研究者詳細 - 横井　暁

Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis 査読有り国際誌

Kitami, K; Yoshihara, M; Tamauchi, S; Sugiyama, M; Koya, Y; Yamakita, Y; Fujimoto, H; Iyoshi, S; Uno, K; Mogi, K; Ikeda, Y; Yokoi, A; Yoshikawa, N; Nishino, K; Niimi, K; Nawa, A; Enomoto, A; Kajiyama, H

MATRIX BIOLOGY 109 巻頁： 70 - 90 2022年5月

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

Ovarian cancer (OvCa), a lethal gynecological malignancy, disseminates to the peritoneum. Mesothelial cells (MCs) act as barriers in the abdominal cavity, preventing the adhesion of cancer cells. However, in patients with OvCa, they are transformed into cancer-associated mesothelial cells (CAMs) via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis. However, attempts for restoring CAMs to their original state have been limited. Here, we investigated whether inhibition of mesenchymal transition and restoration of MCs by vitamin D suppressed the OvCa dissemination in vitro and in vivo. The effect of vitamin D on the mutual association of MCs and OvCa cells was evaluated using in vitro coculture models and in vivo using a xenograft model. Vitamin D restored the CAMs, and thrombospondin-1 (component of the extracellular matrix that is clinically associated with poor prognosis and is highly expressed in peritoneally metastasized OvCa) was found to promote OvCa cell adhesion and proliferation. Mechanistically, TGF-β1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-β signaling. Vitamin D inhibited mesenchymal transition in MCs and suppressed thrombospondin-1 expression via vitamin D receptor/Smad3 competition, contributing to the marked reduction in peritoneal dissemination in vivo. Importantly, vitamin D restored CAMs from a stabilized mesenchymal state to the epithelial state and normalized thrombospondin-1 expression in preclinical models that mimic cancerous peritonitis in vivo. MCs are key players in OvCa dissemination and peritoneal restoration and normalization of thrombospondin-1 expression by vitamin D may be a novel strategy for preventing OvCa dissemination.

DOI： 10.1016/j.matbio.2022.03.003

Is adjuvant chemotherapy necessary for young women with early-stage epithelial ovarian cancer who have undergone fertility-sparing surgery?: a multicenter retrospective analysis 査読有り国際誌

Ikeda, Y; Yoshihara, M; Yoshikawa, N; Yokoi, A; Tamauchi, S; Nishino, K; Niimi, K; Kajiyama, H

BMC WOMENS HEALTH 22 巻 ( 1 ) 頁： 80 - 80 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Women's Health

Objective: In young patients with early-stage epithelial ovarian carcinoma (EOC) who were received fertility-sparing surgery (FSS), the role of adjuvant chemotherapy is unclear. Here, we performed a multicenter study using inverse probability of treatment weighting (IPTW) to explore the effect of chemotherapy on patients’ survival. Methods: Between 1987 and 2015, a retrospective study was carried out, including 1183 patients with stage I EOC. Among them, a total of 101 women with stage I EOC who underwent FSS were investigated, including 64 and 37 patients with or without adjuvant chemotherapy, respectively. Oncologic outcomes were compared between the two arms using original and IPTW cohorts. Results: During 62.6 months (median) of follow-up, recurrence was noted in 11 (17.2%) women in the chemotherapy arm and 6 (16.2%) patients in the observation arm. In the unweighted cohort, the 5-year overall and recurrence-free survival (OS/RFS) rates of chemotherapy and observation arms were 86.3/80.8 and 90.2/79.8%, respectively. There was no significant difference between the two groups {Log-rank: P = 0.649 (OS)/P = 0.894 (RFS)}. In the IPTW cohort after adjusting for various clinicopathologic covariates, we also failed to identify a difference in RFS/OS between the two groups {RFS (chemotherapy vs. observation), HR: 0.501 (95% CI 0.234–1.072), P = 0.075: OS (chemotherapy vs. observation), HR: 0.939 (95% CI 0.330–2.669), P = 0.905}. Conclusions: Even after adjusting clinicopathologic covariates, performing adjuvant chemotherapy may not improve the oncologic outcome in young patients who have undergone FSS.

DOI： 10.1186/s12905-022-01642-z

Significance of platinum distribution to predict platinum resistance in ovarian cancer after platinum treatment in neoadjuvant chemotherapy 査読有り国際誌

Uno, K; Yoshikawa, N; Tazaki, A; Ohnuma, S; Kitami, K; Iyoshi, S; Mogi, K; Yoshihara, M; Koya, Y; Sugiyama, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kikkawa, F; Kato, M; Kajiyama, H

SCIENTIFIC REPORTS 12 巻 ( 1 ) 頁： 4513 - 4513 2022年3月

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

Most patients with ovarian cancer experience recurrence and develop resistance to platinum-based agents. The diagnosis of platinum resistance based on the platinum-free interval is not always accurate and timely in clinical settings. Herein, we used laser ablation inductively coupled plasma mass spectrometry to visualize the platinum distribution in the ovarian cancer tissues at the time of interval debulking surgery after neoadjuvant chemotherapy in 27patients with advanced high-grade serous ovarian cancer. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum throughout the tumor and adjacent stroma. The type A patients treated post-surgery with platinum-based adjuvant chemotherapy showed significantly shorter periods of recurrence after the last platinum-based chemotherapy session (p = 0.020) and were diagnosed with “platinum-resistant recurrence”. Moreover, type A was significantly correlated with worse prognosis (p = 0.031). Post-surgery treatment with non-platinum-based chemotherapy could be effective for the patients classified as type A. Our findings indicate that the platinum resistance can be predicted prior to recurrence, based on the platinum distribution; this could contribute to the selection of more appropriate adjuvant chemotherapy, which may lead to improves prognoses.

DOI： 10.1038/s41598-022-08503-7

Ukai, M; Suzuki, S; Yoshihara, M; Yokoi, A; Yoshikawa, N; Kajiyama, H; Kikkawa, F

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 27 巻 ( 3 ) 頁： 609 - 618 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Clinical Oncology

Background: Previous studies on adjuvant chemotherapy for patients with ovarian clear cell carcinoma (OCCC) have included a limited number of Asian patients with surgical stage I OCCC, despite differences in OCCC survival by race and stage. The aim of this study was to estimate the survival effect of the number of cycles of adjuvant taxane plus carboplatin chemotherapy in Asian patients with surgical stage I OCCC. Methods: We retrospectively identified 227 patients with surgical stage I OCCC at 14 institutions from 1995 to 2017. Kaplan–Meier analysis and Cox proportional hazard regression with inverse probability of treatment weighting (IPTW) adjustment were performed to evaluate overall survival (OS) and recurrence-free survival (RFS) in patients receiving ≤ 3 and 4–6 cycles of taxane plus platinum adjuvant chemotherapy. Results: Eighty-nine and 138 patients received ≤ 3 and 4–6 cycles of adjuvant chemotherapy, respectively. There was no between-group difference in OS or RFS with or without IPTW adjustment. In Cox proportional hazards analysis, 4–6 cycles of adjuvant chemotherapy were not associated with improved OS (HR 1.090; 95% CI 0.518–2.291; p = 0.821) or RFS (HR 1.144; 95% CI 0.619–2.114; p = 0.669) compared to ≤ 3 cycles, even with IPTW adjustment. Subgroup analysis in different substages of stage I OCCC showed that the number of cycles of adjuvant chemotherapy had no impact on OS or RFS. Conclusion: Three or fewer cycles of taxane plus carboplatin chemotherapy may be a reasonable treatment regime for patients with surgical staging I OCCC.

DOI： 10.1007/s10147-021-02075-8

Adipose-mesothelial crosstalk regulates peritoneal tumor microenvironment and accelerates metastasis of ovarian cancer

その他リンク： https://link.springer.com/article/10.1007/s10147-021-02075-8/fulltext.html

Mogi, K; Yoshihara, M; Uno, K; Iyoshi, S; Kitami, K; Sugiyama, M; Koya, Y; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 113 巻頁： 735 - 735 2022年2月

Vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer via THBS1

Kitami, K; Yoshihara, M; Sugiyama, M; Koya, Y; Yamakita, Y; Iyoshi, S; Uno, K; Mogi, K; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nishino, K; Niimi, K; Nawa, A; Kajiyama, H

CANCER SCIENCE 113 巻頁： 729 - 729 2022年2月

Prognostic impact of extracellular miRNAs in patients with high-grade serous ovarian carcinoma

Yoshida, K; Yokoi, A; Matsuzaki, J; Kato, T; Ochiya, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 113 巻頁： 1788 - 1788 2022年2月

Notch signaling contributes to drug resistance acquisition through metabolic alteration in advanced ovarian cancer

Sugiyama, M; Yoshihara, M; Koya, Y; Kitami, K; Uno, K; Iyoshi, S; Mogi, K; Yokoi, A; Nawa, A; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1280 - 1280 2022年2月

Drug repositioning screening for an inhibitor of EV secretion in ovarian cancer cells

Yoshioka, Y; Yokoi, A; Ochiya, T

CANCER SCIENCE 113 巻頁： 1410 - 1410 2022年2月

Discovering novel therapeutic agents for uterine leiomyosarcoma

Nagao, Y; Yokoi, A; Yoshida, K; Watanabe, E; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Yamamoto, Y; Kato, T; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1181 - 1181 2022年2月

Chemical library-based drug repositioning strategy for choriocarcinoma therapy

Watanabe, E; Yokoi, A; Yoshida, K; Yamamoto, Y; Nishino, K; Niimi, K; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1501 - 1501 2022年2月

Anti-tumor capacity of specific contents in small extracellular vesicles derived from ADSCs in ovarian cancer

Yokoi, A; Yoshida, K; Uno, K; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1408 - 1408 2022年2月

バルトリン腺癌との鑑別に難渋したクローン病合併痔瘻癌の1例

松井真実, 新美薫, 吉原雅人, 玉内学志, 横井暁, 池田芳紀, 芳川修久, 西野公博, 梶山広明

日本婦人科腫瘍学会雑誌 40 巻 ( 1 ) 頁： 10 - 16 2022年1月

記述言語：日本語出版者・発行元：公益社団法人日本婦人科腫瘍学会

<p>外陰部腺癌は稀であり，腟前庭後部の病変はバルトリン腺原発と考えやすい．今回クローン病罹患中の外陰部腺癌が，術後に痔瘻癌と判明した症例を経験したので報告する．症例は48歳の女性で，クローン病で内科的治療を継続していた．前医を受診する6カ月前に左腟前庭部に腫瘤が出現し前医を受診した．生検でadenocarcinomaと診断された．腸管由来の可能性も示唆されたため，上下部消化管内視鏡精査を行ったが悪性腫瘍を認めず，バルトリン腺癌疑いで当院を紹介受診した．初診時，左バルトリン腺領域に4 cm大，その腹側の陰核左側に1.5 cm大の腫瘤を認めた．CT検査で両側鼠径リンパ節の軽度腫大を認めた．2週間後に単純外陰切除術，両側鼠径リンパ節生検を施行した．病理診断は中分化腺癌であり，大腸粘膜上皮と腺癌との連続性が確認できたため痔瘻癌と診断した．切除断端は左腟壁深部剥離面が陽性であり，両側鼠径リンパ節にも転移を認めた．前手術から3カ月後に外科にてロボット支援腹腔鏡下腹会陰式直腸切断術，腟会陰切除術，大腸ストーマ造設術，鼠径リンパ節郭清術を施行され，現在化学療法（CAPOX療法）を行っている．外陰部は痔瘻が発生する場所として矛盾しないため，クローン病既往の外陰部腺癌は痔瘻由来の可能性を積極的に考慮し，術前に痔瘻の精査を十分に行う必要がある．</p>

DOI： 10.57291/jsgo.40.1_10

CiNii Research

Integrative transcriptomics analysis for uterine leiomyosarcoma identifies aberrant activation of cell cycle-dependent kinases and their potential therapeutic significance.

Kosuke Yoshida, Akira Yokoi, Tomofumi Yamamoto, Yusuke Hayashi, Jun Nakayama, Tsuyoshi Yokoi, Hiroshi Yoshida, Tomoyasu Kato, Hiroaki Kajiyama, Yusuke Yamamoto

2022年1月

出版者・発行元：Cold Spring Harbor Laboratory

Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates.
Experimental Design: Transcriptome analysis was carried out using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis was then used to identify potential therapeutic target genes for uterine leiomyosarcoma. Moreover, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using the SK-UT-1, SK-LMS-1, and SKN cell lines.
Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The Ingenuity Pathway Analysis showed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI 2536 or prexasertib) were found to exert a superior anti-cancer effect against cell lines at low nanomolar concentrations and induced cell cycle arrest. In SK-UT-1 tumor-bearing mice, BI 2536 monotherapy demonstrated a marked tumor regression. Moreover, the prexasertib and cisplatin combination therapy also reduced tumorigenicity and prolonged survival.
Conclusion: We identified the upregulated expression of PLK1 and CHEK1; their kinase activity was considered to be activated in uterine leiomyosarcoma. BI 2536 and prexasertib demonstrate a significant anti-cancer effect; thus, cell cycle-related kinases may represent a promising therapeutic strategy for treating uterine leiomyosarcoma.

DOI： 10.1101/2022.01.06.22268775

Clinical effects of cervical conization with positive margins in cervical cancer 査読有り国際誌

Nagao, Y; Yokoi, A; Yoshida, K; Sumi, M; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Kajiyama, H

SCIENTIFIC REPORTS 11 巻 ( 1 ) 頁： 23288 - 23288 2021年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Radical surgery after cervical conization is a common approach for the treatment of cervical cancer. In some cases, disease progression is observed after positive margins at conization, but the effect of conization on disease progression remains unclear. Thus, the aim of this study was to investigate the clinical outcomes of positive margins at conization in cervical cancer. A total of 101 patients who underwent cervical conization before radical hysterectomy and pelvic lymph node dissection were considered eligible by reviewing medical records. The association between the positive margins and patient outcomes, including subsequent lymph node metastasis, was evaluated. The rate of lymphovascular space invasion (LVSI) positivity at radical surgery was significantly higher in patients with positive margins (p = 0.017) than in those with negative margins, although there was no significant difference in the rate of pelvic lymph node metastasis (p = 0.155). Moreover, there was no significant difference in the overall survival or progression-free survival between the two groups (p = 0.332 and 0.200, respectively). A positive margin at conization presented no significant prognostic disadvantage; thus, diagnostic conization is one of the most suitable treatment options for early-stage cervical cancer that is difficult to accurately assess.

DOI： 10.1038/s41598-021-02635-y

Extracellular microRNA profiling for prognostic prediction in patients with high-grade serous ovarian carcinoma 査読有り国際誌

Yoshida, K; Yokoi, A; Matsuzaki, J; Kato, T; Ochiya, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 112 巻 ( 12 ) 頁： 4977 - 4986 2021年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

High-grade serous ovarian carcinoma is a leading cause of death in female patients worldwide. MicroRNAs (miRNAs) are stable noncoding RNAs in the peripheral blood that reflect a patient’s condition, and therefore, they have received substantial attention as noninvasive biomarkers in various diseases. We previously reported the usefulness of serum miRNAs as diagnostic biomarkers. Here, we investigated the prognostic impact of the serum miRNA profile. We used the GSE106817 dataset, which included preoperative miRNA profiles of patients with ovarian malignancies. Excluding patients with other malignancy or insufficient prognostic information, we included 175 patients with high-grade serous ovarian carcinoma. All patients except four underwent surgery and received chemotherapy as initial treatment. The median follow-up period was 54.6 months (range, 3.5-144.1 months). Univariate Cox regression analysis revealed that higher levels of miR-187-5p and miR-6870-5p were associated with both poorer progression-free survival (PFS) and overall survival (OS), and miR-1908-5p, miR-6727-5p, and miR-6850-5p were poor prognostic indicators of PFS. The OS and PFS prognostic indices were then calculated using the expression values of three prognostic miRNAs. Multivariate Cox regression analysis showed that both indices were significantly independent poor prognostic factors (hazard ratio for OS and PFS, 2.343 [P =.015] and 2.357 [P =.005], respectively). In conclusion, circulating miRNA profiles can potentially provide information to predict the prognosis of patients with high-grade serous ovarian carcinoma. Therefore, there is a strong demand for early clinical application of circulating miRNAs as noninvasive biomarkers.

DOI： 10.1111/cas.15154