論文 - 青木　大輔

Clinical statistics of gynecologic cancers in Japan

Yamagami, W., Nagase, S., Takahashi, F., Ino, K., Hachisuga, T., Aoki, D. and Katabuchi, H.

J Gynecol Oncol 28 （ 2 ） e32 2017年03月

研究論文（学術雑誌）, 共著,  ISSN  2005-0380

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Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

Iijima, M., Banno, K., Okawa, R., Yanokura, M., Iida, M., Takeda, T., Kunitomi-Irie, H., Adachi, M., Nakamura, K., Umene, K., Nogami, Y., Masuda, K., Tominaga, E. and Aoki, D.

Oncol Lett 13 （ 3 ） 1063 - 1070 2017年03月

研究論文（学術雑誌）, 共著,  ISSN  1792-1074

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

Yoshihama, T., Hirasawa, A., Nomura, H., Akahane, T., Nanki, Y., Yamagami, W., Kataoka, F., Tominaga, E., Susumu, N., Mushiroda, T. and Aoki, D.

Jpn J Clin Oncol 47 （ 2 ） 170 - 174 2017年02月

研究論文（学術雑誌）, 共著,  ISSN  0368-2811

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Effective Selection of a Well-Differentiated Type of Human Uterine Endometrial Carcinoma Cells by Transfection of the Sulfotransferase Gene and Possible Association of Sulfoglycolipids With Well-Differentiated Phenotypes

Tanaka, K., Ishiwata, I., Kubushiro, K., Mikami, M., Aoki, D., Kiguchi, K. and Iwamori, M.

Int J Gynecol Cancer 27 （ 2 ） 267 - 273 2017年02月

研究論文（学術雑誌）, 共著,  ISSN  1048-891X

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A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases

Kuji, S., Watanabe, R., Sato, Y., Iwata, T., Hirashima, Y., Takekuma, M., Ito, I., Abe, M., Nagashio, R., Omae, K., Aoki, D. and Kameya, T.

Gynecol Oncol 144 （ 2 ） 384 - 390 2017年02月

研究論文（学術雑誌）, 共著,  ISSN  0090-8258

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OBJECTIVE: High-grade neuroendocrine carcinoma of uterine cervix (HGNCUC) has been recognized as a highly malignant tumor. Therapeutic strategy specific to neuroendocrine (NE) tumors needs to be considered, but some cases wouldn't allow simple final diagnoses. Insulinoma-associated protein 1 (INSM1), which is a zinc-finger transcription factor related to NE differentiation, is frequently expressed in NE tumors. We investigated the association between INSM1 and HGNCUC, and the possibility of INSM1 as a useful NE marker. METHODS: Thirty-seven cases of formalin-fixed and paraffin-embedded HGNCUCs were evaluated immunohistochemically for conventional NE markers and INSM1. We also surveyed polymerase chain reactions and examined the frequency and the genotype of human papillomavirus (HPV) infections. RESULTS: In HGNCUC, chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) were expressed in 86%, 86% and 68%, respectively. In addition, INSM1 was detected in 95%. Positivity for INSM1 was clearly evaluated histologically, because the intensity of nuclear staining on positive cells was high and nonspecific reactions were minimal. In uni- and multivariate analyses of prognostic factors on stage I and II surgical cases, the association between INSM1 expression and prognosis was insignificant. We confirmed 72% of 29 examined cases had high risk HPV infections (type 16, 14%; type 18, 86%). CONCLUSIONS: This study has clarified that INSM1 is closely related to the development of HGNCUC, and a useful new NE marker in conducting its correct and rapid diagnosis.

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

Adachi, M., Banno, K., Masuda, K., Yanokura, M., Iijima, M., Takeda, T., Kunitomi, H., Kobayashi, Y., Yamagami, W., Hirasawa, A., Kameyama, K., Sugano, K. and Aoki, D.

J Obstet Gynaecol Res 43 （ 2 ） 416 - 420 2017年02月

研究論文（学術雑誌）, 共著,  ISSN  1341-8076

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当科で経験した子宮頸部漿液性腺癌の2例

黒田由香，仲村 勝，飯島朋子，竹田 貴，吉政佑之，宮内安澄，岩田 卓，田中京子，冨永英一郎，進伸幸，田中 守，青木大輔

東京産科婦人科学会会誌 66 （ 1 ） 92 - 96 2017年01月

研究論文（学術雑誌）, 共著

子宮頸がん

田中京子，仲村 勝，森定 徹，岩田 卓，青木大輔： 特集　妊孕性温存 各種がんと生殖機能温存（1） 子宮頸がん． HORMONE FRONTIER IN GYNECOLOGY，23（4）：37-39，2016．12

HORMONE FRONTIER IN GYNECOLOGY 23 （ 4 ） 37 - 39 2016年12月

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Differential micro ribonucleic acid expression profiling in ovarian endometrioma with leuprolide acetate treatment

Kiba, A., Banno, K., Yanokura, M., Asada, M., Nakayama, Y., Aoki, D. and Watanabe, T.

J Obstet Gynaecol Res 42 （ 12 ） 1734 - 1743 2016年12月

研究論文（学術雑誌）, 共著,  ISSN  1341-8076

　概要を見る

AIM: Micro ribonucleic acids (miRNAs) play an important pathological role in endometriosis. Leuprolide acetate, an analog of gonadotropin-releasing hormone, is widely used to treat endometriosis; however, the molecular mechanisms involved in endometriotic tissue regression remain unclear. We performed miRNA expression profiling of clinical ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment. METHODS: We obtained clinical samples from nine normal eutopic endometrium, eight ovarian endometriotic, and 12 leuprolide acetate-treated endometriotic tissues. We compared the miRNA expression profiles of the three groups by performing TaqMan Array MicroRNA Card and bioinformatic analysis. RESULTS: Two miRNAs, miR-939 and miR-154, were upregulated in endometriotic tissue and downregulated in leuprolide acetate-treated endometriotic tissue. Five miRNAs (miR-146a, miR-142-3p, miR-136*, miR-125b-1* and miR-15b*) were unchanged in endometriotic tissue but were upregulated under leuprolide acetate treatment. Ingenuity pathway analysis using predicted target genes for the seven identified miRNAs suggested the involvement of a range of pathways, including axonal guidance, bone morphogenetic protein, phosphatase and tensin homolog and nitric oxide signaling; molecular mechanisms of cancer; and the adipogenesis and signal transducer and activator of transcription 3 (STAT3) pathways. CONCLUSIONS: To our knowledge, this is the first report profiling the miRNAs of endometrioma under leuprolide acetate treatment. The expression of seven miRNAs was modulated, concomitant with the disease state. This result gives new insight into the effects of leuprolide acetate treatment. Further investigation using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry will allow us to validate the results of this study and to explore new therapeutic targets and biomarkers of endometriosis.

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子宮移植

木須伊織，阪埜浩司，青木大輔

産婦人科の実際 65 （ 12 ） 1587 - 1594 2016年11月

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卵巣明細胞腺癌合併妊娠に対して待機的治療を行った2症例

高橋孝幸，野村弘行，二宮委美，岩佐尚美，中平直希，松本 直，山上 亘，片岡史夫，宮越 敬，田中 守，青木大輔

関東連合産科婦人科学会誌 53 （ 4 ） 633 - 639 2016年11月

研究論文（学術雑誌）, 共著

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

Takeda, T., Banno, K., Yanokura, M., Adachi, M., Iijima, M., Kunitomi, H., Nakamura, K., Iida, M., Nogami, Y., Umene, K., Masuda, K., Kobayashi, Y., Yamagami, W., Hirasawa, A., Tominaga, E., Susumu, N. and Aoki, D.

Genes (Basel) 7 （ 10 ）  2016年10月

研究論文（学術雑誌）, 共著,  ISSN  2073-4425

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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.

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早期子宮頸癌に対する機能温存手術としての腹式広汎性子宮頸部摘出術

田中京子，仲村 勝，森定 徹，岩田 卓，青木大輔

産婦人科の実際 65 （ 11 ） 1547 - 1550 2016年10月

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Feasibility study on combination chemotherapy using nogitecan hydrochloride (topotecan) and cisplatin for patients with metastatic, persistent, or recurrent uterine cervical cancer

Shimada, M., Sato, S., Oishi, T., Itamochi, H., Kigawa, J., Takeshima, N., Aoki, D., Aoki, Y., Nambu, Y. and Ochiai, K.

Int J Clin Oncol 21 （ 5 ） 969 - 974 2016年10月

研究論文（学術雑誌）, 共著,  ISSN  1341-9625

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BACKGROUND: The standard chemotherapeutic regimen for stage IVB, persistent, or recurrent uterine cervical cancer is platinum-based combination chemotherapy such as cisplatin (CDDP)/paclitaxel and CDDP/nogitecan hydrochloride (NGT, topotecan). Because it is unclear whether the CDDP/NGT combination chemotherapy is tolerable for Japanese patients, we conducted the present study to assess the feasibility of CDDP/NGT combination chemotherapy. METHODS: Between June 2012 and April 2014, 15 patients with stage IVB, persistent, or recurrent uterine cervical cancer were enrolled in this study. Patients underwent six cycles of NGT at a dose of 0.75 mg/m2, followed immediately by CDDP at a dose of 50 mg/m2 on day 1 by intravenous infusion, and then NGT at a dose of 0.75 mg/m2 on days 2 and 3. RESULTS: Of 15 patients, 9 patients underwent at least 6 cycles of NGT/CDDP combination chemotherapy. Of a total of 83 cycles, 70 cycles (84.3 %) of NGT/CDDP combination chemotherapy could be continued at the starting dose of NGT (0.75 mg/m2). Grade 3/4 hematological toxicities included leukopenia in 10 patients (66.7 %), neutropenia in 15 (100 %), anemia in 6 (40.0 %), thrombocytopenia in 4 (26.7 %), and febrile neutropenia in 4 (26.7 %). The response rate according to RECIST was 27 % (3/11), with partial response in 3 patients. CONCLUSIONS: NGT/CDDP combination chemotherapy may be a tolerable and effective regimen for Japanese patients with stage IVB, persistent, or recurrent uterine cervical cancer. Based on the results of this study, NGT/CDDP combination chemotherapy was approved in Japan in November 2015.

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Enhanced expression of unique gangliosides with GM2-determinant in human uterine cervical carcinoma-derived cell lines

Tanaka, K., Miyazawa, M., Mikami, M., Aoki, D., Kiguchi, K. and Iwamori, M.

Glycoconj J 33 （ 5 ） 745 - 54 2016年10月

研究論文（学術雑誌）, 共著,  ISSN  0282-0080

　概要を見る

Monoclonal antibody YHD-06 generated by immunization with GM2 reacted with gangliosides with GM2-determinant, i.e., GM2, GalNAc-GM1b and GalNAc-GD1a, among which GalNAc-GD1a was characterized as an antigen of autoimmune peripheral neuropathies including Guillain-Barre syndrome. When glycolipids were examined by TLC-immunostaining with YHD-06 in seven human cervical carcinoma-derived cell lines, GM2 was found in all cell lines, amounting to 15.5 % to 57.5 % of total gangliosides. Whereas GalNAc-GD1a was present in three cell lines, amounting to 5.4-17.5 % of total gangliosides, and GalNAc-GM1b in four cell lines in amounts of less than 2 %. The elevated amounts of gangliosides with GM2 determinant were closely correlated with the relative intensities of gene expression of GalNAc transferase, this being characteristic of cervical carcinoma-derived cells. However, in tissues from patients with several histological types of cervical carcinomas, GM3 was ubiquitously expressed in amounts of more than 66 % of total gangliosides, GM2 was expressed in only five of 15 tissues, and both GalNAc-GM1b and GalNAc-GD1a were not even detected in trace amounts. Since GM1 was detected in all tissues in amounts of less than 0.06 mug/mg dried tissue, all cervical carcinoma tissues were revealed to exhibit GM2 synthesis, indicating that enhanced synthesis of gangliosides with GM2 determinant is a characteristic of cultivated cells in vitro. Similarly, although I(3)SO3-GalCer was not present in the squamous cell carcinoma (SCC) tissues, SCC-derived cells selectively expressed II(3)SO3-LacCer. Since enhanced synthesis of GM2 has been reported in SV-40 virus-transfected fibroblasts, papilloma virus might be involved in the expression of GM2 in cervical carcinoma-derived cells.

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Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution

Torii, Y., Fujii, T., Kukimoto, I., Saito, M., Iwata, T., Takahashi, H., Ichikawa, R., Kawai, S., Otani, S. and Aoki, D.

Cancer Sci 107 （ 10 ） 1520 - 1526 2016年10月

研究論文（学術雑誌）, 共著,  ISSN  1347-9032

　概要を見る

Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5-92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.

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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

沖山 愛，山上 亘，坂井健良，真壁 健，二宮委美，野村弘行，片岡史夫，平沢 晃，阪埜浩司，進 伸幸，青木大輔

日本婦人科腫瘍学会雑誌 34 （ 4 ） 620 - 625 2016年10月

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HPV併用検診の有効性検証

森定 徹，青木大輔，齊藤英子

産科と婦人科 83 （ 10 ） 1135 - 1141 2016年10月

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子宮体癌化学療法－JGOG２０４３

野村弘行，岩佐尚美，青木大輔

産科と婦人科 83 （ 10 ） 1148 - 1153 2016年10月

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遺伝性腫瘍領域の新たな潮流

平沢 晃，青木大輔

実験医学 34 （ 16 ） 2671 - 2674 2016年10月

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