論文 - 青木　大輔

卵巣腫瘍・卵管癌・腹膜癌取扱い規約　臨床編

馬場 長，田代浩徳，山上 亘，杉山 徹，青木大輔，片渕秀隆

日本産科婦人科学会雑誌 68 （ 3 ） 1097 - 1116 2016年03月

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分子標的治療薬の婦人科領域への展開

野村弘行，岩佐尚美，吉浜智子，南木佳子，青木大輔

産科と婦人科 83 （ 6 ） 642 - 653 2016年03月

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子宮内膜増殖症（異形増殖症を含む）

進 伸幸，青木大輔

産科と婦人科（産婦人科処方実践マニュアル） 83 （ Suppl. ） 128 - 130 2016年03月

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子宮体癌（進行・再発/高リスク）

山上 亘，青木大輔

産科と婦人科（産婦人科処方実践マニュアル） 83 （ Suppl. ） 135 - 138 2016年03月

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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

横田めぐみ，平沢 晃，堀場裕子，岩田 卓，牧田和也，青木大輔

更年期と加齢のヘルスケア 14 （ 2 ） 316 - 318 2016年02月

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Prognostic factors in patients with uterine carcinosarcoma: a multi-institutional retrospective study from the Japanese Gynecologic Oncology Group

Harano, K., Hirakawa, A., Yunokawa, M., Nakamura, T., Satoh, T., Nishikawa, T., Aoki, D., Ito, K., Ito, K., Nakanishi, T., Susumu, N., Takehara, K., Watanabe, Y., Watari, H. and Saito, T.

Int J Clin Oncol 21 （ 1 ） 168 - 76 2016年02月

研究論文（学術雑誌）, 共著,  ISSN  1341-9625

　概要を見る

BACKGROUND: Uterine carcinosarcomas (UCSs) are rare and aggressive tumors. The prognostic factors are not sufficiently known. METHODS: We performed a multi-institutional, retrospective study of women with stage I-IV UCS, diagnosed between 2007 and 2012. Data obtained from medical records included demographic, clinicopathological, treatment, and outcome information. RESULTS: A total of 486 patients (median age 65 years) were identified-224 (46 %) were stage I, 32 (7 %) were stage II, 139 (28 %) were stage III, and 91 (19 %) were stage IV. Among them, 277 (57 %) had disease recurrence. Median disease-free survival (DFS) was 16.4 months [95 % confidence interval (CI) 15.7-27.2], and median overall survival (OS) was 72.0 months (95 % CI 43.0-not reached). In total, 454 (94 %) patients received adjuvant treatment, and 440 (91 %) received adjuvant chemotherapy. In multivariate analysis, stage III-IV disease, CA-125 level, and lymphovascular space invasion (LVSI) were significantly associated with shorter median DFS. Stage III-IV disease, performance status 2-4, >/=50 % myometrial invasion depth, and postsurgical residual tumor size >1 cm were significantly associated with shorter median OS. Conversely, pelvic lymph node lymphadenectomy was associated with improved DFS and OS. CONCLUSIONS: Stage, performance status, CA-125 level, LVSI, and myometrial invasion were associated with poor prognoses. Pelvic lymphadenectomy was associated with improved survival, and may be necessary for the surgical management of UCS.

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Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning

Irie, H., Banno, K., Yanokura, M., Iida, M., Adachi, M., Nakamura, K., Umene, K., Nogami, Y., Masuda, K., Kobayashi, Y., Tominaga, E. and Aoki, D.

Oncol Lett 11 （ 2 ） 1287 - 1293 2016年02月

共著,  ISSN  1792-1074

　概要を見る

Metformin is a first-line drug used for the treatment of type 2 diabetes. Recently, metformin has been reported to reduce the carcinogenic risk and inhibit tumor cell growth in glioma and breast cancer. The anticancer action of metformin involves the enhancement of phosphorylation of liver kinase B1, activation of adenosine monophosphate-activated protein kinase and inhibition of mammalian target of rapamycin, which reduces cell growth. Metformin is anticipated to exert antitumor effects in gynecological cancer, and its efficacy for the treatment of endometrial, breast and ovarian cancer has been suggested in preclinical studies and clinical trials. Although the effect of metformin on cervical cancer remains to be examined in clinical trials, its antitumor effects have been reported in preclinical studies. Thus, the use of metformin for the treatment of gynecological cancer may become a successful example of drug repositioning, following establishment of the drug's antitumor effects, risk evaluation, screening and validation of efficacy.

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Intravenous low-grade endometrial stromal sarcoma with intracardiac extension: A CASE OF inaccurate tumor location on contrast-enhanced computed tomography

Nogami, Y., Yamagami, W., Maki, J., Banno, K., Susumu, N., Tomita, K., Matsubara, K., Obara, H., Kitagawa, Y. and Aoki, D.

Mol Clin Oncol 4 （ 2 ） 179 - 182 2016年02月

研究論文（学術雑誌）, 共著,  ISSN  2049-9450

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We herein report a case of low-grade endometrial stromal sarcoma with intracardiac extension in a 58-year-old woman with a uterine tumor with intravascular involvement. The tumor was suspected preoperatively to be an endometrial stromal sarcoma by magnetic resonance imaging. The extent of intravascular involvement was determined to be below the level of the renal veins on preoperative contrast-enhanced computed tomography (CT). However, perioperative echography revealed that the tumor extended to the right atrium. An emergency cardiotomy with extracorporeal circulation was required. The risk of tumor embolism was reduced through transection of the inferior vena cava, but the tumor was difficult to remove completely. Postoperative hormonal therapy reduced the size of the residual tumor and no recurrence was detected for 1 year. The preoperative contrast-enhanced CT was unable to detect the free-floating intravascular tumor. This case illustrates a limitation of CT and indicates that accurate determination of the tumor extent for planning a surgical strategy in similar cases should be performed using multiple imaging methods.

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ARID1A gene mutation in ovarian and endometrial cancers (Review)

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

Oncol Rep 35 （ 2 ） 607 - 13 2016年02月

研究論文（学術雑誌）, 共著,  ISSN  1021-335X

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The AT-rich interacting domaincontaining protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genomewide analyses with nextgeneration sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosisassociated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosisassociated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosisassociated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a moleculartargeted drug can inhibit proliferation of ARID1Amutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.

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

Inoue, O., Hamatani, T., Susumu, N., Yamagami, W., Ogawa, S., Takemoto, T., Hirasawa, A., Banno, K., Kuji, N., Tanaka, M. and Aoki, D.

Reprod Biol Endocrinol 14   2 2016年01月

研究論文（学術雑誌）, 共著,  ISSN  1477-7827

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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.

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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

平沢 晃，青木大輔

産科と婦人科 83 （ 1 ） 13 - 19 2016年01月

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Pregnancy Outcomes After Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer: A 13-Year Experience in a Single Tertiary-Care Center

Kasuga, Y., Nishio, H., Miyakoshi, K., Sato, S., Sugiyama, J., Matsumoto, T., Tanaka, K., Ochiai, D., Minegishi, K., Hamatani, T., Iwata, T., Morisada, T., Nakamura, M., Fujii, T., Kuji, N., Aoki, D. and Tanaka, M.

Int J Gynecol Cancer 26 （ 1 ） 163 - 8 2016年01月

研究論文（学術雑誌）, 共著,  ISSN  1048-891X

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OBJECTIVE: To investigate pregnancy outcomes in women after abdominal radical trachelectomy (RT) for early-stage cervical cancer. METHODS: The patients' background, fertility, and pregnancy outcomes were reviewed in a total of 61 pregnancies in 48 of 172 women who underwent abdominal RT at Keio University Hospital between September 2002 and December 2013. RESULTS: There were 5 women with stage IA1, 2 with stage IA2, and 41 with stage IB1. Histological types were as follows: squamous cell carcinoma (n = 36), adenocarcinoma (n = 10), and adenosquamous cell carcinoma (n = 2). The pregnancy rate of women attempting to conceive after abdominal RT was 44% (48/109). The mean +/- SD duration from abdominal RT to conception was 3.1 +/- 1.9 years. Of 61 pregnancies, 42 pregnancies were achieved by fertility treatment (in vitro fertilization-embryo transfer, 39; intrauterine insemination, 3). After excluding one pregnancy without detailed clinical information, there were 42 live births (5 in 22-27 weeks, 11 in 28-33weeks, 20 in 34-36 weeks, and 6 in 37-38 weeks), 13 miscarriages, and 5 ongoing pregnancies. While there were 10 first trimester miscarriages, 3 pregnancies ended in the second trimester owing to chorioamnionitis. The mean gestational age at birth was 33 weeks of pregnancy. Thirty-seven neonates were appropriate-for-date, and one was small-for-date. Six pregnancies exhibited massive bleeding from the residual cervix in the late pregnancy. Preterm birth less than 34 weeks of pregnancy was related to premature rupture of the membrane (P < 0.05). Chorioamnionitis was evident in 9 of 11 pregnancies with preterm premature rupture of the membrane followed by birth at less than 34 weeks of pregnancy. No parturients exhibited lochiometra and endometritis postpartum. CONCLUSIONS: Abdominal RT provided favorable pregnancy outcomes, and fertility treatment could be advantageous to conception. Massive bleeding from the residual cervix as well as ascending infection might be characteristic features during pregnancy after abdominal RT.

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Expression of potential biomarkers associated with homologous recombination repair in patients with ovarian or triple-negative breast cancer

Nomura, H., Kataoka, F., Aoki, D., Jinno, H., Kitagawa, Y., Sato, Y., Womack, C., Wombwell, H., Hodgson, D., O'Connor, M., Harbron, C. and Yin, X.

Cancer Biomark 16 （ 1 ） 145 - 52 2016年

研究論文（学術雑誌）, 共著,  ISSN  1574-0153

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BACKGROUND: Poly(ADP)-ribose polymerase (PARP) inhibitors such as olaparib can induce cell death in cancer cells with homologous recombination (HR) DNA repair deficiencies, such as BRCA1/2 mutations. AIM: To identify prognostic biomarkers of long-term outcomes in cancer patients. METHODS: Immunohistochemistry was used to analyse expression of key HR pathway proteins (ATM, ATR, BRCA1, MDC1, MRE11) and PARP-1 in 100 serous ovarian cancer (SOC) and 100 triple-negative breast cancer (TNBC) tumour samples from Japanese patients. RECIST assessment was used. RESULTS: Patient demographic data and BRCA1/2 mutation status were unavailable. Most proteins listed previously were detected in > 80% of tissue samples, with BRCA1 expression detected in 60-65%. A potential link between BRCA1 expression and overall survival (M stage adjusted) in SOC patients was observed, but was not statistically significant after multiple testing adjustment. Correlations between other biomarker expression and survival were not observed. In TNBC patients, MDC1 staining was associated with progressive disease, but this was not statistically significant; the analysis did not identify significant correlations between biomarker expression and disease control. Limited event numbers prevented assessment of the prognostic value of BRCA1 in TNBC. CONCLUSION: BRCA1 expression may be a candidate for a prognostic biomarker in SOC. Further studies are warranted.

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Survey of Attitudes toward Uterus Transplantation among Japanese Women of Reproductive Age: A Cross-Sectional Study

Kisu, I., Banno, K., Soeda, E., Kurihara, Y., Okushima, M., Yamaguchi, A., Nakagawa, E., Umene, K. and Aoki, D.

PLoS One 11 （ 5 ） e0156179 2016年

研究論文（学術雑誌）, 共著,  ISSN  1932-6203

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OBJECTIVE: Uterus transplantation (UTx) is a potential option for women with uterine factor infertility to have a child, but there has been no large-scale survey of the views on UTx in women of reproductive age in Japan. The present study was aimed to clarify the views of Japanese women of reproductive age on UTx for uterine factor infertility. METHODS: A questionnaire on UTx was conducted by an Internet research company in December 2014 as a cross-sectional study in 3,892 randomly chosen women aged 25 to 39 years old. Responses were analyzed from 3,098 subjects (mean age 32.1+/-4.2 years old), after exclusion of inappropriate respondents in screening. RESULTS: Of the respondents, 62.1%, 34.7% and 18.1% favored adoption, UTx and gestational surrogacy, respectively. In contrast, 7.0%, 21.9% and 63.3% opposed adoption, UTx and gestational surrogacy, respectively. In choices of candidates for UTx based on highest priority, deceased persons (33.8%) and mothers (19.0%) were favored as donors, and women with congenital absence of the uterus (54.4%) and hysterectomy due to a malignant uterine tumor (20.0%) as recipients. Regarding societal acceptance of UTx, the answer rates were 15.7% for "UTx should be permitted", 77.6% for "UTx should be permitted with discussion", and 6.7% for "UTx should not be permitted, even with discussion". Regarding personal opinions on UTx, 44.2% were in favor, 47.5% had no opinion, and 8.3% were against. CONCLUSION: Our results suggest that many Japanese women of reproductive age feel that UTx is socially and individually acceptable, but that concerns requiring further discussion remain among these women. There was also a tendency for UTx to be viewed more favorably than gestational surrogacy.

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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

Masuda, K., Kobayashi, Y., Kimura, T., Umene, K., Misu, K., Nomura, H., Hirasawa, A., Banno, K., Kosaki, K., Aoki, D. and Sugano, K.

Hum Genome Var 3   16002 2016年

研究論文（学術雑誌）, 共著,  ISSN  2054-345X

　概要を見る

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.

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Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology

Yamagami, W. and Aoki, D.

J Obstet Gynaecol Res 41 （ 12 ） 1861 - 9 2015年12月

共著,  ISSN  1341-8076

　概要を見る

The Japan Society of Obstetrics and Gynecology collects and analyzes annual data on gynecologic cancers from member institutions. Here we present the Treatment Annual Report for 2007. Data on the prognosis of 3381 patients with cervical cancer, 3681 with endometrial cancer, and 2367 with ovarian cancer for whom treatment was initiated in 2007 were analyzed in the Treatment Annual Report. In the 2007 Treatment Annual Report, stage I accounted for 53.1%, stage II for 24.4%, stage III for 14.2%, and stage IV for 8.3% of all patients with cervical cancer. Stage I accounted for 64.8%, stage II for 8.2%, stage III for 20.2%, and stage IV for 6.9% of all patients with endometrial cancer. Stage I accounted for 41.4%, stage II for 9.9%, stage III for 30.6%, and stage IV for 8.6% of all patients with ovarian cancer. The 5-year overall survival rates for patients with cervical cancer were 91.8% for stage I, 71.5% for stage II, 53.0% for stage III, and 23.7% for stage IV; those for patients with endometrial cancer were 95.3%, 89.8%, 75.6%, and 29.1%, and those for patients with ovarian surface epithelial-stromal tumors were 91.5%, 76.1%, 46.9%, and 31.3%, respectively.

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Human Papillomavirus Test for Triage of Japanese Women With Low-Grade Squamous Intraepithelial Lesions

Iwata, T., Hasegawa, T., Ochiai, K., Takizawa, K., Umezawa, S., Kuramoto, H., Ohmura, M., Kubushiro, K., Arai, H., Sakamoto, M., Motoyama, T., Watanabe, K. and Aoki, D.

Reprod Sci 22 （ 12 ） 1509 - 15 2015年12月

ISSN  1933-7191

　概要を見る

We evaluated high-risk human papillomavirus (HR-HPV) DNA testing for high-grade cervical intraepithelial neoplasia (CIN) lesions by cobas HPV test and diagnostic HPV16/18 genotyping in Japanese women with low-grade squamous intraepithelial lesions. Of 357 patients, HR-HPV positivity prevalence was 75.6%, and 21.3% had grade 2 or higher CIN lesions (CIN2+), with the highest prevalence at 30 to 34 years. Negative predictive values of HR-HPV for CIN2+ in our patients were 93.1% (any age) and 94.9% (40-50 years). Absolute risk for CIN2+ in HR-HPV positive and HPV16/18 positive individuals was 25.9 and 35.1, respectively. Relative risk for CIN2+ lesions was 5.1 for HPV16/18 positive versus HR-HPV negative, and 3.8 for HR-HPV positive versus HR-HPV negative women. Predictive values of CIN2+ positive were higher for HPV16/18 positive women (any age) than 12 other HPV positive-genotypes, and highest (50%) at 40-50 years. The HPV16/18 genotyping might prevent women (>40 years) at risk of high-grade CIN lesions from undergoing unnecessary colposcopy/overtreatment of nonprogressive lesions.

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Prognostic importance of CDK4/6-specific activity as a predictive marker for recurrence in patients with endometrial cancer, with or without adjuvant chemotherapy

Ikeda, Y., Oda, K., Ishihara, H., Wada-Hiraike, O., Miyasaka, A., Kashiyama, T., Inaba, K., Fukuda, T., Sone, K., Matsumoto, Y., Arimoto, T., Maeda, D., Ikemura, M., Fukayama, M., Kawana, K., Yano, T., Aoki, D., Osuga, Y. and Fujii, T.

Br J Cancer 113 （ 10 ） 1477 - 83 2015年11月

共著,  ISSN  0007-0920

　概要を見る

BACKGROUND: Pathologically low-risk endometrial cancer patients do not receive postoperative treatment; however, 10-15% of these patients show recurrence with poor prognosis. We evaluated the clinical importance of cyclin-dependent kinase 4/6 (CDK4/6) activity, and its significance as a novel biomarker for the prognosis and chemo-sensitivity of endometrioid endometrial carcinoma (EEC). METHODS: Cyclin-dependent kinase 4/6 expression and enzyme activity in 109 tumour samples from patients with EEC were examined with a cell-cycle profiling (C2P) assay. CDK4/6-specific activity (CDK4/6SA) was determined, and its relationship with clinicopathological factors and expression of Ki-67 was analysed. RESULTS: CDK4/6-specific activity was significantly correlated with Ki-67 (P=0.035), but not with any other clinicopathological characteristics. CDK4/6SA was significantly higher (P=0.002) in pathologically low-risk patients (not receiving adjuvant chemotherapy, n=74) than in intermediate- or high-risk patients (receiving adjuvant chemotherapy, n=35). In addition, patients with high CDK4/6SA (>3.0) showed significantly (P=0.024) shorter progression-free survival (PFS) than those with low CDK4/6SA (<3.0). Although Ki-67 expression itself was not a marker for prognosis, the combination of high CDK4/6SA and high Ki-67 expression (>15%) was robustly associated with shorter PFS (P=0.015), and this combination was an independent poor prognostic factor in the low-risk group. Inversely, in the intermediate-/high-risk group, patients with high CDK4/6SA had a tendency of a more favourable prognosis compared with patients with low CDK4/6SA (P=0.063). CONCLUSIONS: CDK4/6-specific activity can be used as a biomarker to predict prognosis and, possibly, chemo-sensitivity. The combination of Ki-67 expression might strengthen the clinical usefulness of CDK4/6SA as a biomarker.

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腹腔鏡下手術が契機となり診断確定に至った卵管癌2症例の経験

仲村 勝，國富晴子，沖山 愛，安康真由香，栗原朋子，坂井健良，宮内安澄，竹本崇史，菅 裕佳子，西尾 浩，森定 徹，岩田 卓，田中京子，冨永英一郎，青木大輔

関東連合産科婦人科学会誌 52 （ 4 ） 811 - 817 2015年11月

解剖に基づいた腹腔鏡手術のトレーニング

片岡史夫，中平直希，二宮委美，今西宣晶，進　伸幸，平形道人，相磯貞和，青木大輔

産科と婦人科 82 （ 11 ） 1284 - 1289 2015年11月

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