論文 - 山上　亘

A phase II trial evaluating the efficacy and safety of repeated high dose medroxyprogesterone acetate (MPA) therapy for patients with recurrent early-stage endometrial cancer or atypical endometrial hyperplasia: Japanese. Gynecologic Oncology Group study (JGOG2051/KGOG2031, REMPA trial)

Sakai K, Yamagami W, Sato Y, Susumu N, Yokoyama Y, Takehara K, Mandai M, Okamoto A

J Gynecol Oncol 35 （ 6 ） e106 - e106 2024年11月

研究論文（学術雑誌）, 共著

子宮体癌における術後補助化学中に壊死性筋膜炎が疑われた1例

真鍋悠歌，横田めぐみ，高畑海音子，和田美智子，山上 亘，田中 守

東京産科婦人科学会会誌 73 （ 4 ） 811 - 817 2024年10月

研究論文（学術雑誌）, 共著, 査読有り

子宮頸管妊娠に対しメトトレキサート（MTX）と子宮動脈塞栓症（UAE）を併用し保存的治療を行った2例

白石 慧，上條慎太郎，佐久間萌子，大岡令奈，松沢優一，内田志穂，祝井麻希，内田明花，山田満稔，山上 亘，田中 守

東京産科婦人科学会会誌 73 （ 4 ） 848 - 853 2024年10月

研究論文（学術雑誌）, 共著, 査読有り

Cost-effectiveness analysis of hospital treatment volume and survival outcomes in endometrial cancer in Japan.

Machida H, Matsuo K, Higashi T, Aoki D, Enomoto T, Okamoto A, Katabuchi H, Nagase S, Mandai M, Yaegashi N, Yamagami W, Mikami M

Journal of gynecologic oncology 35 （ 5 ） e61 2024年09月

研究論文（学術雑誌）, 共著,  ISSN  2005-0380

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Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks

Onji H., Tate S., Sakaue T., Fujiwara K., Nakano S., Kawaida M., Onishi N., Matsumoto T., Yamagami W., Sugiyama T., Higashiyama S., Pommier Y., Kobayashi Y., Murai J.

Oncogene 43 （ 32 ） 2475 - 2489 2024年08月

ISSN  09509232

　概要を見る

The preferential response to PARP inhibitors (PARPis) in BRCA-deficient and Schlafen 11 (SLFN11)-expressing ovarian cancers has been documented, yet the underlying molecular mechanisms remain unclear. As the accumulation of single-strand DNA (ssDNA) gaps behind replication forks is key for the lethality effect of PARPis, we investigated the combined effects of SLFN11 expression and BRCA deficiency on PARPi sensitivity and ssDNA gap formation in human cancer cells. PARPis increased chromatin-bound RPA2 and ssDNA gaps in SLFN11-expressing cells and even more in cells with BRCA1 or BRCA2 deficiency. SLFN11 was co-localized with chromatin-bound RPA2 under PARPis treatment, with enhanced recruitment in BRCA2-deficient cells. Notably, the chromatin-bound SLFN11 under PARPis did not block replication, contrary to its function under replication stress. SLFN11 recruitment was attenuated by the inactivation of MRE11. Hence, under PARPi treatment, MRE11 expression and BRCA deficiency lead to ssDNA gaps behind replication forks, where SLFN11 binds and increases their accumulation. As ovarian cancer patients who responded (progression-free survival >2 years) to olaparib maintenance therapy had a significantly higher SLFN11-positivity than short-responders (<6 months), our findings provide a mechanistic understanding of the favorable responses to PARPis in SLFN11-expressing and BRCA-deficient tumors. It highlight the clinical implications of SLFN11. (Figure presented.)

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Case report of two long term ovarian cancer survivors with brain metastases following multimodal treatment including chemotherapy, radiotherapy and maintenance olaparib: An institutional case series and literature review

Tsuchino Y., Chiyoda T., Jisaka M., Sakamaki T., Hirata M., Takahashi M., Yoshimura T., Sakai K., Wada M., Yamagami W.

Gynecologic Oncology Reports （Gynecologic Oncology Reports）  54   101444 2024年08月

ISSN  2352-5789

　概要を見る

Brain metastasis from ovarian cancer is a very rare condition with a poor prognosis. However, due to its rarity, there is no established treatment strategy. We present a case series of brain metastasis with ovarian cancer, focusing on two long-term survivors treated with multimodal therapy. Among the nine cases, the median survival time after brain metastases was six months (range: 0–58 months). Eight patients had high-grade serous carcinoma (HGSC). Three of the four patients who underwent genetic testing tested positive for germline BRCA2 (gBRCA2) mutation. Two patients survived longer than 4 years after the diagnosis of brain metastases. Both of these patients received chemotherapy, radiation therapy, and olaparib, a molecularly targeted drug, as maintenance therapy. This case series suggests that patients with gBRCA2 mutation-positive HGSC may be at a high risk of developing brain metastases. A multidisciplinary approach, including PARP inhibitors, may improve the prognosis of patients with brain metastases from ovarian cancer.

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原発性卵巣癌が疑われたが審査腹腔鏡により転移性卵巣癌と診断された診断された2例

落合大輔，千代田達幸，西尾 浩，地阪光代，坂巻智美，平田 桃，吉村拓馬，高橋美央，坂井健良，和田美智子，山上 亘，田中 守

東京産科婦人科学会会誌 73 （ 3 ） 627 - 632 2024年07月

研究論文（学術雑誌）, 共著, 査読有り

Detailed report on the clinicopathological factors of patients with endometrial cancer in Japan: a JSOG gynecologic tumor registry-based study

Makabe T, Yamagami W, Takahashi F, Tokunaga H, Yamamoto E, Yokoyama Y, Yoshino K, Kawana K, Nagase S

J Gynecol Oncol 35 （ 4 ） e54 - e54 2024年07月

研究論文（学術雑誌）, 共著

Gastric-type adenocarcinoma of the uterine cervix: clinical features and future directions

Nishio H., Matsuda R., Iwata T., Yamagami W.

Japanese Journal of Clinical Oncology （Japanese Journal of Clinical Oncology）  54 （ 5 ） 516 - 520 2024年05月

ISSN  03682811

　概要を見る

The concept of gastric-type mucinous carcinoma of the uterine cervix (GAS) has been accepted worldwide because of its aggressive clinical behaviour and the absence of high-risk human papilloma virus infection. The World Health Organization (WHO) 2020 classification divides cervical tumours into two categories: human papilloma virus-associated and human papilloma virus-independent. Hence, GAS is now classified as an human papilloma virus-independent gastric type. Because clinical studies have reported that GAS is refractory to conventional treatments such as chemotherapy and radiotherapy, especially at an advanced stage, and has aggressive features with widespread dissemination to unusual sites, such as the omentum, peritoneum and distant organs, it is urgent to establish new treatment strategies by comparing the molecular profiles of human papilloma virus-associated adenocarcinomas. A series of genetic mutations characteristic to GAS encourage the development of future treatment strategies such as targeted therapy and immunotherapy.

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Targeting Galectin 3 illuminates its contributions to the pathology of uterine serous carcinoma

Matoba Y., Zarrella D.T., Pooladanda V., Azimi Mohammadabadi M., Kim E., Kumar S., Xu M., Qin X., Ray L.J., Devins K.M., Kumar R., Kononenko A., Eisenhauer E., Veillard I.E., Yamagami W., Hill S.J., Sarosiek K.A., Yeku O.O., Spriggs D.R., Rueda B.R.

British Journal of Cancer （British Journal of Cancer）  130 （ 9 ） 1463 - 1476 2024年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00070920

　概要を見る

Background: Uterine serous cancer (USC) comprises around 10% of all uterine cancers. However, USC accounts for approximately 40% of uterine cancer deaths, which is attributed to tumor aggressiveness and limited effective treatment. Galectin 3 (Gal3) has been implicated in promoting aggressive features in some malignancies. However, Gal3’s role in promoting USC pathology is lacking. Methods: We explored the relationship between LGALS3 levels and prognosis in USC patients using TCGA database, and examined the association between Gal3 levels in primary USC tumors and clinical-pathological features. CRISPR/Cas9-mediated Gal3-knockout (KO) and GB1107, inhibitor of Gal3, were employed to evaluate Gal3’s impact on cell function. Results: TCGA analysis revealed a worse prognosis for USC patients with high LGALS3. Patients with no-to-low Gal3 expression in primary tumors exhibited reduced clinical-pathological tumor progression. Gal3-KO and GB1107 reduced cell proliferation, stemness, adhesion, migration, and or invasion properties of USC lines. Furthermore, Gal3-positive conditioned media (CM) stimulated vascular tubal formation and branching and transition of fibroblast to cancer-associated fibroblast compared to Gal3-negative CM. Xenograft models emphasized the significance of Gal3 loss with fewer and smaller tumors compared to controls. Moreover, GB1107 impeded the growth of USC patient-derived organoids. Conclusion: These findings suggest inhibiting Gal3 may benefit USC patients.

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めまいを訴える更年期女性への漢方処方と効果

椎名美季，横田めぐみ，大野あゆみ，谷本慧子，堀場裕子，山上 亘

産婦人科漢方のあゆみ 40   26 - 30 2024年04月

研究論文（学術雑誌）, 共著, 最終著者

難治性のほてり・発汗に対して補腎剤が著効した3症例

横田めぐみ，椎名美季，大野あゆみ，谷本慧子，堀場裕子，山上 亘

産婦人科漢方研究のあゆみ 40   58 - 62 2024年04月

研究論文（学術雑誌）, 共著, 最終著者

血清hCG値の推移を観察した妊娠高血圧腎症合併間葉性異形成胎盤の1例

山本大貴，田中邦生，高橋まりな，梶川かおる，秋田啓介，福間優花，大谷利光，池ノ上 学，春日義史，山上 亘，田中 守

東京産科婦人科学会会誌 73 （ 2 ） 402 - 406 2024年04月

研究論文（学術雑誌）, 共著

BRCA1/2 reversion mutations in a pan-cancer cohort

Nakamura K, Hayashi H, Kawano R, Ishikawa M, Aimono E, Mizuno T, Kuroda H, Kojima Y, Niikura N, Kawanishi A, Takeshita K, Suzuki S, Ueno S, Okuwaki K, Sasaki J, Yamaguchi M, Masuda K, Chiyoda T, Yamagami W, Okada C, Nohara S, Tanishima S, Nishihara H

Cancer Sci 115 （ 2 ） 635 - 647 2024年02月

研究論文（学術雑誌）, 共著, 査読有り

Pretreatment systemic inflammatory markers predict survival in endometrial cancer: A Japanese Gynecologic Oncology Group 2043 exploratory data analysis

Nishio S., Murotani K., Yamagami W., Suzuki S., Nakai H., Kato K., Tokunaga H., Nomura H., Yokoyama Y., Takehara K., Okamoto A.

Gynecologic Oncology （Gynecologic Oncology）  181   46 - 53 2024年02月

研究論文（学術雑誌）, 共著,  ISSN  00908258

　概要を見る

Objective: We investigated whether pretreatment systemic inflammatory markers are associated with survival outcomes in patients with endometrial cancer (EC). Methods: Data from the Japanese Gynecologic Oncology Group 2043 were analyzed. Patients who did not receive chemotherapy or were lost to follow-up were excluded. Associations of pretreatment systemic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hemoglobin, albumin, lymphocyte, and platelet (HALP) score, with progression-free survival (PFS) and overall survival (OS) were analyzed. The optimal NLR, PLR, and HALP score cutoff values for PFS and OS were determined. Survival estimates were calculated and compared using the Kaplan–Meier method and log-rank test. Results: We included 712 patients (median age: 55 [range, 28–74] years; body mass index [BMI]: 21.1 [15.2–38.6] kg/m2). For PFS, optimal NLR, PLR, and HALP score cutoff values were 1.48, 0.017, and 35.52, respectively, and for OS, the values were 1.88, 0.026, and 19.87, respectively. At optimal PFS-related cutoff values, NLR was associated with BMI; PLR with age, BMI, and clinical stage; and HALP score with BMI, clinical stage, and lymph node metastasis. At optimal OS-related cutoff values, NLR was associated with BMI, PLR, and BMI; the HALP score was associated with age and BMI. The HALP score was a prognostic factor for PFS (p = 0.025), while PLR and HALP scores were prognostic factors for OS (both p = 0.028). Conclusions: Pretreatment systemic inflammatory markers are associated with survival outcomes in patients with EC, with the HALP score being a prognostic factor for PFS and OS.

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Impact of COVID-19 on gynecological cancer incidence: a large cohort study in Japan

Komatsu H., Ikeda Y., Kawana K., Nagase S., Yoshino K., Yamagami W., Tokunaga H., Kato K., Kimura T., Aoki D.

International Journal of Clinical Oncology （International Journal of Clinical Oncology）  29 （ 1 ） 72 - 77 2024年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

　概要を見る

Background: The influence of the coronavirus disease 2019 (COVID-19) pandemic on the number of newly diagnosed gynecological cancers has not been extensively investigated in Japan. This study determined the impact of COVID-19 on the incidence of gynecological cancer. Methods: Using the Japanese Society of Obstetricians and Gynecologic Oncology registry database, the distribution of the number of patients based on clinical staging or tumor-node-metastasis classifications before and during the COVID-19 pandemic was analyzed to compare the trends. The clinical staging classification of cervical cancer in Japan was based on the International Federation of Gynecology and Obstetrics (FIGO) 2008 from 2018 to 2020 and on the FIGO 2018 from 2021. Since FIGO-2018 classified N1 cases as stage IIIC, we focused on T classification without referencing the clinical staging (FIGO staging) of patients with cervical cancer in 2021. Results: The number of patients with endometrial cancer and malignant ovarian tumors of all clinical stages increased uniformly yearly, while that of those with stage III cervical cancer rapidly increased in 2021 owing to the adoption of the revised classification. On comparing cases of cervical cancer in 2020 and 2021, we found that T1 cases decreased and T2 and T3 cases increased in 2021 compared to those in 2020 (p = 0.006). Cervical intraepithelial neoplasia/adenocarcinoma in situ incidence decreased in 2020 compared to that in 2019 but increased again in 2021. The number of patients with cervical cancer decreased in most prefectures in 2020. Conclusion: The incidence of locally advanced cervical cancer increased during the COVID-19 pandemic.

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Japan Society of Gynecologic Oncology 2022 guidelines for uterine cervical neoplasm treatment

Seino M., Nagase S., Tokunaga H., Yamagami W., Kobayashi Y., Tabata T., Kaneuchi M., Hirashima Y., Niikura H., Yoshino K., Takehara K., Baba T., Katabuchi H., Mikami M.

Journal of Gynecologic Oncology （Journal of Gynecologic Oncology）  35 （ 1 ） e15 - e15 2024年01月

研究論文（学術雑誌）, 査読有り,  ISSN  20050380

　概要を見る

The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2022 for the Treatment of Uterine Cervical Cancer are revised from the 2017 guideline. This guideline aimed to provide standard care for cervical cancer, indicate appropriate current treatment methods for cervical cancer, minimize variances in treatment methods among institutions, improve disease prognosis and treatment safety, reduce the economic and psychosomatic burden of patients by promoting the performance of appropriate treatment, and enhance mutual understanding between patients and healthcare professionals. The guidelines were prepared through the consensus of the JSGO Guideline Committee, based on a careful review of evidence gathered through the literature searches and the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise seven chapters and 5 algorithms. The main features of the 2022 revision are as follows: 1) added discussed points at the final consensus meeting; 2) revised the treatment methods based on the International Federation of Gynecology and Obstetrics 2018 staging system; 3) examined minimally invasive surgery based on Laparoscopic Approach to Cervical Cancer trial; 4) added clinical question (CQ) for treatments of rare histological types, gastric type, and small-cell neuroendocrine carcinoma; 5) added CQ for intensity-modulated radiation therapy; 6) added CQ for cancer genomic profiling test; and 7) added CQ for cancer survivorship. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2022 for the Treatment of Uterine Cervical Cancer.

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Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer

Kitazawa S., Chiyoda T., Nakamura K., Sakai K., Yoshihama T., Nishio H., Kobayashi Y., Iwata T., Banno K., Yamagami W., Nishihara H., Aoki D.

International Journal of Clinical Oncology （International Journal of Clinical Oncology）  28 （ 11 ） 1554 - 1562 2023年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

　概要を見る

Background: Japan’s health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. Methods: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. Results: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. Conclusion: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients’ prognosis and performance status should be considered before performing the test.

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Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: Annual Patient Report for 2020 and Annual Treatment Report for 2015

Yoshino K, Kurita T, Takahashi F, Nagase S; Board members of the 2022 Committee on Gynecologic Oncology of the Japan Society of Obstetrics and Gynecology

J Obstet Gynaecol Res 49 （ 11 ） 2584 - 2592 2023年11月

研究論文（学術雑誌）, 共著

当院における卵巣癌初回化学療法後の維持療法としてのニラパリブ使用経験

鈴木 渉，吉浜智子，平田 桃，家谷佳那，北澤晶子，高橋美央，吉村拓馬，坂井健良，千代田達幸，山上 亘，田中　守，青木大輔

東京産科婦人科学会会誌 72 （ 3 ） 420 - 424 2023年07月

研究論文（学術雑誌）, 査読有り