Japan:JSGO-JSOG joint study (2019)
  • Author(s): H Machida, K Matsuo, W Yamagami, Y Ebina, Y Kobayashi, T Tabata, M Kaneuchi, S Nagase, T Enomoto, M Mikami
  • Organizer: SGO 50th Annual Meeting on Women's Cancer
  • Int'l Joint Research
• [Presentation] Predictors for pathological parametrial invasion in clinical stage iib cervical cancer:A nation-wide cohort study (2019)
  • Author(s): H Tokunaga, M Shimada, K Matsuo, K Nakamura, Y Takei, K Ushijima, T Sumi, T Ohara, Hi Yahata,M Mikami, T Sugiyama
  • Organizer: SGO 50th Annual Meeting on Women's Cancer
  • Int'l Joint Research
• [Presentation] Association of surgical volume for dadical hysterectomy and survival of women (2019)
  • Author(s): M Mikami, K Matsuo, M Shimada, S Yamaguchi, M Matode, T Nakanishi,
  • Organizer: SGO 50th Annual Meeting on Women's Cancer
  • Int'l Joint Research
• [Presentation] Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA) might be a new (2018)
  • Author(s): M Ikeda, M Mikami, K Tanabe, K Matsuo, M Miyazawa, M Hayashi, H Machida,
  • Organizer: ASGO 5th International Workshop on Gynecologic Onclology
  • Int'l Joint Research
• [Presentation] Diagnosis of early stage ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EMC) - the combination assay of A2160 ( Alpha-chain of Complement 4-Binding Protein with Fully-Sialylated Glycans) (2018)
  • Author(s): M Hayashi, M Miyazawa, M Miyazawa, H Machida, M Ikeda, M Shida, THirasawa,
  • Organizer: ASGO 5th International Workshop on Gynecologic Onclology
  • Int'l Joint Research
• [Presentation] Predictors for Positive Surgical Margin of Cervical Intraepithelial Neoplasia Grade 3 After Therapeutic Cervical Conization: A Retrospective Multicenter Study (2018)
  • Author(s): M Yasaka, M Ikeda, M Shida, T Hirasawa, M Mikami, Y Kobayashi, S Nagase, M Yokoyama, T Enomoto, H Katabuchi
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society ( IGCS2018 )
  • Int'l Joint Research
• [Presentation] Trends and Survival Outcomes of Women with Cervical Adenocarcinoma (2018)
  • Author(s): H Machida, I Oiwa, S Amatsu, T Narayama, T Iida, M Shida, T Hirasawa, M Mikami
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society ( IGCS2018 )
  • Int'l Joint Research
• [Presentation] Prevention of Preterm Delivery After Cervical Conization for Cervical (2018)
  • Author(s): T Narayama, M Ikeda, M Shida, T Hirasawa, M Mikami, Y Kobayashi, S Nagase, M Yokoyama, T Enomoto, H Katabuchi
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society ( IGCS2018 )
  • Int'l Joint Research