Published papers

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.

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.

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.

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.

© 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.

　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.

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)

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)