論文 - 青木　大輔

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

Yokota, M., Makita, K., Hirasawa, A., Iwata, T. and Aoki, D.

Menopause 23 （ 9 ） 974 - 83 2016年09月

研究論文（学術雑誌）, 共著,  ISSN  1072-3714

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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.

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Evaluation of allowable time and histopathological changes in warm ischemia of the uterus in cynomolgus monkey as a model for uterus transplantation

Adachi, M., Kisu, I., Nagai, T., Emoto, K., Banno, K., Umene, K., Nogami, Y., Tsuchiya, H., Itagaki, I., Kawamoto, I., Nakagawa, T., Ogasawara, K. and Aoki, D.

Acta Obstet Gynecol Scand 95 （ 9 ） 991 - 8 2016年09月

研究論文（学術雑誌）, 共著,  ISSN  0001-6349

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INTRODUCTION: The objective of this study was to examine the allowable warm ischemic time and pathological changes due to ischemia and reperfusion injury in the uterus of the cynomolgus monkey as a model for uterus transplantation. MATERIAL AND METHODS: Six female cynomolgus monkeys were used in the study. The uterus was resected from the vaginal canal and connected through the bilateral ovarian and uterine arteries and veins only. One animal was used as a control. In the other five animals, the bilateral uterine and ovarian vessels were clamped for 0.5, 1, 2, 4 and 8 h, respectively. Biopsy of the smooth muscle tissue of corpus uteri was performed after each ischemic time and after subsequent reperfusion for 3 h. Biopsy samples were observed by light and electron microscopy. Menstruation recovery was monitored. RESULTS: There were no particular findings in both light and electron microscopy after ischemia for up to 2 h and after subsequent reperfusion. There were no marked changes after ischemia for 4 h, but dilated nuclear pores and rough endoplasmic reticulum swelling were found after reperfusion. These changes also occurred, along with mitochondrial swelling and cristae loss after ischemia for 8 h, and plasma membrane loss, nuclear fragmentation and chromatin condensation were found after reperfusion. Periodical menstruation restarted in all animals with ischemia up to 4 h, but the animal with ischemia for 8 h had amenorrhea and uterine atrophy. CONCLUSIONS: The uterus of the cynomolgus monkey tolerates warm ischemia for up to 4 h.

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Randomized Phase III Trial of Irinotecan Plus Cisplatin Compared With Paclitaxel Plus Carboplatin As First-Line Chemotherapy for Ovarian Clear Cell Carcinoma: JGOG3017/GCIG Trial

Sugiyama, T., Okamoto, A., Enomoto, T., Hamano, T., Aotani, E., Terao, Y., Suzuki, N., Mikami, M., Yaegashi, N., Kato, K., Yoshikawa, H., Yokoyama, Y., Tanabe, H., Nishino, K., Nomura, H., Kim, J. W., Kim, B. G., Pignata, S., Alexandre, J., Green, J., Isonishi, S., Terauchi, F., Fujiwara, K. and Aoki, D.

J Clin Oncol 34 （ 24 ） 2881 - 7 2016年08月

研究論文（学術雑誌）, 共著,  ISSN  0732-183X

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PURPOSE: Clear cell carcinoma (CCC) is a rare histologic subtype that demonstrates poor outcomes in epithelial ovarian cancer. The Japanese Gynecologic Oncology Group conducted the first randomized phase III, CCC-specific clinical trial that compared irinotecan and cisplatin (CPT-P) with paclitaxel plus carboplatin (TC) in patients with CCC. PATIENTS AND METHODS: Six hundred sixty-seven patients with stage I to IV CCC of the ovary were randomly assigned to receive irinotecan 60 mg/m(2) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1 (CPT-P group) every 4 weeks for six cycles or paclitaxel 175 mg/m(2) plus carboplatin area under the curve 6.0 mg/mL/min on day 1 every 3 weeks for six cycles (TC group). The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, and adverse events. RESULTS: Six hundred nineteen patients were clinically and pathologically eligible for evaluation. With a median follow-up of 44.3 months, 2-year progression-free survival rates were 73.0% in the CPT-P group and 77.6% in TC group (hazard ratio, 1.17; 95% CI, 0.87 to 1.58; P = .85). Two-year overall survival rates were 85.5% with CPT-P and 87.4% with TC (hazard ratio, 1.13; 95% CI, 0.80 to 1.61; one-sided P = .76). Grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently with CPT-P, whereas grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently with TC. CONCLUSION: No significant survival benefit was found for CPT-P. Both regimens were well tolerated, but the toxicity profiles differed significantly. Treatment with existing anticancer agents has limitations to improving the prognosis of CCC.

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癌とスタチン

小林佑介，阪埜浩司，青木大輔

薬局 67 （ 9 ） 122 - 126 2016年08月

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遺伝性乳がん卵巣がん

平沢 晃，青木大輔

日本医師会雑誌 145 （ 4 ） 705 - 709 2016年07月

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Profiling of plasma metabolites in postmenopausal women with metabolic syndrome

Iida, M., Harada, S., Kurihara, A., Fukai, K., Kuwabara, K., Sugiyama, D., Takeuchi, A., Okamura, T., Akiyama, M., Nishiwaki, Y., Suzuki, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Banno, K., Aoki, D. and Takebayashi, T.

Menopause 23 （ 7 ） 749 - 58 2016年07月

研究論文（学術雑誌）, 共著,  ISSN  1072-3714

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OBJECTIVE: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population. METHODS: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation. RESULTS: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0 kg/m, 72.1 mg/dL, and 126.1 mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased. CONCLUSIONS: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.

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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

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年07月

Lynch症候群

飯島茂異人，安達将隆，阪埜浩司，青木大輔

産婦人科の実際 65 （ 6 ） 709 - 715 2016年06月

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Optimal cytoreductive surgery in patients with advanced 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.

Gynecol Oncol 141 （ 3 ） 447 - 453 2016年06月

研究論文（学術雑誌）, 共著,  ISSN  0090-8258

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BACKGROUND: The benefits of cytoreductive surgery for uterine carcinosarcoma (UCS) are unknown. The objective of this study was to determine the impact of optimal surgery on advanced UCS patient survival. METHODS: We performed a multi-institutional, retrospective study of women diagnosed with stage IIIIV UCS between 2007 and 2012. Data were obtained retrospectively from medical records, including demographic, clinicopathologic, treatment, and outcome information. Optimal cytoreductive surgery was defined as surgery resulting in a maximum residual tumor of </=1cm. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS), and the Cox regression model was used to examine the impact of selected factors on survival. RESULTS: A total of 225 UCS patients (median age, 63years) were identified, including 136 (60%) with stage III and 89 (40%) with stage IV disease. Among these patients, 170 (76%) received optimal cytoreductive surgery. The median follow-up time was 19months. The median PFS was 11.5months (95% confidence interval [CI], 10.6-13.4) and 8.1months (95% CI, 5.1-9.5) for patients who received optimal and suboptimal cytoreductive surgery, respectively (P<0.0001). The median OS was 37.9months (95% CI, 28.3-not reached) and 18months (95% CI, 9.6-21) for patients who received optimal and suboptimal cytoreductive surgery, respectively (P<0.0001). Residual tumor >1cm was associated with worse OS while pelvic lymph node dissection was associated with improved OS. CONCLUSION: Optimal cytoreductive surgery and pelvic lymph node dissection are associated with improved OS in advanced UCS patients.

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遺伝性腫瘍

平沢 晃，山上 亘，青木大輔

産婦人科の実際 65 （ 6 ） 653 - 659 2016年06月

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改訂FIGO進行期分類の導入と患者登録

山上 亘，青木大輔

臨床腫瘍プラクティス 12 （ 2 ） 125 - 132 2016年05月

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Organ Perfusion for Uterus Transplantation in Non-Human Primates With Assumed Procurement of a Uterus From a Brain-Dead Donor

Kisu, I., Kato, Y., Yamada, Y., Matsubara, K., Obara, H., Emoto, K., Adachi, M., Umene, K., Nogami, Y., Banno, K., Kitagawa, Y. and Aoki, D.

Transplant Proc 48 （ 4 ） 1266 - 9 2016年05月

研究論文（学術雑誌）, 共著,  ISSN  0041-1345

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BACKGROUND: Clinical studies of uterus transplantation have been performed to treat uterine factor infertility. Because the uterus is a pelvic visceral organ, the method of perfusion for the procurement of vital organs from a brain-dead donor should be modified for removal of the uterus. Herein, we report the results of a preliminary study in cynomolgus monkeys of a new perfusion method for uterus transplantation with assumed procurement of a uterus from a brain-dead donor. METHODS: Cynomolgus monkeys were used; thoracolaparotomy was performed on the donor. A perfusion catheter was then placed into the unilateral femoral artery and/or external iliac artery. Cross-clamping was performed for the aorta under the diaphragm and the inferior vena cava was divided in the pleural space. The perfusion solution was then administered via the catheter to perfuse all organs in the abdominal cavity, including those in the pelvic cavity. After the perfusion, gross observation and histopathological examination of abdominal organs were conducted. RESULTS: Gross findings showed that all abdominal organs turned white in all specimens, indicating favorable perfusion of the uterus and all other organs in the abdomen. Pathological findings showed that almost no hemocytes were observed in the vessels of each organ. CONCLUSIONS: With perfusion via the femoral artery and/or external iliac artery, all organs in the abdominal cavity, including the uterus, could be perfused. It was suggested that this technique could be useful for uterus transplantation assuming the procurement of a uterus from a brain-dead donor.

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Anisakiasis mimics cancer recurrence: two cases of extragastrointestinal anisakiasis suspected to be recurrence of gynecological cancer on PET-CT and molecular biological investigation

Nogami, Y., Fujii-Nishimura, Y., Banno, K., Suzuki, A., Susumu, N., Hibi, T., Murakami, K., Yamada, T., Sugiyama, H., Morishima, Y. and Aoki, D.

BMC Med Imaging 16   31 2016年04月

研究論文（学術雑誌）, 共著,  ISSN  1471-2342

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BACKGROUND: We report two cases of anisakiasis lesions that were initially suspected to be recurrence of gynecological cancer by positron emission tomography-computed tomography (PET-CT). Both cases were extragastrointestinal anisakiasis that is very rare. CASE PRESENTATION: The first case was a patient with endometrial cancer. At 19 months after surgery, a new low density area of 2 cm in diameter in liver segment 4 was found on follow-up CT. In PET-CT, the lesion had abnormal (18)fluoro-deoxyglucose (FDG) uptake with elevation in the delayed phase, with no other site showing FDG uptake. Partial liver resection was performed. A pathological examination revealed no evidence of malignancy, but showed necrotic granuloma with severe eosinophil infiltration and an irregular material with a lumen structure in the center. Parasitosis was suspected and consultation with the National Institute of Infectious Diseases (NIID) showed the larvae to be Anisakis simplex sensu stricto by genetic examination. The second case was a patient with low-grade endometrial stromal sarcoma (LG-ESS). At 8 months after surgery, swelling of the mediastinal lymph nodes was detected on CT and peripheral T-cell lymphoma was diagnosed by biopsy. A new peritoneal lesion with abnormal FDG uptake was detected on pre-treatment PET-CT and this lesion was increased in size on post-treatment PET-CT. Tumorectomy was performed based on suspected dissemination of LG-ESS recurrence. The findings in a pathological examination were similar to the first case and we again consulted the NIID. The larvae was identified as Anisakis pegreffi, which is a rare pathogen in humans. Having experienced these rare cases, we investigated the mechanisms of FDG uptake in parasitosis lesions by immunohistochemical staining using antibodies to glucose transporter type 1 (GLUT-1) and hexokinase type 2 (HK-2). While infiltrated eosinophils were negative, macrophages demonstrated positive for both antibodies. Therefore, mechanisms behind FDG uptake may involve macrophages, which is common among various granulomas. This is the first report to investigate parasitosis in such a way. CONCLUSION: These cases suggest that anisakiasis is a potential differential diagnosis for a lesion with FDG uptake in PET-CT, and that it is difficult to distinguish this disease from a recurrent tumor using PET-CT alone.

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子宮頸がんに対する妊孕性温存手術の適応と注意点

田中京子，青木大輔

臨床婦人科産科（知りたい最新情報がすぐわかる！　不妊・不育症診療パーフェクトガイド） 増刊号70 （ 4 ） 15 - 19 2016年04月

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Neoadjuvant chemotherapy for locally advanced cervical cancer

Iwata, T., Miyauchi, A., Suga, Y., Nishio, H., Nakamura, M., Ohno, A., Hirao, N., Morisada, T., Tanaka, K., Ueyama, H., Watari, H. and Aoki, D.

Chin J Cancer Res 28 （ 2 ） 235 - 40 2016年04月

研究論文（学術雑誌）, 共著,  ISSN  1000-9604

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Neoadjuvant chemotherapy followed by surgery (NCS) has not been fully evaluated clinically. Currently, the main regimen of neoadjuvant chemotherapy (NAC) used in NCS includes cisplatin. The antitumor effects of NAC reduce lymph node metastasis and the tumor diameter in patients prior to surgery, and this can reduce the number of high risk patients who require postoperative radiation therapy. Many randomized controlled trials (RCTs) have examined the long-term prognosis of NCS compared to primary surgery, but the utility of NCS remains uncertain. The advent of concurrent chemoradiotherapy (CCRT) has markedly improved the outcome of radiotherapy (RT), and CCRT is now used as a standard method in many cases of advanced bulky cervical cancer. NCS gives a better treatment outcome than radiation therapy alone, but it is important to verify that NCS gives a similar or better outcome compared to CCRT.

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子宮移植の現状と課題

阪埜浩司，木須伊織，青木大輔

Pharma Medica 34 （ 4 ） 39 - 45 2016年04月

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メソトレキセート治療後の頸管妊娠に対し子宮鏡下切除した1例

遠藤豊英，吉政佑之，升田博隆，片倉慧美，日原華子，三木史恵，内田明花，内田 浩，丸山哲夫，田中 守，青木大輔

東京産科婦人科学会会誌 65 （ 2 ） 344 - 349 2016年04月

研究論文（学術雑誌）, 共著

妊娠を契機に発見された浸潤子宮頸癌症例の検討

菅 裕佳子，西尾 浩，宮内安澄，春日義史，仲村 勝，森定 徹，岩田 卓，田中京子，宮越 敬，田中 守，青木大輔

関東連合産科婦人科学会誌 53 （ 1 ） 139 - 145 2016年03月

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The importance of para-aortic lymph nodes in sentinel lymph node mapping for endometrial cancer by using hysteroscopic radio-isotope tracer injection combined with subserosal dye injection: Prospective study

Kataoka, F., Susumu, N., Yamagami, W., Kuwahata, M., Takigawa, A., Nomura, H., Takeuchi, H., Nakahara, T., Kameyama, K. and Aoki, D.

Gynecol Oncol 140 （ 3 ） 400 - 4 2016年03月

研究論文（学術雑誌）, 共著,  ISSN  0090-8258

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OBJECTIVE: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SN) mapping using hysteroscopic sub-endometrial injection of 99m-Technetium labeled phytate (Radio-isotope; RI method) and subserosal Indocyanine green (ICG) injection (Dye method) in patients with endometrial cancer. METHODS: From April 2009 to December 2012, prospective evaluation of 57 Japanese endometrial cancer patients undergoing SN mapping using RI method combined with Dye method was done. To combine RI method or no was determined by a status of RI supply of the tracer injection day. As for 32 cases, both (RI+Dye) methods were used and 23 cases were performed only in Dye method. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of SN, and analysis of the distribution of SNs with metastasis. RESULTS: At least one SN was detected in 100% and average number of detected SNs was 6.0 in RI+Dye method. Sensitivity and NPV were 100%, 100%, respectively. From results of SN mapping, 62.8% of SNs were present in pelvic and 37.1% in para-aortic lymph nodes (PAN). Total 56.3% of lymph nodes with metastasis were present in pelvic and 43.8% in PAN, and the distribution has no difference with SN mapping results (P=0.602). Among 13 cases with metastatic SNs, 76.9% cases showed metastasis in PAN. CONCLUSIONS: This SN mapping procedure for endometrial cancer patients revealed high detection rate, sensitivity, NPV, and also indicated the importance of the SN exploration in PAN area.

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A prospective observational study on chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer by the CINV Study Group of Japan

Mizuno, M., Hiura, M., Kikkawa, F., Numa, F., Yaegashi, N., Narahara, H., Aoki, D., Kimura, E., Kato, H., Shimokawa, M., Sugiyama, T. and Kamura, T.

Gynecol Oncol 140 （ 3 ） 559 - 64 2016年03月

研究論文（学術雑誌）, 共著,  ISSN  0090-8258

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OBJECTIVE: This study was performed to investigate the occurrence of and risk factors for chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer. METHODS: In total, 214 patients with gynecologic cancer who underwent highly emetogenic (HEC) or moderately emetogenic chemotherapy (MEC) were evaluated. We investigated the relationship between CINV and clinical factors and the accuracy of estimation of CINV by medical staff in the acute and late phases. Vomiting was evaluated in terms of frequency, and nausea was evaluated with a 100-mm visual analog scale on days 1 to 7. We also analyzed the risk factors and changes in CINV over time using a generalized linear mixed (GLM) model. RESULTS: The multivariate analysis revealed no significant risk factors for acute CINV. The independent risk factors for delayed nausea were a morning sickness history (odds ratio [OR], 2.687; 95% confidence interval [95% CI], 1.450-4.976; p=0.0017), age (each 1-year increment) (OR, 0.97; 95% CI, 0.944-0.996; p=0.0235), and HEC (OR, 2.134; 95% CI, 1.039-4.383; p=0.0391). The GLM model demonstrated that the independent factors affecting nausea were significant morning sickness (p=0.0101) and HEC (p=0.0136). These data also showed more severe nausea from days 3 to 5, but the negative predictive value for estimation of delayed nausea by medical staff was 57.8%. CONCLUSION: Our data suggest that improvement of preventive antiemetic administration is needed for patients with risk factors to manage delayed CINV caused by HEC and by MEC.

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