Details of a Researcher - Chiyoda, Tatsuyuki

Papers - Chiyoda, Tatsuyuki

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Sentinel node navigation surgery in cervical cancer: a systematic review and metaanalysis.

Chiyoda T, Yoshihara K, Kagabu M, Nagase S, Katabuchi H, Mikami M, Tabata T, Hirashima Y, Kobayashi Y, Kaneuchi M, Tokunaga H, Baba T.

Int J Clin Oncol. 27 ( 8 ) 1247 - 1255 2022.08

Lead author, Accepted

Evaluation of the Role of Intraoperative Frozen Section and Magnetic Resonance Imaging in Endometrial Cancer.

Ooka R, Nanki Y, Yamagami W, Kawaida M, Nagai S, Hirano T, Sakai K, Makabe T, Chiyoda T, Kobayashi Y, Kataoka F, Aoki D

Int J Gynaecol Obstet. 2022.08

Real-world application of next-generation sequencing-based test for surgically resectable colorectal cancer in clinical practice.

Ogiri M, Seishima R, Nakamura K, Aimono E, Matsui S, Shigeta K, Chiyoda T, Tanishima S, Okabayashi K, Nishihara H, Kitagawa Y.

Future Oncol. 2022.07

Efficacy and safety of Olaparib maintenance monotherapy for Japanese patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer.

Yoshihama T, Kuroda Y, Chiyoda T, Takahashi M, Yoshimura T, Saotome K, Nanki Y, Sakai K, Kobayashi Y, Yamagami W, Aoki D.

Int J Clin Oncol. 2022.07

Corresponding author

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group

Yoshida H., Kikuchi A., Tsuda H., Sakamoto A., Fukunaga M., Kaku T., Yoshida M., Shikama A., Kogata Y., Terao Y., Tanikawa M., Yasuoka T., Chiyoda T., Miyamoto T., Okadome M., Nakamura T., Enomoto T., Konno Y., Yahata H., Hirata Y., Aoki Y., Tokunaga H., Usui H., Yaegashi N.

Human Pathology (Human Pathology) 124 24 - 35 2022.06

ISSN 00468177

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

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Characteristics and clinicopathological features of patients with ovarian metastasis of endometrial cancer: a retrospective study.

Matoba Y, Yamagami W, Chiyoda T, Kobayashi Y, Tominaga E, Banno K, Aoki D

J Obstet Gynaecol. 2022.06

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

Akahane T, Masuda K, Hirasawa A, Kobayashi Y, Ueki A, Kawaida M, Misu K, Nakamura K, Nagai S, Chiyoda T, Yamagami W, Hayashi S, Kataoka F, Banno K, Sugano K, Okita H, Kosaki K, Nishihara H, Aoki D

Journal of gynecologic oncology 2022.03

ISSN 2005-0380

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Clinical Usefulness of Endometrial Cytology in Determining the Therapeutic Effect of Fertility Preserving Therapy.

Takuma Yoshimura, Wataru Yamagami, Mio Takahashi, Takuro Hirano, Kensuke Sakai, Takeshi Makabe, Tatsuyuki Chiyoda, Kouji Banno, Daisuke Aoki

Acta cytologica (Acta Cytologica) 66 ( 2 ) 106 - 113 2022.03

ISSN 00015547

INTRODUCTION: The significance of endometrial cytology in determining the therapeutic efficacy of medroxyprogesterone acetate (MPA) therapy is unclear. This study aimed to evaluate the clinical usefulness of endometrial cytology during MPA therapy. METHODS: Overall, 77 patients who underwent dilatation and curettage (D&C) to evaluate the therapeutic efficacy of MPA therapy at our hospital between January 2018 and December 2019 were retrospectively analyzed. The results of D&C, cytological evaluation, and other clinicopathological factors were analyzed based on the patients' medical records. RESULTS: The sensitivity and specificity of cytology were 61% and 92%, respectively, with D&C being the gold standard for diagnosis in 142 D&C/cytological examinations. Among patients with no residual disease on D&C, 5 (4%) had suspicious or positive cytology. Although MPA therapy was terminated in 3 of these patients, only 1 patient had early recurrence, and the frequency of recurrence was similar to that of patients who showed negative results in both D&C and cytology. DISCUSSION/CONCLUSION: The sensitivity of endometrial cytology in determining the therapeutic effect of MPA therapy is low, and we confirmed that the omission of D&C is unacceptable. Our findings also suggested that the addition of cytological evaluation to D&C during MPA therapy had a low clinical significance.

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p53 dysfunction hampers the differentiation of mouse fallopian tube organoids

Nagai Shimpei, Masuda Kenta, Tamura Tomohiro, Otsuki Yuji, Suina Kentaro, Nobusue Hiroyuki, Akahane Tomoko, Chiyoda Tatsuyuki, Kobayashi Yusuke, Banno Kouji, Aoki Daisuke, Saya Hideyuki, Nagano Osamu

CANCER SCIENCE 113 1282 - 1282 2022.02

ISSN 1347-9032

Prospective feasibility study of neoadjuvant dose-dense paclitaxel plus carboplatin with bevacizumab therapy followed by interval debulking surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer patients.

Naomi Iwasa-Inoue, Hiroyuki Nomura, Fumio Kataoka, Tatsuyuki Chiyoda, Tomoko Yoshihama, Yoshiko Nanki, Kensuke Sakai, Yusuke Kobayashi, Wataru Yamagami, Tohru Morisada, Akira Hirasawa, Daisuke Aoki

International journal of clinical oncology (International Journal of Clinical Oncology) 27 ( 2 ) 441 - 447 2022.02

ISSN 13419625

BACKGROUND: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. METHODS: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. RESULTS: Twenty-four patients were included in this study. The median age was 55.5 years (37-80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. CONCLUSIONS: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

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Sentinel node navigation surgery in cervical cancer: a systematic review and metaanalysis.

Tatsuyuki Chiyoda, Kosuke Yoshihara, Masahiro Kagabu, Satoru Nagase, Hidetaka Katabuchi, Mikio Mikami, Tsutomu Tabata, Yasuyuki Hirashima, Yoichi Kobayashi, Masanori Kaneuchi, Hideki Tokunaga, Tsukasa Baba

International journal of clinical oncology (International Journal of Clinical Oncology) 2022

ISSN 13419625

Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99 m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4 cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

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ESMO 2021 meeting report: Gynecologic cancer.

千代田達幸, 青木大輔

月刊腫瘍内科 29 ( 2 ) 2022

ISSN 1881-6568

ARID1A mutation/ARID1A loss is associated with a high immunogenic profile in clear cell ovarian cancer.

Yuka Kuroda, Tatsuyuki Chiyoda, Miho Kawaida, Kohei Nakamura, Eriko Aimono, Takuma Yoshimura, Mio Takahashi, Keiko Saotome, Tomoko Yoshihama, Naomi Iwasa, Kensuke Sakai, Wataru Yamagami, Hiroshi Nishihara, Daisuke Aoki

Gynecologic oncology (Gynecologic Oncology) 162 ( 3 ) 679 - 685 2021.09

Corresponding author, ISSN 00908258

OBJECTIVES: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer. METHODS: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases. RESULTS: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006). CONCLUSIONS: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.

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当院で経験した子宮体部大細胞神経内分泌癌(LCNEC)の3例

平松真生子, 山上亘, 平野卓朗, 吉村拓馬, 千代田達幸, 西尾浩, 仲村勝, 阪埜浩司, 田中守, 青木大輔

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 70 ( 3 ) 493 - 497 2021.07

ISSN 2186-0599

子宮体部原発の大細胞神経内分泌癌(large cell neuroendocrine carcinoma:LCNEC)は稀で予後不良な組織型である。当院で経験した子宮体部LCNEC 3例につき報告する。症例1〜3は51〜75歳。術前に症例1、2は神経内分泌腫瘍を、症例3は癌肉腫を疑い手術を施行し、症例1は不完全切除、症例2、3は完全切除であった。手術進行期は症例1がIVB期、症例2がIIIB期、症例3がIIIC2期で、組織型はいずれもLCNECであったが、症例3のみ一部肉腫様成分が混在した。術後に症例1はpaclitaxel+carboplatin療法を、症例2、3はirinotecan+cisplatin療法を施行し、症例1、2は1年以内に再発したが、症例3は52ヵ月無再発で経過している。子宮体部LCNECは予後不良だが、完全切除可能で他組織型が併存する症例は予後良好である可能性がある。(著者抄録)

特集卵巣癌におけるHRDとPARP阻害薬の効果 11.再発治療時のオラパリブとニラパリブのエビデンス

千代田達幸, 青木大輔

産婦人科の実際 (金原出版) 70 ( 5 ) 537 - 544 2021.05

ISSN 0558-4728

Estimating copy number using next-generation sequencing to determine ERBB2 amplification status

Nakamura K, Aimono E, Oba J, Hayashi H, Tanishima S, Hayashida T, Chiyoda T, Kosaka T, Hishida T, Kawakubo H, Kitago M, Okabayashi K, Funakoshi T, Okita H, Ikeda S, Takaishi H, Nishihara H

Medical Oncology (Medical Oncology) 38 ( 4 ) 36 - 36 2021.04

ISSN 13570560

© 2021, The Author(s). Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

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Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution

Kobayashi Y, Hirasawa A, Chiyoda T, Ueki A, Masuda K, Misu K, Kawaida M, Hayashi S, Kataoka F, Banno K, Kosaki K, Aoki D

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 2 ) 213 - 217 2021.02

ISSN 0368-2811

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com. BACKGROUND: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. METHODS: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. RESULTS: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. CONCLUSIONS: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

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Ovarian cancer organoids recapitulate genomic alterations of the parental tumors.

Nanki Yoshiko, Chiyoda Tatsuyuki, Hirasawa Akira, Ookubo Aki, Itoh Manabu, Yoshimura Takuma, Akahane Tomoko, Yamagami Wataru, Aoki Daisuke

CANCER SCIENCE 112 450 - 450 2021.02

ISSN 1347-9032

A prospective cohort study on the safety and efficacy of bevacizumab combined with chemotherapy in Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer

Nanki Y, Nomura H, Iwasa N, Saotome K, Dozen A, Yoshihama T, Hirano T, Hashimoto S, Chiyoda T, Yamagami W, Kataoka F, Aoki D

Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology) 51 ( 1 ) 54 - 59 2021.01

ISSN 03682811

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. Objective: this prospective cohort study aimed to assess the safety and efficacy of bevacizumab combined with chemotherapy in Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer. Methods: in this study, 40 Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer selected to receive bevacizumab with chemotherapy were enrolled. Patients in poor general condition were excluded. Each patient was monitored prospectively for adverse events, administration status, disease status and survival. Treatment was continued until intolerable adverse events or disease progression. The primary endpoint was safety. Results: bevacizumab plus platinum-based chemotherapy was performed for 30 patients (median cycle; 16.5), while bevacizumab plus non-platinum chemotherapy was performed for 10 patients (median cycle; 5.5). Among bevacizumab-related adverse events, hypertension occurred in 80% of patients, proteinuria in 83%, mucositis in 25%, bleeding in 20%, thromboembolic events in 5.0% and fistula in 2.5%. Gastrointestinal perforation or other life-threatening lethal adverse events were not observed. Response rate and median progression-free survival were 73% and 19.3 months for patients with bevacizumab plus platinum-based chemotherapy, and 30% and 3.9 months for patients with bevacizumab plus non-platinum chemotherapy, respectively. There was no correlation between response rate and occurrence of adverse events such as hypertension or proteinuria. Conclusion: bevacizumab combined with chemotherapy was tolerable and effective for Japanese patients with relapsed ovarian cancer, fallopian tube cancer or primary peritoneal cancer. Hypertension and proteinuria are frequently occurred and managed properly for continuing treatment.

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Atypical vessels in hysteroscopy: Usefulness in prediction of malignant diseases in patients treated with tamoxifen

Oka E, Sakai K, Yamagami W, Hirano T, Makabe T, Yoshihama T, Chiyoda T, Kataoka F, Banno K, Aoki D

Journal of Obstetrics and Gynaecology Research (Journal of Obstetrics and Gynaecology Research) 47 ( 4 ) 1510 - 1515 2021

ISSN 13418076

© 2021 Japan Society of Obstetrics and Gynecology Aim: Tamoxifen (TAM) is widely used in adjuvant endocrine therapy for invasive breast cancer as a selective estrogen modulator, but this treatment has a risk of developing endometrial malignancy. However, hysteroscopic findings during or after TAM treatment are unclear. The aim of this study is to examine the association between hysteroscopic patterns and malignant histological findings during or after treatment with TAM. Methods: The subjects were patients who received TAM after surgery for breast cancer and underwent hysteroscopy at our institution from January 2016 to December 2019. Clinicopathological factors and hysteroscopic findings were collected from medical records and investigated retrospectively. Histologically, atypical endometrial hyperplasia, endometrial cancer, and carcinosarcoma were classified as malignant diseases. Results: A total of 26 patients were eligible for the study. Hysteroscopic findings included an irregular surface of the endometrium (n = 3, 11.5%), atypical vessels (n = 10, 38.5%), papillary structure (n = 3, 11.5%), and polypoid structure (n = 18, 69.2%). Histological examination revealed malignancy in six patients (23.0%). The percentage of atypical vessels in patients with malignancies was significantly higher than that in patients with a normal endometrium or benign lesion (100% vs. 20%, p = 0.0009). The sensitivity and specificity of atypical vessels in hysteroscopy for diagnosis of malignant diseases were 100% and 80%, respectively. Conclusions: Hysteroscopic findings of atypical vessels may be useful for prediction of malignant diseases in patients treated with TAM.

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Current status and future of liquid biopsy in gynecologic cancers

千代田達幸, 青木大輔

月刊Precision Medicine 4 ( 12 ) 2021

ISSN 2434-3625

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Kensuke Sakai, Chizu Tanikawa, Akira Hirasawa, Tatsuyuki Chiyoda, Wataru Yamagami, Fumio Kataoka, Nobuyuki Susumu, Chikashi Terao, Yoichiro Kamatani, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Michiaki Kubo, Nobuo Fuse, Takako Takai-Igarashi, Atsushi Shimizu, Akimune Fukushima, Aya Kadota, Kokichi Arisawa, Hiroaki Ikezaki, Kenji Wakai, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro Tsugane, Daisuke Aoki, Koichi Matsuda

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP) 10 ( 1 ) 1197 2020.12

Research paper (scientific journal), Joint Work, ISSN 2045-2322

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P=6.12x10(-25) with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

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Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing

Yoshiko Nanki, Tatsuyuki Chiyoda, Akira Hirasawa, Aki Ookubo, Manabu Itoh, Masaru Ueno, Tomoko Akahane, Kaori Kameyama, Wataru Yamagami, Fumio Kataoka, Daisuke Aoki

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP) 10 ( 1 ) 12581 2020.12

Research paper (scientific journal), Joint Work, ISSN 2045-2322

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in<3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs.

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PROSPECTIVE FEASIBILITY STUDY OF NEOADJUVANT DOSE-DENSE PACLITAXEL PLUS CARBOPLATIN WITH BEVACIZUMAB THERAPY FOR ADVANCED OVARIAN, FALLOPIAN TUBE AND PRIMARY PERITONEAL CANCER PATIENTS

Nomura H., Iwasa N., Kataoka F., Chiyoda T., Yamagami W., Fujii T., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 30 A150 - A150 2020.11

ISSN 1048-891X

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Uterine cervical cancer associated with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome: A case report and review of the literature

Oka E, Chiyoda T, Iwata T, Yamagami W, Aoki D

Gynecologic Oncology Reports (Gynecologic Oncology Reports) 34 100645 2020.11

ISSN 2352-5789

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Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors

Keiko Saotome, Tatsuyuki Chiyoda, Eriko Aimono, Kohei Nakamura, Shigeki Tanishima, Sachio Nohara, Chihiro Okada, Hideyuki Hayashi, Yuka Kuroda, Hiroyuki Nomura, Nobuyuki Susumu, Takashi Iwata, Wataru Yamagami, Fumio Kataoka, Hiroshi Nishihara, Daisuke Aoki

CANCER MEDICINE (WILEY) 9 ( 20 ) 7407 - 7417 2020.10

Research paper (scientific journal), Joint Work, ISSN 2045-7634

Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. ActionableBRCA1andBRCA2variants were found in 4.5% of each of the cases.ERBB2amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden >= 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P < .005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P < .05) and worse survival (P < .01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P < .05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.

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Lymphadenectomy for primary ovarian cancer: a systematic review and meta-analysis

Tatsuyuki Chiyoda, Manabu Sakurai, Toyomi Satoh, Satoru Nagase, Mikio Mikami, Hidetaka Katabuchi, Daisuke Aoki

Journal of Gynecologic Oncology (Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy) 31 ( 5 ) 1 - 13 2020.09

Research paper (scientific journal), Joint Work, ISSN 20050380

© 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology. Objective: To assess the effectiveness of lymphadenectomy at primary debulking surgery (PDS) on the survival of patients with epithelial ovarian cancer (EOC). Methods: We searched PubMed, Ichushi, and the Cochrane Library. Randomized controlled trials (RCTs) and retrospective cohort studies comparing survival of women with EOC undergoing lymphadenectomy at PDS with that of women without lymphadenectomy were included. We performed a meta-analysis of overall survival (OS), progression-free survival (PFS), and adverse events. Results: For advanced-stage EOC, 2 RCTs including 1,074 women and 7 cohort studies comprising 3,161 women were evaluated. Meta-analysis revealed that lymphadenectomy was associated with improved OS (hazard ratio [HR]=0.80; 95% confidence interval [CI]=0.70– 0.90). However, meta-analysis of 2 RCTs revealed no significant difference in OS between the lymphadenectomy and no-lymphadenectomy groups (OS: HR=1.02; 95% CI=0.85–1.22). For early-stage EOC, 1 RCT comprising 268 women and 4 cohort studies comprising 14,228 women were evaluated. Meta-analysis showed that lymphadenectomy was associated with improved OS (HR=0.75; 95% CI=0.68–0.82). A RCT of early-stage EOC reported that lymphadenectomy was not associated with improved OS (HR=0.85; 95% CI=0.49–1.47). Surgery-related deaths were similar in both groups (risk ratio [RR]=1.00; 95% CI=0.99–1.01); however, blood transfusion was required less frequently in the no-lymphadenectomy group (RR=0.74; 95% CI=0.63–0.86). Conclusions: Meta-analysis of RCTs and observational studies suggest that lymphadenectomy was associated with improved OS in advanced-and early-stage EOC. However, results from RCTs demonstrate that lymphadenectomy was not associated with improved OS in advanced-and early-stage EOC.

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腹腔鏡下子宮筋腫核出術における超音波凝固切開装置と電気メス・クーパーの手術成績の比較検討

松沢優一, 林茂徳, 長谷川慶太, 吉村拓馬, 永井晋平, 平野卓朗, 千代田達幸, 仲村勝, 片岡史夫, 田中守, 青木大輔

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 69 ( 2 ) 147 - 152 2020.04

ISSN 2186-0599

腹腔鏡下子宮筋腫核出術(laparoscopic myomectomy:LM)の際のデバイスとして、ランダム化比較試験で超音波凝固切開装置は電気メスと比較して出血量の減少、手術時間の短縮を有意に認めたとの報告がある。今回当院にてLMを施行した183例を、超音波凝固切開装置使用(A群:80例)、モノポーラ・クーパー使用(B群:103例)にわけ比較検討した。手術時間、出血量に関して2群間の平均値において統計学的有意差は認められず、デバイスの違いによる差は認められなかった。そこで我々は手術時間、出血量に及ぼす影響の強さについて年齢、BMI、摘出筋腫重量、摘出筋腫個数、筋腫最大径、デバイス(A群、B群)、術者の各種因子を用いて重回帰分析を行い、手術時間、出血量に影響を及ぼす因子について検討を行った。手術時間に関しては摘出筋腫個数が、出血量に関しては筋腫最大径が最も影響を与える因子となった。(著者抄録)

Evaluating the importance of routine drainage following laparoscopic pelvic lymph node dissection for gynecological malignancies

Sakai K, Nakamura M, Yamagami W, Chiyoda T, Kobayashi Y, Nishio H, Hayashi S, Nomura H, Kataoka F, Tominaga E, Banno K, Aoki D

International Journal of Gynecology and Obstetrics (International Journal of Gynecology and Obstetrics) 153 ( 3 ) 438 - 442 2020

ISSN 00207292

© 2020 International Federation of Gynecology and Obstetrics Objective: To determine the efficacy of drainage following pelvic lymph node (PLN) dissection, especially for cases involving laparoscopic surgery. Methods: In this retrospective study, 368 patients with malignant gynecological tumors who underwent systemic PLN dissection at Keio University Hospital between January 2012 and October 2018 were enrolled. Drainage tubes were placed in the retroperitoneal fossa in all patients. Medical records were used for data collection. Results: Laparoscopy was performed on 81 patients, and laparotomy was performed on 287 patients. In the laparoscopy group, tubes were removed 1 day post surgery. In the laparotomy group, tubes were removed 1 day post surgery in 167 patients and 4 days post surgery in 120 patients. Compared with the laparotomy group, we determined the laparoscopy group to have a significantly lower prevalence of lymphocyst (6.2% vs 20.2%, p = 0.002) but a similar prevalence of lymphedema (4.9% vs 5.2%), and symptomatic lymphocyst (2.5% vs 4.5%). The two laparotomy groups did not differ significantly with respect to the prevalence of lymphedema (4.8% vs 5.8%), lymphocyst (20.4% vs 20.0%), or symptomatic lymphocyst (4.2% vs 5.0%). Conclusion: Our results suggest that routine drainage should be omitted, especially in cases involving laparoscopic surgery.

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A case of "retained products of conception" treated with hysteroscopic surgery occurring after cesarean delivery in a patient who underwent fertility-preserving therapy for endometrial cancer

Makabe Takeshi, Yamagami Wataru, Hirano Takuro, Sakai Kensuke, Chiyoda Tatsuyuki, Kataoka Fumio, Aoki Daisuke

JAPANESE JOURNAL OF GYNECOLOGIC AND OBSTETRIC ENDOSCOPY (JAPAN SOCIETY OF GYNECOLOGIC AND OBSTETRIC ENDOSCOPY AND MINIMALLY INVASIVE THERAPY) 36 ( 2 ) 317 - 321 2020

ISSN 1884-9938

A 37-year old woman was diagnosed as early-stage endometrial cancer (G1 endometrioid carcinoma) during infertility treatment. The patient desired fertility preservation, and underwent fertility-preserving hormonal therapy. She became pregnant after successful cancer treatment and underwent cesarean section for breech presentation. During the surgery, it was observed that the placenta had adhered to the uterine wall, and it was removed manually. A postoperative examination revealed an intrauterine mass, which was diagnosed as retained products of conception (RPOC). Because active bleeding was not observed, conservative management was initiated. However, the lesion did not resolve. Therefore, we performed hysteroscopic surgery and endometrial curettage to evaluate the recurrence of endometrial cancer. A 2-cm white polypoid lesion was discovered in the uterus, and it was excised using a loop electrode. The resected margin was ischemic with little bleeding. The resected polypoid lesions were pathologically diagnosed as necrotic hyaline tissue, whereas that of the endometrial curettage lesion was endometrial hyperplasia. To determine the method and timing of treatment for RPOC, it is necessary to consider the presence or absence of active bleeding and individual characteristics of patients such as a history of endometrial cancer.

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若年子宮体癌/子宮内膜異型増殖症に対する高用量黄体ホルモン療法の再発例の検討

北澤晶子, 山上亘, 真壁健, 平野卓朗, 坂井健良, 千代田達幸, 小林佑介, 野村弘行, 片岡史夫, 阪埜浩司, 進伸幸, 田中守, 青木大輔

関東連合産科婦人科学会誌 ((一社)関東連合産科婦人科学会) 56 ( 4 ) 591 - 596 2019.11

ISSN 2186-0610

背景:若年の子宮体癌,子宮内膜異型増殖症(AEH)に対する妊孕性温存療法として,medroxyprogesterone acetate(MPA)を用いた高用量黄体ホルモン療法があるがその再発率の高さが問題となる.本研究ではMPA療法後の再発例の特徴を明らかにすることを目的とした.方法:1998〜2015年,当科で初回治療としてMPA療法を施行した182名を対象とし,倫理委員会の承認のもと,臨床病理学的因子や予後について後方視的に解析した.初回治療前の組織型はAEHで再発時AEHであった34例をA群,初回治療時EMG1で再発時AEHであった37例をB群,初回治療時EMG1で再発時EMG1であった27例をC群とした.結果:病変消失率はいずれも100%で,A群はB+C群に比較し再々発率が低く,再々発までの期間が長かった.妊娠例と非妊娠例では再々発率,再々発までの期間に有意差を認めなかった.結論:G1症例では再発時に進行する可能性もあり慎重な管理が求められる.治療後妊娠例は再発が少ないことから病変消失後の積極的な不妊治療がすすめられるが,分娩後も再発する可能性があり継続した管理が求められる.(著者抄録)

CLINICAL IMPACT OF LYMPHADENECTOMY FOR ENDOMETRIAL CANCER IN JAPAN

Yamagami W., Saotome K., Hirano T., Nanki Y., Sakai K., Makabe T., Chiyoda T., Kobayashi Y., Kataoka F., Banno K., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 29 A110 - A110 2019.11

ISSN 1048-891X

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EFFECTIVENESS OF DRAINAGE FOLLOWING LAPAROSCOPIC PELVIC LYMPH NODE DISSECTION

Sakai K., Nakamura M., Yamagami W., Chiyoda T., Kobayashi Y., Nishio H., Hayashi S., Nomura H., Kataoka F., Tominaga E., Banno K., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 29 A580 - A580 2019.11

ISSN 1048-891X

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Plasma circulating tumor DNA as a genomic biomarker for ovarian cancer

Nanki Y., George A. M., Chen Y., Brueffer C., Hirasawa A., Chiyoda T., Akahane T., Aoki D., Saal L. H.

EUROPEAN JOURNAL OF HUMAN GENETICS 27 1670 - 1671 2019.10

ISSN 1018-4813

特集卵巣がん征圧へのマイルストーン 7.「PleSSision検査」の実際

千代田達幸, 四十物絵理子, 早乙女啓子, 西原広史, 青木大輔

産婦人科の実際 (金原出版) 68 ( 3 ) 283 - 288 2019.03

ISSN 0558-4728

連載 FOCUS 卵巣癌実地臨床に導入されたPARP阻害薬

千代田達幸, 同前愛, 早乙女啓子, 青木大輔

臨床婦人科産科 (株式会社医学書院) 73 ( 1 ) 152 - 162 2019.01

ISSN 0386-9865

卵巣癌実地臨床に導入されたPARP阻害薬

AOKI DAISUKE

臨床婦人科産科 73 ( 1 ) 152 - 162 2019.01

Joint Work

SPHK1 is a novel target of metformin in ovarian cancer

Hart P, Chiyoda T, Liu X, Weigert M, Curtis M, Chiang C, Loth R, Lastra R, McGregor S, Locasale J, Lengyel E, Romero I

Molecular Cancer Research (Molecular Cancer Research) 17 ( 4 ) 870 - 881 2019

Joint Work, ISSN 15417786

© 2019 American Association for Cancer Research Inc. All rights reserved. The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in c

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Biomarkers of Gynecological Cancers.

Chiyoda Tatsuyuki, Dozen Ai, Saotome Keiko, Nanki Yoshiko, Aoki Daisuke

Biomarkers in Cancer Therapy-Liquid Biopsy Comes of Age- Springer Nature 133 - 150 2019

Joint Work, Accepted

Sentinel Node Navigation Surgery for Endometrial Cancer

Susumu Nobuyuki, Yamagami Wataru, Kataoka Fumio, Hirano Takuro, Makabe Takeshi, Sakai Kensuke, Chiyoda Tatsuyuki, Nomura Hiroyuki, Hirasawa Akira, Aoki Daisuke

SURGERY FOR GYNECOLOGIC CANCER 295 - 312 2019

ISSN 978-981-13-1518-3

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CLINICOPATHOLOGICAL BACKGROUND AND PROGNOSIS OF ADVANCED OVARIAN CANCER PATIENTS WITHOUT OPTIMAL CYTOREDUCTION AT PRIMARY SURGERY

Saotome K., Nomura H., Dozen A., Nanki Y., Yoshihama T., Iwasa N., Chiyoda T., Yamagami W., Kataoka F., Hirasawa A., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 828 - 828 2018.09

ISSN 1048-891X

UNSUCCESSFUL HIGH-DOSE HORMONAL THERAPY FOR ENDOMETRIAL CANCER OR ATYPICAL ENDOMETRIAL HYPERPLASIA.

Tamagawa M, Yamagami W, Hirano T, Makabe T, Sakai K, Ninomiya T, Chiyoda T, Nomura H, Kataoka F, Hirasawa A, Banno K, Susumu N, Aoki D

INTERNATIONAL JOURNAL OF GYNECOLOGIC CANCER 28 ( S2 ) 1189 - 1189 2018.09

Research paper (conference, symposium, etc.), Joint Work, Accepted

THE RELATIONSHIP BETWEEN THE COPY NUMBER AMPLIFICATION OF FGF3/FGF4 AND THE EFFICACY OF SORAFENIB IN GYNECOLOGIC CANCER

Yamagami W., Kataoka F., Hirano T., Sakai K., Makabe T., Chiyoda T., Nomura H., Hirasawa A., Tsuda H., Nishio K., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 218 - 218 2018.09

ISSN 1048-891X

THE EFFICACY OF REPEATED HORMONAL THERAPY FOR INTRAUTERINE RECURRENCE FOLLOWING FERTILITY PRESERVING HORMONAL THERAPY FOR ENDOMETRIAL CANCER OR ATYPICAL ENDOMETRIAL HYPERPLASIA.

Hirano T, Yamagami W, Susumu N, Makabe T, Sakai K, Ninomiya T, Chiyoda T, Nomura H, Kataoka F, Hirasawa A, Banno K, Aoki D

INTERNATIONAL JOURNAL OF GYNECOLOGIC CANCER 28 ( S2 ) 1092 - 1092 2018.09

Research paper (conference, symposium, etc.), Joint Work, Accepted, ISSN 1048-891X

PREGNANCY RATES BY AGE GROUPS IN FERTILITY-PRESERVING HORMONAL THERAPY IN YOUNG PATIENTS WITH EARLY STAGE ENDOMETRIAL CANCER.

Susumu N., Yamagami W., Hirano T., Makabe T., Sakai K., Chiyoda T., Nomura H., Kataoka F., Saitoh E., Hirasawa A., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 55 - 55 2018.09

ISSN 1048-891X

HIGH-DOSE MEDROXYPROGESTERONE ACETATE FOR ATYPICAL POLYPOID ADENOMYOMA OF THE UTERUS; A VALID FERTILITY-PRESERVING METHOD

Chiyoda T., Yamagami W., Hirano T., Kiyokawa S., Makabe K., Sakai K., Nomura H., Kataoka F., Susumu N., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 1060 - 1060 2018.09

ISSN 1048-891X

CORRELATION BETWEEN THE RELATIVE DOSE INTENSITY OF PACLITAXEL PLUS CARBOPLATIN THERAPY AND CLINICAL BACKGROUND FACTORS IN PATIENTS WITH OVARIAN CANCER

Dozen A., Nomura H., Saotome K., Nanki Y., Yoshihama T., Iwasa N., Chiyoda T., Yamagami W., Kataoka F., Hirasawa A., Aoki D.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 666 - 666 2018.09

ISSN 1048-891X

PARP inhibitors and quality of life in ovarian cancer

Aoki, Daisuke, Chiyoda, Tatsuyuki

LANCET ONCOLOGY 19 ( 8 ) 1012 - 1014 2018.08

Research paper (scientific journal), ISSN 1470-2045

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Ascites-derived and tissue-derived ovarian cancer cell primary 3D cultures aimed for personalized medicine.

Nanki Yoshiko, Hirasawa Akira, Nomura Hiroyuki, Okubo Aki, Itoh Manabu, Akahane Tomoko, Chiyoda Tatsuyuki, Kataoka Fumio, Tominaga Eiichiro, Aoki Daisuke

CLINICAL CANCER RESEARCH 24 ( 15 ) 72 - 72 2018.08

ISSN 1078-0432

有害事象によりベバシズマブ投与を中止した婦人科がん症例の検討

AOKI DAISUKE

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 67 ( 3 ) 396 - 400 2018.07

Joint Work, ISSN 2186-0599

ベバシズマブは婦人科がんにおいて日常的に用いられる分子標的薬となっているが、特有の有害事象により投与継続が困難となるケースを経験する。そこで本研究ではベバシズマブ投与中止の原因となった重篤な有害事象と臨床的背景を明らかにすることを目的とした。ベバシズマブ併用化学療法を2013年12月から開始した上皮性卵巣癌、卵管癌、腹膜癌(以下卵巣癌)48例および2017年1月から開始した子宮頸癌12例の計60例について後方視的に有害事象とその発現時期を検討した。卵巣癌は初発投与19例、再発投与29例の計48例、子宮頸癌は初発投与1例、再発投与11例の計12例を組み入れた。卵巣癌の年齢中央値は54歳(37〜76歳)、ベバシズマブ投与サイクル数中央値は15回(1〜68回)であった。子宮頸癌の年齢中央値は50歳(33〜68歳)、ベバシズマブ投与サイクル数中央値は5.5回(1〜10回)であった。卵巣癌48例中有害事象による投与中止例は4例あり、内訳は高度蛋白尿・ネフローゼ2例(4.2%)、腸炎1例(2.08%)、血栓塞栓症1例(2.08%)であった。子宮頸癌12例中有害事象による投与中止例は3例あり、全例血栓塞栓症(25%)であった。血液毒性、高血圧による投与中止例は認めず、出血および消化管穿孔、瘻孔は認めなかった。有害事象の発現時期について高度蛋白尿・ネフローゼは17、23サイクル終了時、血栓塞栓症はそれぞれ1、1、2、8サイクル終了時に認めた。高度蛋白尿・ネフローゼは投与数を重ねてから出現し、血栓塞栓症は投与開始後早期に認めた。検討した症例数は少ないものの、子宮頸癌では卵巣癌に比較して血栓塞栓症を多く認める可能性が示唆され、今後症例の蓄積が必要である。(著者抄録)

Development of pseudoaneurysm in cesarean section scar pregnancy: a case report and literature review

Kiyokawa, Shunki, Chiyoda, Tatsuyuki, Ueno, Kazunori, Saotome, Keiko, Kim, Seon-Hye, Nakada, Sakura

JOURNAL OF MEDICAL ULTRASONICS (Springer Tokyo) 45 ( 2 ) 357 - 362 2018.04

Research paper (scientific journal), Joint Work, ISSN 1346-4523

Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy. It is becoming more common, but it can lead to uterine rupture and severe hemorrhage. Here, we report a case of a 37-year-old woman with CSP complicated with pseudoaneurysm. The pseudoaneurysm emerged following focal injection of methotrexate (MTX) and potassium chloride with systemic MTX treatment. Due to a risk of sudden bleeding, uterine artery embolization (UAE) was recommended, but the patient hoped to avoid this if possible. Because the serum human chorionic gonadotropin level and the gestational sac were still persistent, dilation and curettage were performed with interventional radiologists on standby. Severe hemorrhage occurred and continued during the procedure, which necessitated emergent UAE. We reviewed six CSP case reports with vascular abnormalities, and all of them necessitated UAE, surgical excision, or hysterectomy. In the case of CSP combined with pseudoaneurysm, treatment should be planned carefully considering the risk of massive hemorrhage.

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Hysteroscopic Transcervical Resection for Atypical Polypoid Adenomyoma of the Uterus: AValid, Fertility-Preserving Option

Chiyoda, Tatsuyuki, Lin, Bao-Liang, Saotome, Keiko, Kiyokawa, Shunki, Nakada, Sakura

JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY (Elsevier B.V.) 25 ( 1 ) 163 - + 2018.01

Research paper (scientific journal), Joint Work, ISSN 1553-4650

Study Objective To evaluate hysteroscopic transcervical resection (TCR) for atypical polypoid adenomyoma of the uterus (APA). Design Retrospective study (Canadian Task Force classification II-2). Setting Single tertiary hospital. Patients Women who underwent TCR for APA at Kawasaki Municipal Hospital between 2003 and 2015. Interventions Clinical records were obtained. Measurements and Main Results Thirty-five patients with APA were evaluated. The median patient age was 35 years (range, 23–43 years), and the median tumor diameter was 22 mm (range, 9–51 mm). The median duration of observation after the first TCR was 34.0 months (range, 4.2–133.7 months). In 19 patients, the tumor recurred after the first TCR. A second TCR was performed in 13 patients, 11 of whom experienced recurrence. A third TCR was performed in 7 patients, all 7 of whom experienced recurrence. A fourth TCR was performed in 4 patients, 3 of whom experienced recurrence. The recurrence rate after the second TCR was higher than that after the first TCR (71.4%–84.6% vs 54.3%
p &lt
.01, t test). The median disease-free interval was 12.4 months after the first TCR, 15.3 months after the second TCR, 10.5 months after the third TCR, and 10.9 months after the fourth TCR. Seven patients progressed to endometrial cancer
however, there was no mortality. Six of the 35 patients conceived, and 4 had a normal spontaneous delivery. Conclusion Owing to disease-free intervals that follow treatment, TCR is a promising treatment modality as a fertility-preserving option for patients with APA under careful observation. Twenty percent of patients with APA develop cancer
however, the present study showed no mortality.

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【婦人科がん最近の話題】遺伝性乳癌卵巣癌

Chiyoda Tatsuyuki

東京産婦人科医会誌 , 2018, (51), p.20 51 20 2018

【遺伝性がんはここまで解明された】遺伝性卵巣がん（解説/特集）

Chiyoda Tatsuyuki　#HHirasawa Akira</U　#H Aoki Daisuke</U

成人病と生活習慣病 (東京医学社) 47 ( 7 ) 861 - 866 2017.07

Research paper (scientific journal), Joint Work

Loss of BRCA1 in the cells of origin of ovarian cancer induces glycolysis

Chiyoda Tatsuyuki, Hart Peter C., Eckert Mark A., McGregor Stephanie M., Lastra Ricardo R., Hamamoto Ryuji, Nakamura Yusuke, Yamada S. Diane, Olopade Olufunmilayo I., Lengyel Ernst, Romero Iris L.

Cancer Prevention Research (AMER ASSOC CANCER RESEARCH) 10 ( 4 ) 255 - 266 2017.04

ISSN 1940-6207

Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of developing epithelial ovarian cancer. However, beyond the role of BRCA1 in DNA repair, little is known about other mechanisms by which BRCA1 impairment promotes carcinogenesis. Given that altered metabolism is now recognized as important in the initiation and progression of cancer, we asked whether the loss of BRCA1 changes metabolism in the cells of origin of ovarian cancer. The findings show that silencing BRCA1 in ovarian surface epithelial and fallopian tube cells increased glycolysis. Furthermore, when these cells were transfected with plasmids carrying deleterious BRCA1 mutations (5382insC or the P1749R), there was an increase in hexokinase-2 (HK2), a key glycolytic enzyme. This effect was mediated by MYC and the STAT3. To target the metabolic phenotype induced by loss of BRCA1, a drug-repurposing approach was used and aspirin was identified as an agent that counteracted the increase in HK2 and the increase in glycolysis induced by BRCA1 impairment. Evidence from this study indicates that the tumor suppressor functions of BRCA1 extend beyond DNA repair to include metabolic endpoints and identifies aspirin as an ovarian cancer chemopreventive agent capable of reversing the metabolic derangements caused by loss of BRCA1.

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Elevated preoperative neutrophil

Nanki Yoshiko, Chiyoda Tatsuyuki, Kataoka Fumio, Nomura Hiroyuki, Nakadaira Naoki, Iwasa Naomi, Hashimoto Shiho, Arima Hirokazu, Susumu Nobuyuki, Aoki Daisuke

Journal of Obstetrics and Gynaecology Research (WILEY) 43 ( 4 ) 744 - 748 2017.04

ISSN 1341-8076

Aim: To examine the usefulness of the neutrophil : lymphocyte (N/L) ratio as a cost-effective and simple diagnostic marker of mature cystic teratoma (MCT) with malignant transformation (MT). Methods: A retrospective chart review was performed between 1998 and 2013 of 12 MCT patients with MT and between 2009 and 2013 of 130 patients with benign MCT. Data were collected on age, tumor size, white blood cell count with differential counts, tumor marker levels, and presenting features. Results: Older age, greater tumor size, higher CA19-9 or CA125, higher neutrophil count, and higher N/L ratio were associated with MT on univariate analysis. White blood cell count; lymphocyte count; and the tumor marker squamous cell carcinoma antigen were not associated with MT. Older age (≥median), larger tumor size (≥10 cm), and high N/L ratio (≥5.0) were predictors of MT (hazard ratio, 11.51, 5.87, and 11.11, respectively). Six of 12 patients were diagnosed with MT on preoperative magnetic resonance imaging and five of 12 had an N/L ratio ≥5.0. Conclusions: Neutrophil : lymphocyte ratio is a potential preoperative diagnostic marker of MT. The optimal cut-off should be determined in future large-scale studies.

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Retrospective Analysis on the Feasibility and Efficacy of Docetaxel-Cisplatin Therapy for Recurrent Endometrial Cancer

Ninomiya Tomomi, Yamagami Wataru, Susumu Nobuyuki, Makabe Takeshi, Sakai Kensuke, Wada Michiko, Takigawa Aya, Chiyoda Tatsuyuki, Nomura Hiroyuki, Kataoka Fumio, Hirasawa Akira, Banno Kouji, Aoki Daisuke

Anticancer Research (INT INST ANTICANCER RESEARCH) 36 ( 4 ) 1751 - 1758 2016.04

ISSN 0250-7005

AIM: There is poor evidence regarding effective treatment for recurrent endometrial cancer. We treated patients with recurrent endometrial cancer with docetaxel-cisplatin (DP) therapy as second-line or third-line chemotherapy. We aimed to evaluate the feasibility and efficacy of DP therapy for patients with recurrent endometrial cancer.PATIENT AND METHODS: We included 26 patients diagnosed with recurrent endometrial cancer, who underwent DP chemotherapy at our Institution. Docetaxel at 70 mg/m(2)and cisplatin at 60 mg/m(2)were administered by intravenous injection every 3 weeks. We retrospectively analyzed the clinicopathological factors associated with the response rate (RR) and prognosis. We also analyzed the adverse effects of DP therapy.RESULTS: Median follow-up was 33.8 months and the median number of therapy cycles was six. Grade 3 or 4 adverse effects included leukopenia (66%), neutropenia (81%), anemia (9%), diarrhea (12%), general fatigue (12%), liver dysfunction (4%), peripheral neuropathy (4%), and hyponatremia (4%). RR was 58% and the median progression-free survival (PFS) was 7.5 months. The group with a treatment-free interval of 6 months or more tended to have better PFS than that with less than 6 months (p=0.01). The group with a platinum-free interval of 6 months or more had significantly better PFS than that with less than 6 months (p=0.09). Although the history of taxane usage was not relevant to prognosis, a taxane-free interval of 12 months or more was associated with a tendency for better PFS (p=0.06).CONCLUSION: DP therapy was fully feasible and demonstrated efficacy for patients with recurrent endometrial cancer.

LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C

Masuda Kenta, Chiyoda Tatsuyuki, Sugiyama Naoyuki, Segura-Cabrera Aldo, Kabe Yasuaki, Ueki Arisa, Banno Koji, Suematsu Makoto, Aoki Daisuke, Ishihama Yasushi, Saya Hideyuki, Kuninaka Shinji

PLoS One (PUBLIC LIBRARY SCIENCE) 10 ( 2 ) 2015.02

ISSN 1932-6203

In budding yeast, the Mitotic Exit Network (MEN) regulates anaphase promoting complex/cyclosome (APC/C) via the Dbf2-Cdc14 signaling cascade. Dbf2 kinase phosphorylates and activates Cdc14 phosphatase, which removes the inhibitory phosphorylation of the APC/C cofactor Cdh1. Although each component of the MEN was highly conserved during evolution, there is presently no evidence supporting direct phosphorylation of CDC14 by large tumor suppressor kinase 1 (LATS1), the human counterpart of Dbf2; hence, it is unclear how LATS1 regulates APC/C. Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly. Nocodazole-induced phosphorylation of T7 was reduced by knockdown of LATS1 and LATS2 in HeLa cells, indicating that both of these kinases contribute to the phosphorylation of CDC26 in vivo. The T7 residue of CDC26 is critical for its interaction with APC6, a tetratricopeptide repeat-containing subunit of APC/C, and mutation of this residue to Asp (T7D) reduced the interaction of CDC26 with APC6. Replacement of endogenous CDC26 in HeLa cells with exogenous phosphor-mimic T7D-mutated CDC26 increased the elution size of APC/C subunits in a gel filtration assay, implying a change in the APC/C assembly upon phosphorylation of CDC26. Furthermore, T7D-mutated CDC26 promoted the ubiquitination of polo-like kinase 1, a well-known substrate of APC/C. Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C.

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Effectiveness of third-line chemotherapy in recurrent ovarian cancer patients

Yoshihama T., Chiyoda T., Kataoka F., Nomura H., Iguchi Y., Hashimoto S., Yamagami W., Tominaga E., Susumu N., Tsuda H., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 36 ( 4 ) 424 - 427 2015

ISSN 0392-2936

Objective: Despite recent advances in the treatment of recurrent ovarian cancer, little evidence exists describing the benefit of third-line chemotherapy. The present authors previously reported that the treatment-free interval (TFI) after second-line chemotherapy may predict a survival benefit of third-line chemotherapy, however the length of TFI was uncertain due to limited cases. In this study, the authors evaluated the length of TFI, which is correlated with the effectiveness of third-line chemotherapy and a prognostic factor of third-line chemotherapy. Materials and Methods: The authors reviewed the medical records of 85 women with recurrent ovarian cancer who received third-line chemotherapy after a paclitaxel/carboplatin (PC) regimen as first-line chemotherapy. Results: The response rate [complete response (CR) + partial response (PR)] and clinical benefit rate [(CBR): CR + PR + stable disease (SD)] during the TFI after second-line chemotherapy for 0-3 months, 3-6 months, and 6-12 months and ≥ 12 months were 9.8%, 0%, 0%, 43.8% and 15.7%, 50%, 66.7%, and 93.8%, respectively. The median overall survival (OS) from the onset of third-line chemotherapy was longer for TFI ≥3 months than for TFI 0-3 months (795 days vs. 281 days, p < 0.001). Finally, according to univariate (HR = 0.256;p < 0.001) and multivariate (HR = 0.264; p < 0.001) analyses, TFI was the independent significant prognostic factor for OS. Conclusions: TFI less than three months after second-line chemotherapy may predict little survival benefit of third-line chemotherapy.

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IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress

Shimizu Takatsune, Sugihara Eiji, Yamaguchi-Iwai Sayaka, Tamaki Sakura, Koyama Yuko, Kamel Walied, Ueki Arisa, Ishikawa Tomoki, Chiyoda Tatsuyuki, Osuka Satoru, Onishi Nobuyuki, Ikeda Hiroko, Kamei Junzo, Matsuo Koichi, Fukuchi Yumi, Nagai Toshihiro, Toguchida Junya, Toyama Yoshiaki, Muto Akihiro, Saya Hideyuki

Cancer Research (AMER ASSOC CANCER RESEARCH) 74 ( 22 ) 6531 - 6541 2014.11

ISSN 0008-5472

Osteosarcoma is a malignant bone tumor in children and adolescents characterized by intrinsic therapeutic resistance. The IGF2 is expressed at elevated levels in osteosarcoma after treatment with chemotherapy, prompting an examination of its functional contributions to resistance. We found that continuous exposure to IGF2 or insulin in the absence of serum created a dormant growth state in osteosarcoma cells that conferred resistance to various chemotherapeutic drugs in vitro. Mechanistic investigations revealed that this dormant state correlated with downregulation of downstream signaling by the IGF1 receptor, heightened cell survival, enhanced autophagy, and the presence of extracellular glutamine. Notably, inhibiting autophagy or depleting glutamine was sufficient to increase chemotherapeutic sensitivity in osteosarcoma xenografts in mice. Clinically, we confirmed that IGF expression levels were elevated in human osteosarcoma specimens from patients who received chemotherapy. Together, our results suggest that activation of IGF or insulin signaling preserves the survival of osteosarcoma cells under chemotherapeutic stress, providing a drug-resistant population that may engender minimal residual disease. Attenuating this survival mechanism may help overcome therapeutic resistance in osteosarcoma.

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Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

Nobusue Hiroyuki, Onishi Nobuyuki, Shimizu Takatsune, Sugihara Eiji, Oki Yoshinao, Sumikawa Yuko, Chiyoda Tatsuyuki, Akashi Koichi, Saya Hideyuki, Kano Koichiro

Nature Communications (NATURE PUBLISHING GROUP) 5 3368 2014

ISSN 2041-1723

Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. Here we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. Induction of adipocyte differentiation results in disruption of actin stress fibres through downregulation of RhoA-ROCK signalling. The consequent rapid increase in monomeric G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. Moreover, we found that MKL1 and PPARγ act in a mutually antagonistic manner in the adipocytic differentiation programme. Our findings thus provide new mechanistic insight into the relation between the dynamics of cell shape and transcriptional regulation during cellular differentiation.

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Simultaneous analysis of the gene expression profiles of cancer and stromal cells in endometrial cancer

Iguchi Yoko, Ito Yoichi M., Kataoka Fumio, Nomura Hiroyuki, Tanaka Hideo, Chiyoda Tatsuyuki, Hashimoto Shiho, Nishimura Sadako, Takano Masashi, Yamagami Wataru, Susumu Nobuyuki, Aoki Daisuke, Tsuda Hiroshi

Genes Chromosomes and Cancer (WILEY-BLACKWELL) 53 ( 9 ) 725 - 737 2014

ISSN 1045-2257

To address the role of cancer-stroma interactions, we performed gene expression profiling of both cancer and stroma, using matching samples of endometrial cancer (EC), and analyzed the relationship between the gene expression pattern and prognosis in EC. Sixty EC cases were included in this study (38 nonrecurrent and 22 recurrent). Cancer and stroma were separated by performing laser capture microdissection, and microarray analysis was performed separately on cancer and stromal cells. Genes related with progression-free survival (PFS) in cancer and stroma were analyzed using the Cox regression model, and we established a formula, based on the gene expression pattern of cancer and stroma, to predict recurrence using logistic regression. We estimated the accuracy of the formula using the 0.632 method. All cases were classified based on the 79 selected genes of cancer and stroma related to PFS, based on unsupervised clustering. A total of 143 genes in cancer, and 79 genes in stroma were significantly related with PFS. The estimated area under the curve of receiver operating characteristics curve in cancer and stroma to predict recurrence were 0.800 and 0.758, respectively. Based on the 79 genes of cancer, the 22 recurrent cases were divided into two groups, which generally correlated with the histological grade. In contrast, based on the 79 genes of stroma, the 22 recurrent cases displayed homogeneous gene expression, unrelated to the histological grade. We conclude that gene expression profiles of cancer and stroma can predict the recurrence of EC and stromal that gene expression does not depend on the cancer grade.

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腹腔鏡を用いて子宮筋腫を核出した後に子宮肉腫を発症した2例

千代田達幸, 片岡史夫, 野村弘行, 有馬宏和, 橋本志歩, 桑波田美智子, 野上侑哉, 山上亘, 進伸幸, 吉村泰典, 青木大輔

日本産科婦人科内視鏡学会雑誌 ((一社)日本産科婦人科内視鏡学会) 29 ( Suppl.I ) 164 - 164 2013.08

ISSN 1884-9938

Gene scoring model to predict recurrence in low- and intermediate-risk uterine endometrial cancer: Establishment of uterine print

Tatsuyuki Chiyoda, Yoichi M. Ito, Fumio Kataoka, Wataru Yamagami, Hiroyuki Nomura, Hiroshi Tsuda, Hideo Tanaka, Masashi Takano, Sadako Nishimura, Yoko Iguchi, Shiho Hashimoto, Tomoko Yoshihama, Nobuyuki Susumu, Daisuke Aoki

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 31 ( 15 ) 1733 - 1739 2013.05

ISSN 0732-183X

卵巣成熟嚢胞性奇形腫の悪性転化を好中球/リンパ球比(N/L比)で予測できるか

澤野佳子, 千代田達幸, 片岡史夫, 野村弘行, 山上亘, 津田浩史, 井口蓉子, 橋本志歩, 冨永英一郎, 進伸幸, 吉村泰典, 青木大輔

関東連合産科婦人科学会誌 ((一社)関東連合産科婦人科学会) 50 ( 2 ) 334 - 334 2013.05

ISSN 2186-0610

The APC/C activator Cdh1 regulates the G2/M transition during differentiation of placental trophoblast stem cells

Naoe Hideaki, Chiyoda Tatsuyuki, Ishizawa Jo, Masuda Kenta, Saya Hideyuki, Kuninaka Shinji

Biochemical and Biophysical Research Communications 430 ( 2 ) 757 - 762 2013.01

ISSN 0006-291X

Differentiation of placental trophoblast stem (TS) cells to trophoblast giant (TG) cells is accompanied by transition from a mitotic cell cycle to an endocycle. Here, we report that Cdh1, a regulator of the anaphase-promoting complex/cyclosome (APC/C), negatively regulates mitotic entry upon the mitotic/endocycle transition. TS cells derived from homozygous Cdh1 gene-trapped (Cdh1^GT/GT) murine embryos accumulated mitotic cyclins and precociously entered mitosis after induction of TS cell differentiation, indicating that Cdh1 is required for the switch from mitosis to the endocycle. Furthermore, the Cdh1^GT/GT TS cells and placenta showed aberrant expression of placental differentiation markers. These data highlight an important role of Cdh1 in the G2/M transition during placental differentiation.

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The origin of stroma surrounding epithelial ovarian cancer cells

Akahane Tomoko, Hirasawa Akira, Tsuda Hiroshi, Kataoka Fumio, Nishimura Sadako, Tanaka Hideo, Tominaga Eiichiro, Nomura Hiroyuki, Chiyoda Tatsuyuki, Iguchi Yoko, Yamagami Wataru, Susumu Nobuyuki, Aoki Daisuke

International Journal of Gynecological Pathology (LIPPINCOTT WILLIAMS & WILKINS) 32 ( 1 ) 26 - 30 2013.01

ISSN 0277-1691

Cancer stroma is thought to play an important role in tumor behavior, including invasion or metastasis and response to therapy. Cancer stroma is generally thought either to be non-neoplastic cells, including tissue-marrow or bone-marrow-derived fibroblasts, or to originate in epithelial mesenchymal transition of cancer cells. In this study, we evaluated the status of the p53 gene in both the cancer cells and the cancer stroma in epithelial ovarian cancer (EOC) to elucidate the origin of the stroma. Samples from 16 EOC patients were included in this study. Tumor cells and adjacent nontumor stromal cells were microdissected and DNA was extracted separately. We analyzed p53 sequences (exons 5-8) of both cancer and stromal tissues in all cases. Furthermore, we examined p53 protein expression in all cases. Mutations in p53 were detected in 9 of the 16 EOCs: in 8 of these cases, the mutations were detected only in cancer cells. In 1 case, the same mutation (R248Q) was detected in both cancer and stromal tissues, and p53 protein expression was detected in both the cancer cells and the cancer stroma. Most cancer stroma in EOC is thought to originate from non-neoplastic cells, but some parts of the cancer stroma might originate from cancer cells.

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LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression

Chiyoda Tatsuyuki, Sugiyama Naoyuki, Shimizu Takatsune, Naoe Hideaki, Kobayashi Yusuke, Ishizawa Jo, Arima Yoshimi, Tsuda Hiroshi, Ito Masaaki, Kaibuchi Kozo, Aoki Daisuke, Ishihama Yasushi, Saya Hideyuki, Kuninaka Shinji

Journal of Cell Biology (ROCKEFELLER UNIV PRESS) 197 ( 5 ) 625 - 641 2012.05

ISSN 0021-9525

In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. In contrast, no phosphatase substrates of LATS1/WARTS kinase, the mammalian equivalent of Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase- targeting subunit 1) as a new substrate for LATS1. LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1. An MYPT1 mutant (S445A) failed to dephosphorylate Thr 210 of PLK1 (pololike kinase 1), thereby activating PLK1. This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. Consistent with this, LATS1-depleted HeLa cells or fibroblasts from LATS1 knockout mice showed increased PLK1 activity. We also found deoxyribonucleic acid (DNA) damage-induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. Furthermore, LATS1 knockdown cells showed reduced G2 checkpoint arrest after DNA damage. These results indicate that LATS1 phosphorylates a phosphatase as does the yeast Dbf2 and demonstrate a novel role of LATS1 in controlling PLK1 at the G2 DNA damage checkpoint.

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Induction of ZEB proteins by inactivation of RB protein is key determinant of mesenchymal phenotype of breast cancer

Arima Yoshimi, Hayashi Hidemi, Sasaki Mikako, Hosonaga Mari, Goto Takaaki M., Chiyoda Tatsuyuki, Kuninaka Shinji, Shibata Tatsuhiro, Ohata Hirokazu, Nakagama Hitoshi, Taya Yoichi, Saya Hideyuki

Journal of Biological Chemistry (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC) 287 ( 11 ) 7896 - 7906 2012.03

ISSN 0021-9258

Wepreviously showed that depletion of the retinoblastoma protein (RB) induces down-regulation of the adhesion molecule E-cadherin and thereby triggers the epithelial-mesenchymal transition. To further characterize the effect of RB inactivation on the phenotype of cancer cells, we have now examined RB expression in human breast cancer cell lines and clinical specimens. We found that RB-inactive cells exhibit a mesenchymal-like morphology and are highly invasive. We also found that ZEB proteins, transcriptional repressors of the E-cadherin gene, are markedly up-regulated in these cells in a manner sensitive to the miR-200 family of microRNAs. Moreover, depletion of ZEB in RB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial marker expression. These results implicate ZEB in induction of the epithelial-mesenchymal transition, as well as in maintenance of the mesenchymal phenotype in RB-inactive cells. We also developed a screening program for inhibitors of ZEB1 expression and thereby identified several cyclin-dependent kinase inhibitors that blocked both ZEB1 expression and RB phosphorylation. Together, our findings suggest that RB inactivation contributes to tumor progression not only through loss of cell cycle control but also through up-regulation of ZEB expression and induction of an invasive phenotype.

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EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy

Kataoka Fumio, Tsuda Hiroshi, Arao Tokuzo, Nishimura Sadako, Tanaka Hideo, Nomura Hiroyuki, Chiyoda Tatsuyuki, Hirasawa Akira, Akahane Tomoko, Nishio Hiroshi, Nishio Kazuto, Aoki Daisuke

Genes Chromosomes and Cancer (WILEY-BLACKWELL) 51 ( 3 ) 300 - 312 2012.03

ISSN 1045-2257

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and α-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC.

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Expression profiles of carcinosarcoma of the uterine corpus-are these similar to carcinoma or sarcoma?

Chiyoda Tatsuyuki, Tsuda Hiroshi, Tanaka Hideo, Kataoka Fumio, Nomura Hiroyuki, Nishimura Sadako, Takano Masashi, Susumu Nobuyuki, Saya Hideyuki, Aoki Daisuke

Genes Chromosomes and Cancer (WILEY-BLACKWELL) 51 ( 3 ) 229 - 239 2012.03

ISSN 1045-2257

Uterine carcinosarcoma (CS) is usually classified as uterine endometrial carcinoma (EC). However, CS is more aggressive even compared with high grade EC. CS is also reported to undergo epithelial to mesenchymal transition (EMT). In this study, we compared the gene expression profiles of CS, EC, and uterine sarcoma (US) and evaluated the role of EMT and chromosomal aberrations in CS tumor formation. Frozen tissues of 46 patients (14 CS, 24 EC, and 8 US) were included. The similarity was examined by Gene Set Enrichment Analysis (GSEA), Fisher's exact test, and clustering using "intrinsic gene set". We examined the expression of 39 EMT-related genes and evaluated TGF-beta signaling by phospho-SMAD2/3 (p-SMAD2/3) staining. Chromosomal regions differing between CS and EC were identified by chromosomal GSEA and comparative genomic hybridization (CGH) microarrays. Three statistical methods confirmed that CS resembled US rather than EC. Acquired markers of EMT were upregulated and attenuated markers of EMT were downregulated in CS. Immunohistochemistry showed that carcinomatous region of CS have higher expression of p-SMAD2/3 than EC (P = 0.008). Chromosomal GSEA showed that genes located at 19q13 had higher expression in CS. Furthermore, CGH microarray indicated that the TGFB1 locus at 19q13.1 was amplified in 4 of 7 samples. Based on the expression profile, CS resembles US rather than EC. TGF-beta signaling is activated in CS and chromosomal gains at 19q13, which includes the TGFB1 locus, suggest that this may contribute to high expression of TGF-beta and thereby EMT phenotype of CS.

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Role of circulating free Alu DNA in endometrial cancer

Tanaka Hideo, Tsuda Hiroshi, Nishimura Sadako, Nomura Hiroyuki, Kataoka Fumio, Chiyoda Tatsuyuki, Tanaka Kyoko, Iguchi Yoko, Susumu Nobuyuki, Aoki Daisuke

International Journal of Gynecological Cancer (LIPPINCOTT WILLIAMS & WILKINS) 22 ( 1 ) 82 - 86 2012.01

ISSN 1048-891X

Background: Endometrial cancer (EC) is the most common cancer of the female genital tract. However, no screening method for EC has been established yet. In this study, we evaluated the cell-free DNA in EC. Methods: Fifteen healthy individuals, 9 with benign gynecologic diseases, and 53 with ECs were included in this study. Alu sequences in free DNA fragments were used as surrogate markers, and cell-free DNA density was measured by quantitative real-time polymerase chain reaction. Results: The cell-free DNA levels in ECs tended to be higher than in benign condition (healthy individuals + benign gynecologic diseases, n = 24; P = 0.095). There was no significant difference in cell-free DNA among stage or histological grade of EC, and no significant change in cell-free DNA before and after operation (P = 0.25): Moreover, in 19 ECs, cell-free DNA decreased after operation, however, in 6 ECs, cell-free DNA did not decrease. Three ECs recurred, and cell-free DNA did not decrease in these cases. Conclusions: Measurement of cell-free DNA is not useful for EC screening; however, the change of cell-free DNA in a patient may be a prognostic biomarker of EC.

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Retrospective study comparing irinotecan and pegylated liposomal doxorubicin in treatment of recurrent platinum-refractory/resistant epithelial ovarian cancer

Nomura H., Tsuda H., Kataoka F., Chiyoda T., Yamagami W., Tominaga E., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 33 ( 1 ) 86 - 89 2012

ISSN 0392-2936

Purpose: The standard regimen for platinum-resistant/refractory recurrent epithelial ovarian cancer (EOC) remains to be determined. In this study, we retrospectively compared the effect of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in the treatment of platinum-resistant recurrent EOC. Methods: Thirty patients who received salvage chemotherapy with CPT-11 or PLD were included in the study. CPT-11 (100 mg/m ²) was administered intravenously on days 1, 8 and 15 every four weeks. PLD (50 mg/m ²) was administered on day 1 every four weeks. Treatment was repeated, provided that no disease progression or intolerable toxicity occurred. Results: Response rate in the CPT-11 group and PLD group showed no difference at 26.7% (p = 0.66) in both, while non-PD rate was 73.3% vs 33.3% (p < 0.05), respectively. Progression-free survival after CPT-11 treatment and PLD treatment was 28.4 weeks and 16.8 weeks (p = 0.07), respectively. Hand-foot syndrome and mucositis were more common in the PLD group than in the CPT-11 group (p < 0.05). Conclusions: The results indicate that CPT-11 is a promising drug for the treatment of platinum-resistant recurrent EOC.

Successfully treated case of epithelioid sarcoma of the vulva.

Chiyoda Tatsuyuki, Ishikawa Mitsuya, Nakamura Masaru, Ogawa Mariko, Takamatsu Kiyoshi

The journal of obstetrics and gynaecology research (WILEY-BLACKWELL) 37 ( 12 ) 1856 - 1859 2011.12

ISSN 1341-8076

Epithelioid sarcoma of the vulva is an extremely rare and aggressive tumor. This tumor most commonly occurs on the labia majora in women of reproductive age. The molecular pathogenesis remains largely unknown. Only 20 cases of vulvar epithelioid sarcoma have been reported to date and more than half have had poor outcomes. We report a successfully treated case of vulvar epithelioid sarcoma in a 33-year-old woman. We performed a radical vulvectomy with flap reconstruction. Three years after surgery, the patient remains well, showing no evidence of recurrence. Early tissue diagnosis of vulvar epithelioid sarcoma is essential because this tumor can be clinically misdiagnosed as a benign lesion. Gynecologists should be aware of this rare tumor variant and carefully plan the treatment.

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Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12

Kobayashi Yusuke, Shimizu Takatsune, Naoe Hideaki, Ueki Arisa, Ishizawa Joe, Chiyoda Tatsuyuki, Onishi Nobuyuki, Sugihara Eiji, Nagano Osamu, Banno Kouji, Kuninaka Shinji, Aoki Daisuke, Saya Hideyuki

American Journal of Pathology 179 ( 3 ) 1471 - 1482 2011.09

ISSN 0002-9440

Gestational choriocarcinoma is a malignant trophoblastic tumor. The development of novel molecular-targeted therapies is needed to reduce the toxicity of current multiagent chemotherapy and to treat successfully the chemoresistant cases. The molecular mechanisms underlying choriocarcinoma tumorigenesis remain uncharacterized, however, and appropriate choriocarcinoma animal models have not yet been developed. In this study, we established a choriocarcinoma model by inoculating mice with induced-choriocarcinoma cell1 (iC ³-1) cells, generated from HTR8/SVneo human trophoblastic cells retrovirally transduced with activated H-RAS (HRASV12). The iC ³-1 cells exhibited constitutive activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and developed into lethal tumors in all inoculated mice. Histopathological analysis revealed that the tumors consisted of two distinct types of cells, reminiscent of syncytiotrophoblasts and cytotrophoblasts, as seen in the human choriocarcinoma. The tumors expressed HLA-G and cytokeratin (trophoblast markers) and hCG (a choriocarcinoma marker). Comparative analysis of gene expression profiles between iC ³-1 cells and parental HTR8/SVneo cells revealed that iC ³-1 cells expressed matrix metalloproteinases, epithelialmesenchymal transition-related genes, and SOX3 at higher levels than parental trophoblastic cells. Administration of SOX3-specific short-hairpin RNA decreased SOX3 expression and attenuated the tumorigenic activity of iC ³-1 cells, suggesting that SOX3 overexpression might be critically involved in the pathogenesis of choriocarcinoma. Our murine model represents a potent new tool for studying the pathogenesis and treatment of choriocarcinoma.

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The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress

Ishizawa Jo, Kuninaka Shinji, Sugihara Eiji, Naoe Hideaki, Kobayashi Yusuke, Chiyoda Tatsuyuki, Ueki Arisa, Araki Kimi, Yamamura Ken Ichi, Matsuzaki Yumi, Nakajima Hideaki, Ikeda Yasuo, Okamoto Shinichiro, Saya Hideyuki

Cancer Science (WILEY-BLACKWELL) 102 ( 5 ) 967 - 974 2011.05

ISSN 1347-9032

Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo.

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Overexpression of cofilin 1 can predict progression-free survival in patients with epithelial ovarian cancer receiving standard therapy

Nishimura Sadako, Tsuda Hiroshi, Kataoka Fumio, Arao Tokuzo, Nomura Hiroyuki, Chiyoda Tatsuyuki, Susumu Nobuyuki, Nishio Kazuto, Aoki Daisuke

Human Pathology (W B SAUNDERS CO-ELSEVIER INC) 42 ( 4 ) 516 - 521 2011.04

ISSN 0046-8177

The aim of this study was to examine the relation between cofilin 1 expression and progression-free survival in advanced epithelial ovarian cancer. We performed quantitative reverse transcriptase polymerase chain reaction and immunohistochemical analysis in 78 patients with advanced epithelial ovarian cancer (excluding those with mucinous and clear-cell types). All patients received the standard therapy, including staging laparotomy and adjuvant chemotherapy consisting of carboplatin and paclitaxel. Of 78 samples, RNA from 62 samples was available for reverse transcriptase polymerase chain reaction analysis. We defined cofilin 1 high expression as relative gene expression equal to or higher than the median and low expression as gene expression lower than median. The progression-free survival was longer in cofilin 1 low-expression cases than in high-expression cases (P = .039). Multivariate analysis demonstrated that stage and cofilin 1 expression were significant predictors of progression-free survival. Of the 78 samples, 54 were appropriate for immunohistochemical study. In 35 of those 54 cases, cofilin 1 protein expression was detected. The progression-free survival was longer in cofilin 1 protein-negative cases than in protein-positive cases (P = .042). Expression of cofilin 1 may predict the progression-free survival of patients with advanced epithelial ovarian cancer receiving standard therapy.

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Expression of hypoxia-inducible 2 (HIG2) protein in uterine cancer

Nishimura S., Tsuda H., Nomura H., Kataoka F., Chiyoda T., Tanaka H., Tanaka K., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 32 ( 2 ) 146 - 149 2011

ISSN 0392-2936

For both cervical cancer (UCC) and endometrial cancer (EMC) there are no effective prognostic markers. In this study, we evaluated HIG2 protein expression in 332 uterine cancers (186 UCCs and 146 EMCs) and examined the relationship between HIG2 protein expression and clinical factors, including prognosis. Totally, HIG2 expression was detected in 58% of UCC and 66% of EMC. However, there was no significant relationship between HIG2 expression and age, clinical stage and histology in either UCC or EMC. In addition, HIG2 protein expression was not related to prognosis of UCC or EMC. The positivity rate of HIG2 protein was 56% and 61% in early-stage UCC and EMC, respectively and 67% in non-squamous cell carcinoma of UCC. The positivity rate of HIG2 protein was high even in early-stage UCC and EMC.

The chemosensitivity of nodal metastases in recurrent epithelial ovarian cancer

Kataoka F., Tsuda H., Nomura H., Chiyoda T., Tominaga E., Suzuki A., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 32 ( 2 ) 160 - 163 2011

ISSN 0392-2936

Purpose: In this study, we compared second-line chemotherapy effects of nodal metastases with other metastases sites. Methods: The medical records of 44 women with recurrent ovarian cancer who received second-line chemotherapy were retrospectively reviewed. Results: Median age at the time of second-line chemotherapy was 55 years (range: 31-74). Recurrent sites were as follows: 29 patients had a solitary site (abdominal cavity: 8; lymph node: 3; pelvic cavity: 10; liver: 4; lung: 4) and 15 patients had multiple sites In total, the response rate was 30% (CR: 8, PR: 5). The response rate in sensitive cases was higher than in refractory/resistant cases (50% vs 5% p = 0.002). However, age, chemotherapy regimen, histologic type and number of diseases were not related with chemotherapy effect. In all diseases, response rate tended to be higher in lymph node disease than in the others (44% vs 27%). In both sensitive and refractory/resistant cases, response rate tended to be higher in lymph node disease. Conclusion: The response rate for lymph node diseases tended to be relatively high. Further study analyzing survival will be required to conclude the chemotherapy effect.

The anaphase-promoting complex/cyclosome activator Cdh1 modulates Rho GTPase by targeting p190 RhoGAP for degradation

Naoe Hideaki, Araki Kimi, Nagano Osamu, Kobayashi Yusuke, Ishizawa Jo, Chiyoda Tatsuyuki, Shimizu Takatsune, Yamamura Ken Ichi, Sasaki Yutaka, Saya Hideyuki, Kuninaka Shinji

Molecular and Cellular Biology (AMER SOC MICROBIOLOGY) 30 ( 16 ) 3994 - 4005 2010.08

ISSN 0270-7306

Cdh1 is an activator of the anaphase-promoting complex/cyclosome and contributes to mitotic exit and G₁ maintenance by targeting cell cycle proteins for degradation. However, Cdh1 is expressed and active in postmitotic or quiescent cells, suggesting that it has functions other than cell cycle control. Here, we found that homozygous Cdh1 gene-trapped (Cdh1 ^GT/GT) mouse embryonic fibroblasts (MEFs) and Cdh1-depleted HeLa cells reduced stress fiber formation significantly. The GTP-bound active Rho protein was apparently decreased in the Cdh1-depleted cells. The p190 protein, a major GTPase-activating protein for Rho, accumulated both in Cdh1 ^GT/GT MEFs and in Cdh1-knockdown HeLa cells. Cdh1 formed a physical complex with p190 and stimulated the efficient ubiquitination of p190, both in in vitro and in vivo. The motility of Cdh1-depleted HeLa cells was impaired; however, codepletion of p190 rescued the migration activity of these cells. Moreover, Cdh1^GT/GT embryos exhibited phenotypes similar to those observed for Rho-associated kinase I and II knockout mice: eyelid closure delay and disruptive architecture with frequent thrombus formation in the placental labyrinth layer, respectively. Furthermore, the p190 protein accumulated in the Cdh1^GT/GT embryonic tissues. Our data revealed a novel function for Cdh1 as a regulator of Rho and provided insights into the role of Cdh1 in cell cytoskeleton organization and cell motility.

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Lymph node metastasis in grossly apparent stages I and II epithelial ovarian cancer

Nomura Hiroyuki, Tsuda Hiroshi, Susumu Nobuyuki, Fujii Takuma, Banno Kouji, Kataoka Fumio, Tominaga Eiichiro, Suzuki Atsushi, Chiyoda Tatsuyuki, Aoki Daisuke

International Journal of Gynecological Cancer (LIPPINCOTT WILLIAMS & WILKINS) 20 ( 3 ) 341 - 345 2010.04

ISSN 1048-891X

Objectives: Incidence of lymph node metastasis is relatively high even in early-stage epithelial ovarian cancers (EOC). Lymphadenectomy is important in the surgical treatment of EOC; however, the exact role of lymphadenectomy in the management of EOC remains unclear. In this study, we evaluated lymph node metastasis in stages I and II EOC patients. Patients and Methods: Seventy-nine patients with stage I/II EOC underwent initial surgery, and 68 patients received adjuvant platinum and taxane chemotherapy after surgery at Keio University Hospital. The patients were evaluated with respect to age at diagnosis, clinical stage, histology, histological grade, and tumor laterality. Results: Of the 79 patients, 10 (12.7%) had lymph node metastasis. Of these, 4 (5.1%) had lymph node metastasis in paraaortic lymph node (PAN) only, 1 (1.3%) in pelvic lymph node (PLN) only, and 5 (6.3%) in both PAN and PLN. The incidence of serous-type lymph node metastasis in PAN, PAN + PLN, and total was higher than nonserous type (25% vs 1.5%, P < 0.0001;25% vs 3.0%, P = 0.001; 50% vs 5.9%, P < 0.0001). However, there was no significant difference between lymph node status and T factor or histological grade. In 78% of patients (7/9), metastases in contralateral lymph nodes were present (contralateral, 2; bilateral, 5). There was no significant difference in progression-free survival between node-positive and node-negative groups (P = 0.47). Conclusions: Based on diagnostic value, the result suggests that the role of lymphadenectomy might differ by histological type, as its therapeutic effect might be unclear. A multicenter analysis is essential for confirmation.

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The sensitivity and specificity of a new formula to distinguish endometrioid type endometrial carcinoma from ovarian endometrial carcinoma

Nishimura Sadako, Ito Yoichi M., Tsuda Hiroshi, Ohnishi Yoshitaka, Kataoka Fumio, Nomura Hiroyuki, Chiyoda Tatsuyuki, Suzuki Atsushi, Susumu Nobuyuki, Aoki Daisuke, Hatae Masayuki

European Journal of Obstetrics Gynecology and Reproductive Biology (ELSEVIER SCIENCE BV) 148 ( 1 ) 67 - 72 2010.01

ISSN 0301-2115

Objectives: Endometrioid type adenocarcinoma sometimes occupies both endometrium and ovary and in some cases the origin cannot be determined. Study design: In this study, we established a formula to distinguish ovarian endometrioid cancer (EOC) from endometrioid type endometrial cancer (EEC), based on our previous report of cyclin and KI67 expression pattern by immunohistochemistry of 36 EECc and 37 OECc by the logistic regression. We calculated the diagnostic accuracy using 92 test samples retrospectively and finally could diagnose the origin of 16 cases in whom endometrioid type adenocarcinoma arose in both ovary and endometrium and could be determined by Scully's criteria, and 15 cases in whom endometrioid type adenocarcinoma arose in both ovary and endometrium and Scully's criteria were not usuful retrospectively. Results: The estimated formula is as follows: Logit(Prob(EOC)) = -1.1437 - 0.0853 CNA + 0.0423 CNB + 0.173 CND1 + 0.0129 CNE + 0.0224 CNF + 0.0508 KI67, where Prob(EOC) is the probability that a clinical sample is EOC. If Prob(EOC) is larger than 0.5, the diagnosis is ovarian cancer; if less than 0.5 it is endometrial cancer. Finally, using the formula, 37 of 48 EECs (77.1%) and 33 of 44 EOCs (75.0%) were correctly classified, with an accuracy of 76.1% (p < 0.0001), retrospectively. In 12 of the 16 cases (75%) who could be determined by Scully's criteria, the origin determined by Scully's criteria was concordant with the origin determined by the formula retrospectively. In the other 15 cases, 12 cases were judged as ovary/ovary, 2 cases were judged as uterus/uterus and 1 case was judged as uterus/ovary. Conclusion: The formula we established was thought to be useful to distinguish the origin of the cases in whom endometrioid type adenocarcinoma arises in both ovary and endometrium.

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Effects of third-line chemotherapy for women with recurrent ovarian cancer who received platinum/taxane regimens as first-line chemotherapy

Chiyoda T., Tsuda H., Nomura H., Kataoka F., Tominaga E., Suzuki A., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 31 ( 4 ) 364 - 368 2010

ISSN 0392-2936

Purpose: At present, it remains unclear whether the third-line chemotherapy has clinical benefit. In this study, we retrospectively evaluated the effect of third-line chemotherapy. Methods: We reviewed the medical records of 40 women with recurrent epithelial ovarian cancer (EOC) who received third-line chemotherapy after platinum/taxan regimens as first line chemotherapy. Results: In the first recurrence, 23 cases were platinum-sensitive and 17 cases were platinum-resistant. The cases for which the treatment-free interval from second-line chemotherapy (TFI) was ≥ 3 months had a higher non-PD rate than those with TFI < 3 months (86% vs 33%, p = 0.002). In addition, the median overall survival (OS) was longer for TFI ≥ 3 months than for TFI < 3 months (1195 days vs 235 days, p = 0.004). Finally, TFI was an independent significant prognostic factor by univariate (HR 3.28, p = 0.006) and multivariate (HR 3.21, p = 0.018) proportional hazard tests. Conclusion: TFI from second-line chemotherapy may predict a survival benefit of third-line chemotherapy.

Can ABCF2 protein expression predict the prognosis of uterine cancer?

Nishimura S., Tsuda H., Miyagi Y., Hirasawa A., Suzuki A., Kataoka F., Nomura H., Chiyoda T., Banno K., Fujii T., Susumu N., Aoki D.

British Journal of Cancer (NATURE PUBLISHING GROUP) 99 ( 10 ) 1651 - 1655 2008.11

ISSN 0007-0920

Uterine cervical and endometrial cancers are common malignant solid neoplasms for which there are no useful prognostic markers. In this study, we evaluate the relationship between ATP-binding cassette superfamily F2 (ABCF2) expression and clinical factors including clinical stage, histologic type, grade and prognosis in uterine cervical and endometrial cancer. Two hundred and sixty seven cervical and 103 endometrial cancers were studied. ATP-binding cassette superfamily F2 cytoplasmic expression was detected by immunohistochemical staining and scored as positive or negative. Among cervical cancer cases, 149 (55.8%) expressed ABCF2. The overall survival was longer in ABCF2-negative than ABCF2-positive cases (P=0.0069). Statistically significant prognostic factors for survival were ABCF2 positivity (risk ratio (rr)=1.437), old age (rr=1.550) and advanced stage (rr=2.577). ATP-binding cassette superfamily F2 positivity was an independent prognostic factor by multivariate proportional hazard test (P=0.0002). Among endometrial cancer cases, 72 (69.9%) were cytoplasmic ABCF2 positive. However, there was no significant relationship between ABCF2 expression and age, clinical stage, histologic type, histologic grade, oestrogen receptor status or prognosis. ATP-binding cassette superfamily F2 expression may be a useful prognostic marker in cervical but not endometrial cancer. The role of ABCF2 protein may differ depending on the type of cancer.

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Sox21 is a repressor of neuronal differentiation and is antagonized by YB-1

Ohba Hiroyuki, Chiyoda Tatsuyuki, Endo Emmy, Yano Masato, Hayakawa Yoshika, Sakaguchi Masanori, Darnell Robert B., Okano Hirotaka J., Okano Hideyuki

Neuroscience Letters (ELSEVIER SCI IRELAND LTD) 358 ( 3 ) 157 - 160 2004.04

ISSN 0304-3940

Sox21, a high-mobility group box transcription factor, is expressed throughout the immature neural stem/progenitor population in ventricular zone but not in the cortical plate in embryonic mouse brain and its expression is restricted to the subventricular zone in the adult brain. In undifferentiated PC12 cells, endogenous Sox21 expression is detected but its expression ceases during the nerve growth factor (NGF)-induced neuronal differentiation. Overexpression of Sox21 results in a substantial repression of NGF-induced neurite outgrowth in PC12 cells. Further, we biochemically identified a Sox21-associating protein, Y-box binding protein 1 which not only binds to Sox21 but also partially restores NGF-induced neurite outgrowth of PC12 cells inhibited by Sox21. These results suggest that Sox21 is a repressor of neuronal differentiation in the developing nervous system.

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