研究者詳細 - 平沢　晃

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

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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. 国際誌

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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. 査読国際誌

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Scopus

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

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年5月

横田めぐみ, 牧田和也, 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

日本女性医学学会雑誌 22 ( 2 ) 133 - 137 2015年4月

記述言語：日本語出版者・発行元：(一社)日本女性医学学会

【目的】当科「健康維持外来」では、2007年5月より初診時の血液検査項目に、甲状腺刺激ホルモン(TSH)と遊離サイロキシン(fT4)の2項目を甲状腺機能のスクリーニングのために加えている。今回我々は、当外来初診患者に認められた甲状腺機能異常について、潜在性甲状腺機能異常も含めて検証したので報告する。【対象と方法】2007年5月より2014年4月末までの7年間に当外来を受診した初診患者537例(平均年齢51.7歳)に施行した血清TSHおよびfT4の値から、各症例の甲状腺機能を評価した。そしてこれらの測定値が当院で規定されている基準範囲を逸脱している症例については、当外来初診後の甲状腺機能に関する診療経過等について、外来診療録より追跡調査を行った。【結果】(1)症例全体としては、甲状腺機能および血清脂質はいずれも基準範囲であり、体格因子に関しても同様であった。(2)537例中499例(92.9%)は、TSH値とfT4値いずれもが基準範囲であった。甲状腺機能低下症と臨床診断された症例が1例(0.2%)、甲状腺の機能亢進状態であった症例は6例(1.1%)認められた。(3)潜在性甲状腺機能亢進症と診断された症例は、537例中4例(0.7%)に認められた。(4)潜在性甲状腺機能低下症と診断された症例は、537例中23例(4.4%)に認められ、2項目ともに基準範囲であった症例以外では最も多かった。(5)基準範囲例と潜在性甲状腺機能低下症例の2群間では、年齢・体格因子・血清脂質に有意差を認めなかった。【考察】当外来受診患者の9割以上の症例で甲状腺機能は正常であったが、潜在性甲状腺機能低下症例が少なからず存在することが判明し、その罹患率はわが国における人間ドック受診者を対象とした報告に匹敵するものであった。従って、主に更年期女性を対象としている当外来において甲状腺機能のスクリーニング検査を行うことは、有用であると考えられた。(著者抄録)

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－

進伸幸, 平沢晃, 山上亘, 片岡史夫, 岩田卓, 牧田和也, 阪埜浩司, 青木大輔

日本女性医学学会雑誌 22 ( 2 ) 282 - 104 2015年4月

Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer. 査読国際誌

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年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

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 査読

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年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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. 国際誌

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 25 ( 3 ) 440 - 6 2015年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

安達将隆, 阪埜浩司, 増田健太, 植木有紗, 平沢晃, 冨永英一郎, 青木大輔

産婦人科の実際 64 ( 3 ) 377 - 383 2015年3月

Osteoporosis is less frequent in endometrial cancer survivors with hypertriglyceridemia. 国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 1 ) 127 - 131 2015年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Scopus

臓器・領域別家族性腫瘍の臨床卵巣癌招待査読

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年

遺伝性乳癌卵巣癌招待査読

平沢晃, 増田健太, 青木大輔

臨床画像 31 ( 10 ) 220 - 221 2015年

子宮体癌の予防とヘルスケア招待査読

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年

遺伝性乳癌卵巣癌の遺伝子検査査読

平沢晃, 増田健太, 青木大輔

産科と婦人科 82 ( Sup ) 202 - 205 2015年

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招待査読

平沢晃, 増田健太, 青木大輔

産科と婦人科 82 ( 6 ) 639 - 643 2015年

記述言語：日本語出版者・発行元：(株)診断と治療社

遺伝性乳癌卵巣癌(HBOC)の原因遺伝子であるBRCA1またはBRCA2(BRCA1/2)の遺伝子変異保持者(mutant carrier)に対する有効な卵巣癌スクリーニング法は確立されていない。BRCA1/2遺伝子変異保持者に対してリスク低減卵管卵巣摘出術(RRSO)を実施することにより卵巣癌や卵管癌の発症リスクが低減することは確実である。また卵巣癌や乳癌による死亡率を低減することもほぼ確実とされている。RRSOの検体からはoccult cancerが見つかることもあるため病理医との連携が重要である。RRSO施行後は腹膜癌の発症リスクが残るため引き続きサーベイランスが必要であるとともに、卵巣摘出に伴うエストロゲン欠落症状にも対応する。(著者抄録)

J-GLOBAL