2024/03/25 更新

写真a

タマウチ サトシ
玉内 学志
TAMAUCHI Satoshi
所属
医学部附属病院 産科婦人科 病院講師
職名
病院講師

学位 1

  1. 医学博士 ( 2019年3月   名古屋大学 ) 

研究分野 1

  1. ライフサイエンス / 産婦人科学

現在の研究課題とSDGs 2

  1. 婦人科癌患者の妊孕性温存治療

  2. 卵巣癌の新規治療法の開発

 

論文 76

  1. An update of oncologic and obstetric outcomes of radical trachelectomy for early-stage cervical cancer: The need for further minimally invasive treatment

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

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   50 巻 ( 2 ) 頁: 175 - 181   2024年2月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aims: To investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early-stage cervical cancer and to evaluate the potential role of fertility-preserving treatments in improving pregnancy outcomes while oncologic status is stable. Methods: In this single-institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early-stage cervical cancer who underwent RT at Nagoya University Hospital. Results: The cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies. Conclusions: RT is a viable treatment option for selected patients with early-stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

    DOI: 10.1111/jog.15824

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  2. The influence of radical trachelectomy on endometrial thickness in in vitro fertilization-embryo transfer

    Yabuki, A; Muraoka, A; Tamauchi, S; Seki, T; Takeda, T; Sonehara, R; Miyake, N; Nakamura, T; Osuka, S; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   50 巻 ( 2 ) 頁: 218 - 224   2024年2月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aim: Both morbidity and mortality rates of cervical cancer are increasing, especially in reproductive-aged women. Radical trachelectomy (RT) is an effective fertility-preserving surgery for early-stage cervical cancer. This study aimed to determine the influence of RT on endometrial thickness during in vitro fertilization-embryo transfer (IVF-ET). Methods: Forty-four patients had undergone RT, and 23 women undergoing IVF-ET treatment (105 ET cycles) were included. Endometrial thickness during hormone replacement therapy (HRT) was retrospectively evaluated and compared between patients with and without RT. Results: Eleven patients (50 ET cycles) in the RT group and 12 (52 ET cycles) in the control group were investigated. Compared with the control group, higher ET cancellation rates were observed in patients in the RT group (1 of 52 cycles [control group] vs. 8 of 50 cycles [RT group], p < 0.01). Endometrial thinning was not affected by patient age at first IVF-ET treatment, history of artificial abortion, preservation of uterine arteries during RT, or postoperative chemotherapy (p = 0.27, 1, 1, and 1, respectively). Conclusions: Our data revealed that RT influenced endometrial thickness in IVF-ET. This was not affected by the background of the patients or perioperative management in this study. We could not reveal the underlying mechanism, but it is postulated that the transient postoperative uterine blood flow status and postoperative infections may have some effect on the endometrium. To resolve these issues, accumulation of evidences are required. We recommend informing patients about the impact of RT on IVF-ET before starting assisted reproductive technology (ART).

    DOI: 10.1111/jog.15841

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  3. Effect of radical trachelectomy on ovarian reserve: A single-institute prospective study

    Nakagawa, A; Tamauchi, S; Sato, M; Yoshihara, M; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Osuka, S; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   50 巻 ( 2 ) 頁: 212 - 217   2024年2月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aim: Reduced responses to controlled ovarian stimulation (COS) after radical trachelectomy (RT) have been previously reported. We aimed to assess the effect of RT on ovarian reserve by measuring anti-Müllerian hormone (AMH) levels before and after the procedure in this prospective study. Methods: We included 12 patients who underwent RT between September 2019 and December 2021 in this study. Serum AMH levels were measured preoperatively, 1 month postoperatively, and 6 months postoperatively. Differences in the AMH levels were assessed using a paired t-test. Results: The median age of the patients was 30.6 years, and the median follow-up time was 30.1 months. AMH levels at 1 and 6 months postoperatively did not show a consistent trend. At 1 month postoperatively, the average AMH level decreased insignificantly but returned to preoperative levels at 6 months. The differences in AMH levels before and after RT were insignificant. Conclusion: Our findings indicate that RT did not affect ovarian reserve as measured by AMH levels. However, the relationship between unchanged ovarian reserve and reduced response to COS remains unclear. Further research with larger sample sizes and additional measures of ovarian function is needed to corroborate these results and investigate the long-term effects of RT on ovarian reserve. Understanding these mechanisms will help guide surgical practices and provide patients with valuable information about their reproductive outcomes after RT.

    DOI: 10.1111/jog.15828

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  4. Mean platelet volume as a potential biomarker for survival outcomes in ovarian clear cell carcinoma

    Yoshikawa, N; Matsukawa, T; Hattori, S; Iyoshi, S; Yoshida, K; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yokoi, A; Niimi, K; Kawai, M; Kajiyama, H

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   28 巻 ( 12 ) 頁: 1680 - 1689   2023年12月

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    記述言語:英語   出版者・発行元:International Journal of Clinical Oncology  

    Objective: This study aimed to explore the prognostic value of mean platelet volume (MPV) in patients with ovarian clear cell carcinoma (OCCC) and evaluate the predictive performance of a random forest model incorporating MPV and other key clinicopathological factors. Methods: A total of 204 patients with OCCC treated between January 2004 and December 2019 were retrospectively analyzed. Clinicopathological characteristics and preoperative laboratory data were collected, and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional hazards models. An optimal MPV cutoff was determined by receiver operating characteristic (ROC) curve analysis. A random forest model was then constructed using the identified independent prognostic factors, and its predictive performance was evaluated. Results: The ROC analysis identified 9.3 fL as the MPV cutoff value for predicting 2-year survival. The MPV-low group had lower 5-year overall survival and progression-free survival rates than the MPV-high group (p = 0.003 and p = 0.034, respectively). High MPV emerged as an independent prognostic factor (p = 0.006). The random forest model, incorporating the FIGO stage, residual tumors, peritoneal cytology, and MPV, demonstrated robust predictive performance (area under the curve: 0.905). Conclusion: MPV is a promising prognostic indicator in OCCC. Lower MPV correlated with worse survival rates, advocating its potential utility in refining patient management strategies. The commendable predictive performance of the random forest model, integrating MPV and other significant prognostic factors, suggests a pathway toward enhanced survival prediction, thereby warranting further research.

    DOI: 10.1007/s10147-023-02417-8

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  5. Establishment and characterization of a non-gestational choriocarcinoma patient-derived xenograft model

    Oda, Y; Niimi, K; Yoshida, K; Tamauchi, S; Yokoi, A; Yasui, Y; Nishiko, Y; Shibata, M; Shimizu, Y; Yoshihara, M; Ikeda, Y; Yoshikawa, N; Nishino, K; Yamamoto, E; Kajiyama, H

    BMC CANCER   23 巻 ( 1 ) 頁: 1103   2023年11月

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    記述言語:英語   出版者・発行元:BMC Cancer  

    Background: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. Methods: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdc scid 1l2rg tm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. Results: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. Conclusions: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

    DOI: 10.1186/s12885-023-11626-3

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  6. 9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins

    Mogi, K; Koya, Y; Yoshihara, M; Sugiyama, M; Miki, R; Miyamoto, E; Fujimoto, H; Kitami, K; Iyoshi, S; Tano, S; Uno, K; Tamauchi, S; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Yamakita, Y; Tomita, H; Shibata, K; Nawa, A; Tomoda, Y; Kajiyama, H

    SCIENTIFIC REPORTS   13 巻 ( 1 ) 頁: 19208   2023年11月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25–50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

    DOI: 10.1038/s41598-023-44365-3

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  7. Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer

    Suzuki, H; Yokoi, A; Uno, K; Yoshida, K; Kitagawa, M; Asano-Inami, E; Matsuo, S; Nagao, Y; Suzuki, K; Nakamura, K; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kajiyama, H; Yamamoto, Y

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   680 巻   頁: 211 - 219   2023年11月

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    記述言語:英語   出版者・発行元:Biochemical and Biophysical Research Communications  

    Introduction: Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. Materials and methods: ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. Results: ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. Conclusion: ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

    DOI: 10.1016/j.bbrc.2023.09.022

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  8. The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer

    Uno, K; Yoshikawa, N; Kitami, K; Mori, S; Shibata, T; Iyoshi, S; Fujimoto, H; Mogi, K; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kato, K; Hoshiba, T; Oguchi, H; Kajiyama, H

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   53 巻 ( 10 ) 頁: 942 - 949   2023年10月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Objective: The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. Methods: We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. Results: The median values of the sarcopenia index (cm2/m2) ± standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4 ± 1.0, 1.7 ± 0.6 and 12.6 ± 3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29-5.97, P = 0.009) and overall survival (hazard ratio = 3.13, 95% confidence interval = 1.18-8.26, P = 0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio = 3.74, 95% confidence interval = 1.31-10.72, P = 0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P = 0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio = 2.06, P = 0.045) in multivariate analysis and recurrence-free survival (P = 0.009) in patients with advanced stage. Conclusions: The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

    DOI: 10.1093/jjco/hyad086

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  9. Unclear tumor border in magnetic resonance imaging as a prognostic factor of squamous cell cervical cancer

    Sato, M; Tamauchi, S; Yoshida, K; Yoshihara, M; Ikeda, Y; Yoshikawa, N; Kajiyama, H

    SCIENTIFIC REPORTS   13 巻 ( 1 ) 頁: 15392   2023年9月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Magnetic resonance imaging (MRI) is used for pretreatment staging in cervical cancer. In the present study, we used pretreatment images to categorize operative cases into two groups and evaluated their prognosis. A total of 53 cervical cancer patients with squamous cell carcinoma who underwent radical hysterectomy were included in this study. Based on MRI, the patients were classified into two groups, namely clear and unclear tumor border. For each patient, the following characteristics were evaluated: overall survival; recurrence-free survival; lymph node metastasis; lymphovascular space invasion; and pathological findings, including immunohistochemical analysis of vimentin. The clear and unclear tumor border groups included 40 and 13 patients, respectively. Compared with the clear tumor border group, the unclear tumor border group was associated with higher incidence rates of recurrence (3/40 vs. 3/13, respectively), lymphovascular space invasion (24/40 vs. 13/13, respectively), lymph node metastasis (6/40 vs. 10/13, respectively), and positivity for vimentin (18/40 vs. 10/13, respectively). Despite the absence of significant difference in recurrence-free survival (p = 0.0847), the unclear tumor border group had a significantly poorer overall survival versus the clear tumor border group (p = 0.0062). According to MRI findings, an unclear tumor border in patients with squamous cell cervical cancer is linked to poorer prognosis, lymph node metastasis, and distant recurrence of metastasis.

    DOI: 10.1038/s41598-023-42787-7

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  10. DDIT4 Facilitates Lymph Node Metastasis via the Activation of NF-kB Pathway and Epithelial-Mesenchymal Transition

    Lin, XX; Yoshikawa, N; Liu, WT; Matsukawa, T; Nakamura, K; Yoshihara, M; Koya, Y; Sugiyama, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Shimizu, Y; Kajiyama, H

    REPRODUCTIVE SCIENCES   30 巻 ( 9 ) 頁: 2829 - 2841   2023年9月

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    記述言語:英語   出版者・発行元:Reproductive Sciences  

    This study was aimed to identify a novel metastasis-promoting molecule and elucidate its functional and prognostic roles in cervical cancer. DDIT4 (DNA-damage-inducible transcript 4), a hypoxia-inducible gene, was identified by analyzing multiple microarray databases. The correlation between DDIT4 expression in immunohistochemistry and clinicopathological characteristics in the public database and our cohort was evaluated by statistical analysis. Transwell® assay and wound-healing assay to determine cell migration and invasion were performed. DDIT4 was knocked down using siRNA or lentiviral vectors. The potential downstream pathways of DDIT4 were explored and verified by a gene set enrichment analysis and western blotting. The in vivo metastatic capability was determined with the use of an intraperitoneal injection mouse model. In the analysis of the public database and our cohort, DDIT4 high expression was significantly related to short overall survival and lymph node metastasis in patients with early-stage cervical cancer. The knockdown of DDIT4 attenuated the migration and invasion activity of tumor cells in vitro and reduced the expression of epithelial–mesenchymal transition (EMT)-related proteins and the NF-κB pathway in cervical cancer cells. DDIT4 also promoted tumor progression in the mouse model. Our results indicate that DDIT4 can be a prognostic indicator in cervical cancer and promote lymph node metastasis, augmenting malignancy via the EMT and NF-kB pathways.

    DOI: 10.1007/s43032-023-01230-y

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  11. Niraparib as a therapeutic agent for the treatment of ovarian cancer meningeal dissemination with <i>BRCA1</i> mutation

    Nei, T; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Niimi, K; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   49 巻 ( 7 ) 頁: 1875 - 1879   2023年7月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    This study analyzed a 63-year-old woman with hereditary BRCA1 mutation. She underwent interval debulking surgery after neoadjuvant chemotherapy for high-grade serous ovarian carcinoma (HGSOC). After 2 years of postoperative chemotherapy, she developed headache and dizziness, and a suspected metastatic cerebellar mass in left ovary was detected. Pathological analysis of the mass revealed HGSOC, which was removed surgically. Eight months and another 6 months after the surgery, local recurrence was noted; hence, she underwent CyberKnife treatment. After 3 months, cervical spinal cord metastasis was found, evidenced by left shoulder pain. Moreover, meningeal dissemination was present around the cauda equina. Chemotherapy treatment, including bevacizumab, was ineffective and increased lesions were observed. After CyberKnife treatment for the cervical spinal cord metastasis, niraparib was initiated for the meningeal dissemination. The cerebellar lesions and meningeal dissemination improved within 8 months of niraparib treatment. Although meningeal dissemination is challenging to treat, niraparib may be useful in BRCA-mutated HGSOC.

    DOI: 10.1111/jog.15663

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  12. Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway

    Chang, X; Tamauchi, S; Yoshida, K; Yoshihara, M; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kiyono, T; Yamamoto, Y; Kajiyama, H

    GYNECOLOGIC ONCOLOGY   173 巻   頁: 31 - 40   2023年6月

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    記述言語:英語   出版者・発行元:Gynecologic Oncology  

    Objectives: Ovarian cancer constitutes one of the most common causes of cancer-related deaths, and preventing chemotherapy resistance and recurrence in patients with ovarian cancer remains a challenge. Herein, we aimed to identify the effect of luteolin, a novel therapeutic agent targeting vaccinia-related kinase 1 (VRK1), on high-grade serous ovarian cancer (HGSOC). Methods: Phosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to determine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intraperitoneal luteolin administration were assessed in patient-derived xenograft models via several methods, including the assessment of tumor size and immunohistochemistry of phospho-p53, phosphor-HistoneH3 and cleaved caspase 3. Results: Luteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Compared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 signaling pathway. The human phosphokinase array revealed distinct p53 upregulation in luteolin-treated cells, as confirmed by p53 phosphorylation at ser15 and ser46 using western blot analysis. In patient-derived xenograft models, oral or intraperitoneal luteolin administration substantially suppressed tumor growth. Moreover, combination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines. Conclusions: Luteolin demonstrated considerable anticancer effect on HGSOC cells, reduced VRK1 expression, and activated the p53 signaling pathway, thereby inducing apoptosis and cell cycle arrest in G2/M and inhibiting cell proliferation. Furthermore, luteolin exhibited a synergistic effect with cisplatin both in vivo and in vitro. Thus, luteolin can be considered a promising cotreatment option for HGSOC.

    DOI: 10.1016/j.ygyno.2023.04.003

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  13. Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma

    Nagao, Y; Yokoi, A; Yoshida, K; Sugiyama, M; Watanabe, E; Nakamura, K; Kitagawa, M; Asano-Inami, E; Koya, Y; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kato, T; Yamamoto, Y; Kajiyama, H

    PHARMACOLOGICAL RESEARCH   189 巻   頁: 106693   2023年3月

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    記述言語:英語   出版者・発行元:Pharmacological Research  

    Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

    DOI: 10.1016/j.phrs.2023.106693

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  14. Identifying Copy Number Variations in Extracellular Vesicles as a Novel Biomarker of High Grade Serous Ovarian Carcinoma

    Uekusa, R; Yokoi, A; Kitagawa, M; Yoshida, K; Yoshihara, M; Tamauchi, S; Niimi, K; Matsuzaki, J; Yamamoto, Y; Kajiyama, H

    CANCER SCIENCE   114 巻   頁: 1063 - 1063   2023年2月

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  15. The prognostic significance of DDIT4 in endometrial cancer

    Yoshikawa, N; Yoshida, K; Liu, WT; Matsukawa, T; Hattori, S; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Shimizu, Y; Niimi, K; Kajiyama, H

    CANCER BIOMARKERS   37 巻 ( 4 ) 頁: 217 - 225   2023年

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    記述言語:英語   出版者・発行元:Cancer Biomarkers  

    BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.

    DOI: 10.3233/CBM-220368

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  16. Hypoalbuminemia for the prediction of survival in patients with stage IVB cervical cancer

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

    PLOS ONE   17 巻 ( 9 ) 頁: e0273876   2022年9月

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    記述言語:英語   出版者・発行元:PLoS ONE  

    We evaluated the prognostic significance of malnutrition in patients with metastatic cervical cancer. In this study, we retrospectively analyzed the cases of 43 patients with stage IVB (FIGO2018) cervical cancer treated at our institute from December 2004 to December 2017. We determined the correlation between clinicopathological characteristics and survival by performing univariate and multivariate analyses. The serum albumin value at diagnosis was used as an index of malnutrition. The median follow-up period was 16.4 months (range, 0.9–91.4 months). On Kaplan-Meier analysis, the 1- and 2-year overall survival (OS) rates for all patients were 61.6% and 48.6%, respectively. The optimal serum albumin for predicting 1-year survival was 3.3 g/dL, as determined by the receiver operating characteristic curve to maximize the area under the curve. The OS of the patients with albumin >3.3 g/ dL (n = 28) was significantly better than that of the patients with albumin ≤3.3 g/dL (n = 15) (p = 0.004). The univariate and multivariate analyses revealed that pretreatment serum albumin and mode of primary treatment were significantly associated with survival in patients with stage IVB cervical cancer. Hypoalbuminemia was an unfavorable prognostic factor for patients with metastatic cervical cancer.

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  17. 特集 知っておきたい! 合併症を伴う婦人科がん診療up to date 11.精神疾患を有する婦人科がん患者の留意点

    玉内 学志

    産婦人科の実際   71 巻 ( 8 ) 頁: 865 - 871   2022年8月

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    出版者・発行元:金原出版  

    DOI: 10.18888/sp.0000002236

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  18. Survival benefits of retroperitoneal lymphadenectomy for optimally-resected advanced ovarian high-grade serous carcinoma: a multi-institutional retrospective study

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

    JOURNAL OF GYNECOLOGIC ONCOLOGY   33 巻 ( 4 ) 頁: e40   2022年7月

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    記述言語:英語   出版者・発行元:Journal of Gynecologic Oncology  

    Objective: The survival benefits of retroperitoneal lymphadenectomy (RLNA) for epithelial ovarian cancer (EOC) remain controversial because clinical behaviors differ among subtypes. The purpose of the present study was to clarify whether RLNA increases the survival rate of advanced high-grade serous carcinoma (HGSC). Methods: This was a retrospective cohort analysis of 3,227 patients with EOC treated between 1986 and 2017 at 14 institutions. Among them, 335 patients with stage IIB-IV HGSC who underwent optimal cytoreduction (residual tumor of <1 cm) were included. Patients were divided into the RLNA group (n=170) and non-RLNA group (n=165). All pathological slides were assessed based on a central pathological review. Oncologic outcomes were compared between the two groups in the original and weighted cohorts adjusted with the inverse probability of treatment weighting. Results: The median observation period was 49.8 (0.5–241.5) months. Overall, 219 (65%) out of 335 patients had recurrence or progression, while 146 (44%) died of the disease. In the original cohort, RLNA was a significant prognostic factor for longer progression-free survival (PFS) (hazard ratio [HR]=0.741; 95% confidence interval [CI]=0.558–0.985) and overall survival (OS) (HR=0.652; 95% CI=0.459–0.927). In the weighted cohort in which all variables were well balanced as standardized differences decreased, RLNA was also a significant prognostic factor for more favorable oncologic outcomes (PFS, adjusted HR=0.742; 95% CI=0.613–0.899) and OS, adjusted HR=0.620; 95% CI=0.488–0.787). Conclusion: The present study demonstrated that RLNA for stage III-IV HGSC with no residual tumor after primary debulking surgery contributed to better oncologic outcomes.

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  19. Is cystectomy an option as conservative surgery for young patients with borderline ovarian tumor? A multi-institutional retrospective study

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

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   157 巻 ( 2 ) 頁: 437 - 443   2022年5月

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    記述言語:英語   出版者・発行元:International Journal of Gynecology and Obstetrics  

    Objective: To investigate the impact of cystectomy for borderline ovarian tumor (BOT) on tumor recurrence compared with salpingo-oophorectomy using inverse probability of treatment weighting (IPTW). Methods: A central pathologic review and a search of the medical records from 14 collaborating institutions from 1986 to 2017 identified 4708 women with a malignant ovarian neoplasm. Data for young women with Stage I BOT were extracted. To compare recurrence-free survival between the surgery groups, Cox regression analyses and the IPTW-adjusted Kaplan-Meier method were employed. Results: During a median follow-up of 62.0 (1.2–270.4) months, 10 of the 285 patients identified (3.5%) developed recurrence. In multivariate analysis, the practice of cystectomy was not a significant prognostic indicator of recurrence-free survival (hazard ratio [95% confidence interval] 1.276 [0.150–10.864]; P = 0.823). In the IPTW-adjusted cohort, the 5-year recurrence-free survival rates were 95.8% and 96.0% in patients receiving cystectomy and salpingo-oophorectomy, respectively (P = 0.378). Conclusion: If patients are selected appropriately, cystectomy in itself may not increase tumor recurrence in young women with early-stage BOT. A large-scale prospective clinical study is necessary to validate this finding.

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  20. Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis

    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

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    記述言語:英語   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.

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  21. Is adjuvant chemotherapy necessary for young women with early-stage epithelial ovarian cancer who have undergone fertility-sparing surgery?: a multicenter retrospective analysis

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

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

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    記述言語:英語   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.

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  22. Significance of platinum distribution to predict platinum resistance in ovarian cancer after platinum treatment in neoadjuvant chemotherapy

    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   2022年3月

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    記述言語:英語   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.

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

    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

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  24. 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

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  25. 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

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  26. 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

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    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

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  27. Clinical effects of cervical conization with positive margins in cervical cancer

    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   2021年12月

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    記述言語:英語   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.

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  28. 特集 図解 分子メカニズムから理解する婦人科がんの薬物療法 【各論】 Ⅰ 卵巣悪性腫瘍 2.胚細胞腫瘍

    玉内 学志, 梶山 広明

    産婦人科の実際   70 巻 ( 12 ) 頁: 1472 - 1478   2021年11月

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    出版者・発行元:金原出版  

    DOI: 10.18888/sp.0000001964

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  29. Achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy

    Tamauchi, S; Moriyama, Y; Suzuki, S; Ikeda, Y; Yoshikawa, N; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   47 巻 ( 11 ) 頁: 4101 - 4105   2021年11月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Cervical cancer is a human papilloma virus-related disease, whereas endometrial cancer and atypical endometrial hyperplasia (AEH) are hormone-related diseases, so co-occurrence of the two is possible. However, scientific studies about such cases are rare. We encountered a case of cervical adenocarcinoma and AEH in a 33-year-old nulliparous woman. Two fertility-sparing treatments were performed, a radical trachelectomy for the cervical cancer and high-dose medroxyprogesterone acetate treatment for the AEH. After remission of the diseases, the patient became pregnant by in vitro fertilization and delivered a baby at 36 weeks' gestation by cesarean section. Although the patient had two uterine malignancies, proper evaluation of the diseases, consultation with the patient and her husband, and appropriate management led to fertility preservation, and live birth was achieved.

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  30. Impact of incomplete surgery and adjuvant chemotherapy for the intraoperative rupture of capsulated stage I epithelial ovarian cancer: a multi-institutional study with an in-depth subgroup analysis

    Yoshihara, M; Tamauchi, S; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Kajiyama, H

    JOURNAL OF GYNECOLOGIC ONCOLOGY   32 巻 ( 5 ) 頁: e66   2021年9月

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    記述言語:英語   出版者・発行元:Journal of gynecologic oncology  

    OBJECTIVE: The aim of the present study was to examine the effects of incomplete surgery and adjuvant chemotherapy on the prognosis of patients with intraoperative rupture of capsulated stage I epithelial ovarian cancer (OvCa). METHODS: A regional retrospective study was conducted between 1986 and 2019. Among 4,730 patients with malignant ovarian tumors, 534 women with International Federation of Gynecology and Obstetrics stage IA and IC1 epithelial OvCa were eligible. Differences in survival outcomes were examined between patients with stage IA and IC1 tumors and the effects of uterine preservation, complete-staging lymphadenectomy, and adjuvant chemotherapy were investigated by an in-depth subgroup analysis. To analyze therapeutic effects, baseline imbalances were adjusted using propensity score (PS). RESULTS: The prognosis of patients with stage IC1 tumors was worse than those with stage IA. Surgical spill did not affect the site of recurrence. In the PS-adjusted subgroup analysis, uterine preservation (hazard ratio [HR]=1.669; 95% confidence interval [CI]=1.052-2.744), incomplete-staging lymphadenectomy (HR=1.689; 95% CI=1.211-2.355), and the omission of adjuvant chemotherapy (HR=3.729; 95% CI=2.090-6.653) significantly increased the HR of recurrence for patients with stage IC1 tumors compared to those with stage IA tumors. Adjuvant chemotherapy decreased the impact of rupture with uterine preservation (HR=0.159; 95% CI=0.230-1.168) or incomplete-staging lymphadenectomy (HR=0.987; 95% CI=0.638-1.527). CONCLUSION: The present results suggest intraoperative rupture of capsulated stage I epithelial OvCa is associated with a poor prognosis. When chemotherapy is given for patients receiving incomplete surgery, there is no longer an increased risk of recurrence observed with the rupture.

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  31. Metabolome analysis reveals a diversity of cancer tissues in advanced epithelial ovarian cancer

    Yoshida, K; Yoshikawa, N; Kitami, K; Tamauchi, S; Ikeda, Y; Yokoi, A; Nishino, K; Niimi, K; Kajiyama, H

    CANCER CELL INTERNATIONAL   21 巻 ( 1 ) 頁: 314   2021年6月

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    記述言語:英語   出版者・発行元:Cancer Cell International  

    Background: Epithelial ovarian cancer remains one of the leading causes of cancer deaths among women worldwide, and advanced epithelial ovarian cancer frequently metastasizes to the omentum. The characteristics of metastatic cancer may differ from those of primary ovarian cancer and reflect the unique omental microenvironment. This study investigated metabolomic differences in epithelial ovarian cancers. Methods: Patients with advanced epithelial ovarian cancer were eligible for this study. Five patients underwent surgery and resection of paired primary ovarian and omental metastatic cancer at Nagoya University. Metabolome analysis was performed in these paired cancer and metastatic cancer tissues through a facility service (C-SCOPE) at Human Metabolome Technologies, Inc. The concentrations of 116 compounds were measured by CE-TOFMS and CE-QqQMS, and 30 metabolic parameters were calculated. For statistical analyses, Welch’s t-test was used for comparisons between two independent groups. Results: Metabolite profiles were all different, which reflects diversity among these cancer tissues. Of the measured compounds, urea was the only metabolite that was significantly decreased in omental metastatic cancers compared with the primary cancers (p = 0.031). Moreover, in omental metastatic cancers, the pentose phosphate pathway was more dominant than glycolysis. Furthermore, in some cases, lactic acids in omental metastatic cancers were markedly decreased compared with primary cancers. With regard to histological subtype, the total levels of amino acids, especially the percentage of glutamine, were significantly enriched in serous carcinomas compared with nonserous carcinomas (p = 0.004 and p = 0.001). Moreover, the reduced forms of glutathione and polyamines were also more abundant in serous carcinomas than in nonserous carcinomas (p = 0.025 and 0.048). Conclusions: The metabolite profiles differed depending on tumor location and histological subtype. Metabolome analysis may be a useful tool for identifying cancer diagnostic and prognostic markers.

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  32. Significance of Concurrent Chemoradiotherapy as Primary Treatment in Patients with Metastatic Cervical Cancer

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

    CURRENT ONCOLOGY   28 巻 ( 3 ) 頁: 1663 - 1672   2021年6月

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    記述言語:英語   出版者・発行元:Current Oncology  

    (1) This study investigated the prognostic impact of tumor size in patients with metastatic cervical cancer. (2) Methods: Seventy-three cervical cancer patients in our institute were stratified into two groups based on distant metastasis: para-aortic lymph node metastasis alone (IIIC2) or spread to distant visceral organs with or without para-aortic lymph node metastasis (IVB) to identify primary tumor size and concurrent chemoradiotherapy. (3) Results: The overall survival (OS) for patients with a tumor >6.9 cm in size was significantly poorer than that for patients with a tumor ≤6.9 cm in the IVB group (p = 0.0028); the corresponding five-year OS rates in patients with a tumor ≤6.9 and >6.9 cm were 53.3% and 13.4%, respectively. In the multivariate analysis, tumor size and primary treatment were significantly associated with survival in metastatic cervical cancer. (4) Conclusions: Tumor size ≤6.9 cm and concurrent chemoradiotherapy as the primary treatment were favorable prognostic factors for patients with metastatic cervical cancer.

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  33. Does complete-staging lymphadenectomy improve survival outcomes in stage I endometrioid epithelial ovarian carcinoma? A multi-institutional retrospective study with propensity score-weighted analysis

    Yoshihara, M; Tamauchi, S; Iyoshi, S; Kitami, K; Uno, K; Tano, S; Matsui, S; Kajiyama, H

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   51 巻 ( 3 ) 頁: 387 - 392   2021年3月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Background: We investigated the prognostic impact of complete-staging lymphadenectomy on patients with clinically apparent Stage I endometrioid epithelial ovarian carcinoma. Methods: We conducted a regional multi-institutional retrospective study between 1986 and 2018. Amongst 4897 patients with malignant ovarian tumours diagnosed under central pathological review, 259 women with Stage I endometrioid epithelial ovarian carcinoma were eligible. We evaluated differences in survival of patients with both pelvic and para-aortic lymphadenectomy (Group A) and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation (Group B). To analyse the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results: In total, 145 patients (56.0%) received both pelvic and para-aortic lymphadenectomy. With propensity score-based adjustment, estimated survival was better in Group A compared with that in Group B but not significant. Pelvic and para-aortic lymphadenectomy also led to no significant improvement of overall survival in most of the subgroups. However, point estimations of the hazard ratio for lymphadenectomy in patients with an age of 45 or younger (hazard ratio, 0.304; 95% confidence interval, 0.094-0.982), a Grade 1-2 (hazard ratio, 0.441; 95% confidence interval, 0.204-0.954) and T1c2-3 tumour (hazard ratio, 0.449; 95% confidence interval, 0.164-1.231) were better compared with those with the opposite characteristics. Conclusions: Complete-staging lymphadenectomy was not a significant prognostic factor in patients with Stage I endometrioid epithelial ovarian carcinoma, where we still need to explore appropriate candidate for the procedure.

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  34. The role of chrXq27.3 miRNA cluster in advanced ovarian clear cell carcinoma

    Yoshida, K; Yokoi, A; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Nishino, K; Niimi, K; Kikkawa, F; Kajiyama, H

    CANCER SCIENCE   112 巻   頁: 291 - 291   2021年2月

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  35. How do peritoneal mesothelial cells on adipose tissue attract ovarian cancer cells?

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

    CANCER SCIENCE   112 巻   頁: 341 - 341   2021年2月

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    記述言語:日本語  

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  36. Active vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer

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

    CANCER SCIENCE   112 巻   頁: 351 - 351   2021年2月

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    記述言語:日本語  

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  37. Visualization of platinum resistance through mapping trace elements

    Uno, K; Yoshikawa, N; Yoshihara, M; Tazaki, K; Kato, M; Kitami, K; Iyoshi, S; Tamauchi, S; Sugiyama, M; Koya, Y; Kajiyama, H

    CANCER SCIENCE   112 巻   頁: 906 - 906   2021年2月

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    記述言語:日本語  

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  38. Intra-tumoral polarity induced by Notch signaling can be a novel therapeutic target for advanced ovarian cancer

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

    CANCER SCIENCE   112 巻   頁: 363 - 363   2021年2月

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    記述言語:日本語  

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  39. Luteolin suppresses Ovarian Cancer progression via decrease the expression of VRK1

    Chang, XY; Kajiyama, H; Yoshikawa, N; Yokoi, A; Tamauchi, S; Yoshihara, M

    CANCER SCIENCE   112 巻   頁: 770 - 770   2021年2月

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    記述言語:日本語  

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  40. ESTABLISHMENT AND CHARACTERISATION OF PATIENT-DERIVED XENOGRAFT MODELS FOR MALIGNANT GYNECOLOGIC TUMORS

    Suzuki, S; Tamauchi, S; Shimizu, Y; Yoshihara, M; Nakamura, K; Yoshikawa, N; Kajiyama, H; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   27 巻   頁: 1382 - 1382   2017年11月

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  41. EVALUATING THE LONG TERM PROGNOSTIC FACTOR AND THE ROLE OF CYTOREDUCTION IN THE OVERALL POPULATION OF PATIENTS WITH CLINICAL AND SURGICAL STAGE IV ENDOMETRIAL CARCINOMA

    Shimizu, Y; Kajiyama, H; Suzuki, S; Yoshikawa, N; Nakamura, K; Yoshihara, M; Tamauchi, S; Yoshida, K; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   27 巻   頁: 1213 - 1213   2017年11月

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  42. ESTABLISHMENT AND CHARACTERISATION OF PATIENT-DERIVED XENOGRAFT MODELS FOR MALIGNANT GYNECOLOGIC TUMORS

    Suzuki, S; Tamauchi, S; Shimizu, Y; Yoshihara, M; Nakamura, K; Yoshikawa, N; Kajiyama, H; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   27 巻   頁: 494 - 494   2017年11月

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  43. 特集 サインから読み解く婦人科画像診断 9. 婦人科超音波のサイン 2. Dermoid cone,acoustic shadow,hair ball

    玉内 学志, 梶山 広明

    画像診断   37 巻 ( 9 ) 頁: 959 - 959   2017年7月

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    出版者・発行元:学研メディカル秀潤社  

    DOI: 10.15105/gz.0000000065

    CiNii Research

  44. Reduced response to controlled ovarian stimulation after radical trachelectomy: A pitfall of fertility-sparing surgery for cervical cancer 国際誌

    Tamauchi, S; Kajiyama, H; Osuka, S; Moriyama, Y; Yoshihara, M; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   154 巻 ( 1 ) 頁: 162 - 168   2021年7月

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    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 Gynecology and Obstetrics  

    Objective: To clarify the decrease in response to controlled ovarian stimulation in patients who receive in vitro fertilization treatment after radical trachelectomy. Methods: The outcomes of ovarian stimulation were retrospectively evaluated and compared between patients who have undergone radical trachelectomy and control patients who had male factor infertility or unexplained infertility. Results: A total of 30 ovarian stimulation cycles in 14 radical trachelectomy patients and 54 cycles in 30 control patients were reviewed. The median age at ovarian stimulation was 34.8 years in the radical trachelectomy group and 36.5 years in the control group. Compared with the control group, the radical trachelectomy group had significantly lower mean estradiol concentration (1461.7 pg/ml, SD 775.0 vs. 1950.9 pg/ml, SD 1057.3, P = 0.029) during controlled ovarian stimulation cycle and smaller median number of retrieved oocytes (5, range 1–14 vs. 8, range 1–19, P = 0.007), despite the higher use of gonadotropin (3527.5 IU, SD 1313.4 vs. 2670.8 IU, SD 905.1, P = 0.001). Conclusion: The response to controlled ovarian stimulation decreased after radical trachelectomy.

    DOI: 10.1002/ijgo.13529

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  45. Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance 国際誌

    Yoshida, K; Yokoi, A; Sugiyama, M; Oda, S; Kitami, K; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F; Yokoi, T; Kajiyama, H

    ONCOGENE   40 巻 ( 7 ) 頁: 1255 - 1268   2021年2月

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

    Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.

    DOI: 10.1038/s41388-020-01595-3

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  46. Establishment of a patient-derived xenograft model and cell line of malignant transformation of mature cystic teratoma of the ovary 国際誌

    Tamauchi, S; Suzuki, S; Xuboya, C; Yoshihara, M; Yoshida, K; Ikeda, Y; Yoshikawa, N; Kajiyama, H; Kikkawa, F

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   47 巻 ( 2 ) 頁: 713 - 719   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aim: Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare gynecological malignancy and commonly arises in women older than 50 years of age. The most common histological type of MTMCT is squamous cell carcinoma (SCC), and the prognosis is extremely poor. Patient-derived xenograft (PDX) models are promising animal models for preclinical drug screening. Here, we report the generation of a new PDX model of MTMCT, and a new cell line established from the tumors of PDX model animals. Methods: Tumor tissue was obtained from a 32-year-old patient with MTMCT. To generate PDX, NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) mice, a strain of super-immunodeficient mice, were used. Tumor-bearing mice were sacrificed, followed by the collection of these tumors and re-transplantation into new NSG mice (in vivo passage). Tumor samples were also cultured in vitro. Adherent cells were continuously cultured and passaged, a cell line was established. Results: In the primary PDX mouse, tumor engraftment was confirmed 30 days after tumor implantation. After three times in vivo passage, we confirmed that the cryopreserved tumors could be engrafted even when transplanted into BALB/c nude mice. Using the tumor tissue at the time of the first in vivo passage, a new cell line NOSCC1 was established. PDX tumors and cell-line derived xenograft tumors exhibited similar morphology of SCC. Conclusion: We established a new PDX model of MTMCT and a new cell line of it, which may be important tools for the development of new therapies and the elucidation of the carcinogenic mechanisms of MTMCT.

    DOI: 10.1111/jog.14596

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  47. A uterine pseudotumor of immunoglobulinG4-related disease

    Senda, Y; Ikeda, Y; Tamauchi, S; Yoshikawa, N; Kikkawa, F; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   47 巻 ( 1 ) 頁: 430 - 435   2021年1月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Immunoglobulin G4-related disease (IgG4-RD) is characterized by systemic lesions presenting as swellings, nodules and wall thickenings. The first-line therapy is glucocorticoids. This disease is common among middle-aged and elderly men, and its uterine mass formation is uncommon. We encountered a 39-year-old nulliparous woman with an IgG4-related uterine mass and enlarged pelvic lymph nodes. Complete remission was achieved by fertility-sparing resection of the uterine mass without glucocorticoids. This case showed that IgG4-RD can present as a uterine mass and we need to be careful of its diagnostic and therapeutic strategies because an IgG4-related uterine mass is difficult to distinguish from sarcoma or malignant lymphoma. Our case also demonstrated that IgG4-related lymphadenopathy could regress spontaneously without complete lymphadenectomy or glucocorticoids when IgG4-RD does not affect vital organs. A pelvic mass with hyperproteinemia may be a hint to remind us of IgG4-RD and may trigger a preoperative immunoglobulin test.

    DOI: 10.1111/jog.14531

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  48. Sarcopenia as a Predictor of Survival Among Patients With Organ Metastatic Cervical Cancer 国際誌

    Yoshikawa, N; Shirakawa, A; Yoshida, K; Tamauchi, S; Suzuki, S; Kikkawa, F; Kajiyama, H

    NUTRITION IN CLINICAL PRACTICE   35 巻 ( 6 ) 頁: 1041 - 1046   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nutrition in Clinical Practice  

    Background: This study was conducted to investigate the prognostic significance of sarcopenia in patients with organ metastatic cervical cancer. Methods: Accordingly, the data of 40 patients with organ metastatic cervical cancer treated at our institute from December 2004 to December 2017 were retrospectively analyzed. The correlation between clinicopathological characteristics and survival was then evaluated using univariate and multivariate analyses. Psoas muscle index (PMI), calculated from the psoas muscle area at the L3 vertebral-body level using computed tomography images obtained for pretreatment evaluation, was adopted as an index of sarcopenia. Results: The median follow-up period was 14 months (range, 1–91 months). Kaplan-Meier analysis showed a 3- and 5-year overall survival (OS) rate of 46.1% and 35.8% for all patients, respectively. Receiver operating characteristic curve maximizing the area under the curve showed that the optimal PMI for predicting 1-year survival was 3.72 cm2/m2. Patients with a PMI > 3.72 cm2/m2 had significantly better OS than those with a PMI ≤ 3.72 cm2/m2 (P =.046). Multivariate analysis revealed that only PMI was significantly associated with OS in patients with organ metastatic cervical cancer. Furthermore, patients with a PMI > 3.72 cm2/m2 who underwent concurrent chemoradiotherapy (CCRT) had a longer OS than those receiving other therapies (P <.001). Conclusions: High PMI was determined to be a favorable prognostic factor for patients with organ metastatic cervical cancer. Moreover, patients with organ metastatic cervical cancer who have a PMI > 3.72 cm2/m2 may benefit from CCRT as an initial treatment.

    DOI: 10.1002/ncp.10482

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  49. Does uterine preservation affect survival outcomes of patients with stage I ovarian sex cord-stromal cell tumours? A multi-institutional study 国際誌

    Yoshihara, M; Tamauchi, S; Iyoshi, S; Kitami, K; Uno, K; Yoshikawa, N; Ikeda, Y; Kawai, M; Nagasaka, T; Kajiyama, H

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY   254 巻   頁: 52 - 56   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:European Journal of Obstetrics and Gynecology and Reproductive Biology  

    Objective: Sex cord-stromal tumours of the ovary are relatively uncommon neoplasms that account for 3 % of all ovarian cancers. Uterine preservation with careful staging is achievable; however, conservative surgery remains controversial. This study examined the prognostic effects of uterine preservation in patients with stage I sex cord-stromal tumours. Study design: This retrospective cohort study was undertaken between January 1986 and February 2019, and the clinicopathological data of 4897 women with malignant ovarian tumours were collected. Seventy-seven patients with stage I sex cord-stromal tumours were eligible for inclusion. The characteristics and survival outcomes of these patients were examined. To investigate the prognostic effects of uterine-preserving surgery, baseline imbalances between patients with and without uterine-preserving surgery were adjusted using an inverse probability of treatment weighting with propensity scores composed of independent clinical variables. Results: The mean ages of patients in the uterine-preserving surgery and non-uterine-preserving surgery groups were 39.8 and 57.8 years, respectively. After inverse probability of treatment weighting adjustments, no significant differences in overall survival (p = 0.205) or recurrence-free survival (p=0.071) were observed between the uterine-preserving surgery and non-uterine-preserving surgery groups. Estimated 10-year overall survival rates were 98.7 % in the uterine-preserving surgery group and 95.9 % in the non-uterine-preserving surgery group, and 10-year recurrence-free survival rates were 87.2 % in the uterine-preserving surgery group and 78.2 % in the non-uterine-preserving surgery group. Uterine-preserving surgery did not significantly affect the site of tumour recurrence. Conclusion: Uterine-preserving surgery may be a feasible surgical option for patients with stage I sex cord-stromal tumours. Further research is needed to guarantee prognostic accuracy and develop effective therapeutic approaches for sex cord-stromal tumours.

    DOI: 10.1016/j.ejogrb.2020.09.009

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  50. Follicular dendritic cell sarcoma of the uterine cervix: a case report 国際誌

    Nakamura, T; Yoshihara, M; Tamauchi, S; Kajiyama, H; Kikkawa, F

    BMC WOMENS HEALTH   20 巻 ( 1 ) 頁: 182 - 182   2020年8月

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    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  

    Background: Follicular dendritic cell sarcoma (FDCS) is a rare mesenchymal tumor that mostly occurs in systemic lymph nodes. FDCS in the uterine cervix has not yet been reported. Case presentation: A 49-year-old woman was referred to our department with a cervical tumor, which was histologically suspected to be undifferentiated carcinoma. She underwent hysterectomy, salpingo-oophorectomy, and pelvic lymphadenectomy after neoadjuvant chemotherapy with paclitaxel and carboplatin. The resected specimen contained high numbers of spindle cells and was immunohistochemically confirmed to be FDCS. The tumor was completely resected and recurrence was not detected at a 16-month follow-up. Conclusion: FDCS is an extremely rare malignant tumor in the uterine cervix, and an accurate diagnosis and complete resection are essential for a good prognosis.

    DOI: 10.1186/s12905-020-01045-y

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  51. Impact of uterus-preserving surgery on Stage I primary mucinous epithelial ovarian carcinoma: A multi-institutional study with propensity score-weighted analysis

    Yoshihara, M; Kajiyama, H; Tamauchi, S; Iyoshi, S; Yokoi, A; Suzuki, S; Kawai, M; Nagasaka, T; Takahashi, K; Matsui, S; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   150 巻 ( 2 ) 頁: 177 - 183   2020年8月

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    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 Gynecology and Obstetrics  

    Objective: To investigate the clinical characteristics of women with Stage I primary mucinous epithelial ovarian carcinoma (mEOC) and evaluate the impact of uterus-preserving surgery (UPS) in terms of survival prognosis. Methods: A regional multi-institutional retrospective study conducted between January 1986 and March 2017 by reviewing records of the Tokai Ovarian Tumor Study Group. Clinical and pathologic data and survival outcomes were assessed for women with Stage I primary mEOC. The baseline imbalance between women with and those without UPS was adjusted by an inverse probability of treatment weighting method using the propensity score (PS) of independent clinical variables. Results: Among 4730 women with malignant ovarian tumors, 185 had Stage I primary mEOC and were included in the study. The mean age was 47.6 years (range 12–87 years), and 56 (30.3%) women underwent UPS. After PS-based adjustment, women in the UPS group did not have a poorer prognosis regarding overall survival (P=0.776) or recurrence-free survival (P=0.683). Even after age stratification, there was no statistical difference in survival outcomes between the UPS and non-UPS groups. Conclusion: UPS was not associated with decreased survival and may be a treatment option for women with Stage I primary mEOC irrespective of age.

    DOI: 10.1002/ijgo.13244

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  52. The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma

    Kajiyama, H; Suzuki, S; Yoshikawa, N; Tamauchi, S; Shibata, K; Kikkawa, F

    JOURNAL OF GYNECOLOGIC ONCOLOGY   31 巻 ( 4 ) 頁: e47 - 11   2020年7月

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    記述言語:英語   出版者・発行元:Journal of Gynecologic Oncology  

    Objective: The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. Methods: Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB–IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors. Results: The median follow-up duration of all surviving women was 52.8 (1.6–184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633–2.187; p=0.615). Conclusions: This study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

    DOI: 10.3802/jgo.2020.31.e47

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  53. The Preoperative Prognostic Nutritional Index for the Prediction of Outcomes in Patients with Early-Stage Ovarian Clear Cell Carcinoma 国際誌

    Yoshikawa, N; Yoshida, K; Tamauchi, S; Ikeda, Y; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F; Kajiyama, H

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 7135 - 7135   2020年4月

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    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  

    The prognostic nutritional index (PNI), which reflects preoperative malnutrition, is useful for predicting the incidence of postoperative complications and has been reported in recent years to predict the long-term prognosis of various malignancies. The purpose of this study was to clarify the significance of PNI as a prognostic factor for early-stage clear cell ovarian carcinoma. A total of 82 patients with stage I–II (FIGO 2014) ovarian clear cell carcinoma undergoing primary surgery at our hospital from January 2005 to December 2017 were enrolled. PNI was calculated using the formula: 10 × serum albumin (g/ dL) + 0.005 × peripheral blood lymphocyte count (/mm3). Preoperative PNI exhibited relatively high area under the curve value (0.709) for 5 year survival, and the optimal cutoff value was 46.5. The overall survival was significantly shorter in the PNI-low group than in the PNI-high group. Multivariate analysis showed that high PNI was a significant independent prognostic factor for favorable prognosis (hazard ratio = 0.102, p = 0.010). There was no significant difference in recurrence-free survival between the two groups (p = 0.220), but the postrecurrence survival was significantly longer in the PNI-high group than in the PNI-low group (p = 0.0383). The preoperative PNI was a useful predictor of prognosis, even in early-stage ovarian clear cell carcinoma.

    DOI: 10.1038/s41598-020-64171-5

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  54. The Therapeutic Effects of Goreisan, a Traditional Japanese Herbal Medicine, on Lower-Limb Lymphedema after Lymphadenectomy in Gynecologic Malignancies: A Case Series Study 国際誌

    Yoshikawa, N; Kajiyama, H; Otsuka, N; Tamauchi, S; Ikeda, Y; Nishino, K; Niimi, K; Suzuki, S; Utsumi, F; Shibata, K; Kikkawa, F

    EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE   2020 巻   頁: 6298293 - 6298293   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Evidence-based Complementary and Alternative Medicine  

    Background. Lower-limb lymphedema (LLL) is a chronic and progressive complication of gynecologic cancer treatment, including pelvic lymphadenectomy. This study aims to investigate the therapeutic effect of goreisan, a traditional Japanese medicine, which has been used for hydrostatic modulation on patients with LLL. Methods. Patients diagnosed with LLL in our hospital in 2018 were included and principally treated with complex decongestive therapy (CDT), including elastic clothing and lymph drainage. The patients who received a combination therapy of CDT and goreisan (CDT-G group) were prescribed goreisan extract granules, with a dose of 7.5 g per os daily in three doses. Patients who were not prescribed goreisan received CDT alone (CDT group). The severity of lymphedema was evaluated by the estimated limb volume calculated by limb circumferences and the ratio of extracellular water (ECW) to total body water (TBW). Results. Nineteen women with LLL after pelvic lymphadenectomy were included in the study. The number of patients in the CDT and CDT-G groups was 8 and 11, respectively. There were no statistically significant differences between the CDT and CDT-G groups in terms of patient characteristics and severity of LLL before treatment. Reduction in ECW/TBW in the CDT-G group (in the whole body and the affected lower limb) after the intervention was significantly more remarkable than that in the CDT group. Conclusions. Goreisan-based Japanese herbal therapy may be effective in patients with LLL after retroperitoneal lymphadenectomy.

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  55. Is standard radical surgery necessary for elderly patients with early-stage epithelial ovarian carcinoma? ∼Propensity score matched analysis∼ 国際誌

    Kajiyama, H; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Niimi, K; Suzuki, S; Shibata, K; Kikkawa, F

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 4 ) 頁: 411 - 418   2020年4月

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

    Objective: The impact of 'standard full-staged radical surgery (SRS)' on overall survival (OS) in elderly patients with early-stage epithelial ovarian cancer (EOC) remains unclear. In the current study, we investigated the impact of SRS on OS in elderly patients with early-stage EOC in a multicentric analysis using a propensity score (PS)-matching technique. Methods: Between 1986 and 2017, 3227 patients with EOC were registered and accumulated by the Tokai Ovarian Tumor Study Group, consisting of 14 collaborating institutions, after a central pathological review. Among them, 204 elderly patients aged older than or equal to 65 years who had a stage I EOC were analyzed, including 72 patients who had received SRS (Group I) and 132 who had undergone non-SRS limited surgery (Group II). Oncologic outcomes were compared between the two groups using a PS-matching technique to adjust for various clinicopathologic risk factors. Results: The median follow-up duration of all surviving patients was 55.9 months. Consequently, 54 patients (26.5%) developed recurrence. In addition, 33 patients (16.2%) died of the disease. In the original cohort, the 5-year OS rates of Groups I and II were 95.8 and 82.3%, respectively. We identified a marginally significant difference between the two groups (Log-rank: P = 0.086). In the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the two groups [OS (Group I vs. II), HR: 0.766 (95% CI: 0.271-2.165), P = 0.615]. Conclusions: After adjustment for clinicopathologic factors, non-SRS limited surgery may not worsen the oncologic outcome in elderly women with early-stage EOC. A large-scale clinical study is necessary to validate the findings.

    DOI: 10.1093/jjco/hyz194

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  56. CCL2 secreted from cancer-associated mesothelial cells promotes peritoneal metastasis of ovarian cancer cells through the P38-MAPK pathway

    Yasui, H; Kajiyama, H; Tamauchi, S; Suzuki, S; Peng, Y; Yoshikawa, N; Sugiyama, M; Nakamura, K; Kikkawa, F

    CLINICAL & EXPERIMENTAL METASTASIS   37 巻 ( 1 ) 頁: 145 - 158   2020年2月

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    記述言語:英語   出版者・発行元:Clinical and Experimental Metastasis  

    Epithelial ovarian cancer (EOC) is considered to secrete various factors in order to promote peritoneal dissemination through cell-to-cell interaction between cancer and mesothelial cells. We previously revealed that TGF-β secreted from EOC induces normal human peritoneal mesothelial cells (HPMCs) to differentiate into cancer-associated mesothelial cells (CAMCs). However, the relationship between tumor cells and CAMCs in EOC is still unclear. We hypothesized that CAMCs also secrete chemokines that attract cancer cells and induce peritoneal dissemination of EOC. We examined chemokines secreted from HPMCs and CAMCs by human chemokine array, and revealed that conditioned medium of CAMCs (CAMCs-CM) included many types of chemokines. The signals of CCL2 were the highest compared with other chemokines. The secretion and relative expression of CCL2 were significantly higher in CAMCs. Recombinant CCL2 promoted trans-mesothelial migration of HPMCs and the migration and invasion by EOC cells. In addition, CCL2 secreted from CAMCs promoted invasion of EOC cells. Furthermore, the neutralizing antibody of CCL2 reduced invasion by EOC. Clinical outcomes of patients whose tissue expressed higher CCR2 were significantly poorer than in patients whose tissue expression was lower. CCL2 activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK). In addition, CAMCs-CM activated the p38 MAPK pathway. Phosphorylation of p38 MAPK reduced with the presence of neutralizing antibody of CCL2. In conclusion, these data indicate CCL2 in CAMCs-CM promoted the malignant potential of EOC. CCL2 plays a crucial role in the tumor microenvironment of EOC.

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  57. The role of additional hysterectomy after concurrent chemoradiation for patients with locally advanced cervical cancer

    Yoshida, K; Kajiyama, H; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   25 巻 ( 2 ) 頁: 384 - 390   2020年2月

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    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: The standard treatment for cervical cancer is chemoradiation although some patients showed treatment resistance. The purpose of this study was to investigate the clinical efficacy of surgery after chemoradiation for cervical cancer. Methods: Patients with FIGO stage IB2 to IIB cervical cancer were included in the study between 2005 and 2015. A total of 50 patients who underwent surgery after neoadjuvant chemoradiation and 76 patients who received only chemoradiation were compared. Baseline differences between the two groups were adjusted with inverse probability of treatment weighting method using propensity scores composed of the following independent variables: age, stage, tumor size, lymph node metastasis, and histological subtypes. Results: Median follow-up was 64.8 (range 4.8–143.9) months. After adjustment with inverse probability of treatment weighting, Kaplan–Meier curves showing adjusted progression-free survival and overall survival were significantly longer in the neoadjuvant chemoradiation compared with the chemoradiation-only group (p = 0.027 and p = 0.017, respectively). Moreover, in patients with squamous cell carcinoma, recurrence in previously irradiated field and recurrence both in and out of previously irradiated field were significantly decreased in the neoadjuvant chemoradiation compared with the chemoradiation-only group (3.1% and 18.4%, respectively; OR 0.142, p = 0.001]. Adverse events of surgery after chemoradiation were acceptable, although temporary hydronephrosis was frequently observed (23.1%). Conclusions: Surgery after chemoradiation reduced pelvic recurrence, and as a result, patients who underwent neoadjuvant chemoradiation showed more favorable survival outcomes compared with those who only underwent chemoradiation.

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  58. Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis

    Yoshihara, M; Kajiyama, H; Tamauchi, S; Iyoshi, S; Yokoi, A; Suzuki, S; Kawai, M; Nagasaka, T; Takahashi, K; Matsui, S; Kikkawa, F

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 2 ) 頁: 145 - 151   2020年2月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Background: The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. Methods: We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results: Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P = 0.696) and recurrence-free survival (P = 0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. Conclusions: The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

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  59. Clinical Significance of Ubiquitin-associated Protein 2-like in Patients With Uterine Cervical Cancer 国際誌

    Yoshida, K; Kajiyama, H; Inami, E; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Utsumi, F; Niimi, K; Suzuki, S; Shibata, K; Nawa, A; Kikkawa, F

    IN VIVO   34 巻 ( 1 ) 頁: 109 - 116   2020年1月

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

    Background: Ubiquitin-associated protein 2-like (UBAP2L) has been demonstrated to be associated with the progression of multiple types of cancer. However, the function of UBAP2L in uterine cervical cancer remains unclear. Materials and Methods: Between 2005 and 2015, 84 patients who underwent surgery were included in this study. The patients were stratified into two groups on the basis of immunohistochemical staining for UBAP2L, and survival analysis was performed. Moreover, loss-of-function analysis was performed using the cervical cancer cell lines CaSki and SiHa. Results: Based on immunohistochemistry, the overall survival in patients with low UBAP2L expression was significantly longer than that of those with high UBAP2L expression (p=0.045). The in vitro experiment revealed that knockdown of UBAP2L remarkably inhibited cell proliferation in both live cell imaging and the MTS assay. Conclusion: Patients with high UBAP2L expression had unfavorable prognosis and UBAP2L appears to play an important role in proliferation.

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  60. Impact of age on clinicopathological features and survival of epithelial ovarian neoplasms in reproductive age

    Hanatani, M; Yoshikawa, N; Yoshida, K; Tamauchi, S; Ikeda, Y; Nishino, K; Niimi, K; Suzuki, S; Kawai, M; Kajiyama, H; Kikkawa, F

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   25 巻 ( 1 ) 頁: 187 - 194   2020年1月

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    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: Little is known about the effect of age on the prognosis of epithelial ovarian neoplasms. In the reproductive age, fertility-sparing surgery had been widely implemented. This study aimed to elucidate impact of age on the clinicopathologic characteristics and survival of epithelial ovarian neoplasms in the reproductive age. Methods: The clinical records of patients diagnosed as epithelial ovarian cancer or epithelial borderline ovarian tumor at the age of 40 years or younger at multiple institutions in the Tokai Ovarian Tumor Study Group were reviewed retrospectively. All patients were stratified into two age groups: group A (≤ 30 years) and group B (31–40 years). Univariate and multivariate analyses were performed to evaluate overall survival and disease-free survival. Results: A total of 583 patients (325 patients: cancer, 258 patients: borderline) were included. The median follow-up time was 62.0 months (range 1–270 months). Compared with group B, group A had a significantly higher rate of borderline tumor (66.7% vs. 32.7%, p < 0.001); stage I disease (85.9% vs. 70.4%, p < 0.001); mucinous type (69.2% vs. 35.6%, p < 0.001); conservative surgery (83.8% vs. 41.6%, p < 0.001); no adjuvant chemotherapy (67.2% vs. 44.7%, p < 0.001); and CA125 ≤ 35 U/mL (39.4% vs. 28.8%, p < 0.05). There was a significant difference in the overall survival (p = 0.0051) and the disease-free survival (p = 0.0039) between the two groups. Multivariate analysis revealed that the independent prognostic factors for the overall survival were age, stage, histology, and ascitic fluid cytology. Conclusion: In epithelial ovarian neoplasms, younger patients had a survival advantage over older patients.

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  61. Complete Response of Recurrent Small Cell Carcinoma of the Uterine Cervix to Paclitaxel, Carboplatin, and Bevacizumab Combination Therapy

    Nakao, Y; Tamauchi, S; Yoshikawa, N; Suzuki, S; Kajiyama, H; Kikkawa, F

    CASE REPORTS IN ONCOLOGY   13 巻 ( 1 ) 頁: 373 - 378   2020年1月

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    記述言語:英語   出版者・発行元:Case Reports in Oncology  

    We report a case of recurrent small cell carcinoma of the uterine cervix that showed a complete response to paclitaxel, carboplatin, and bevacizumab (TC + Bev) combination therapy. Small cell carcinoma of the uterine cervix is extremely rare, with an incidence of only 1.3% in Japan, and a poor outcome. The patient was a 62-year-old woman with a chief complaint of irregular vaginal bleeding. Magnetic resonance imaging showed a 10-cm irregular mass from the uterine corpus's posterior wall to the cervix. Abdominal total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling were performed for suspected uterine sarcoma. Histopathological findings revealed small cell carcinoma with lymph node metastasis. Although 6 cycles of etoposide + cisplatin were performed, para-aortic lymph node recurrence was found 3 months after chemotherapy. Subsequently, the patient received 8 cycles of TC + Bev, which eliminated the metastases. The patient is currently alive at 24 months.

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  62. Expression of connective tissue growth factor as a prognostic indicator and its possible involvement in the aggressive properties of epithelial ovarian carcinoma 国際誌

    Shimbo, A; Kajiyama, H; Tamauchi, S; Yoshikawa, N; Ikeda, Y; Nishino, K; Suzuki, S; Niimi, K; Sakata, J; Kikkawa, F

    ONCOLOGY REPORTS   42 巻 ( 6 ) 頁: 2323 - 2332   2019年12月

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

    Recently, connective tissue growth factor (CTGF) was demonstrated to be associated with aggressive characteristics, including proliferation, invasion and metastasis, in a number of malignancies. Here, we investigated the expression and function of CTGF in epithelial ovarian carcinoma (EOC) to clarify its molecular mechanism and clinical significance. Paraffin sections from clinical samples of EOC (N=104) were immunostained with the CTGF antibody, and then the staining positivity was semiquantitatively examined. Moreover, we explored the role of CTGF expression in the migration-promoting effect on and chemoresistance of EOC cells. The results revealed that of the 104 EOC patients, the low and high CTGF staining expression rates were 65 (62.5%) and 39 (37.5%), respectively. Patients belonging to the higher-level CTGF group showed poorer progression-free (PFS) and overall survival (OS) rates than those in the lower-level group [PFS (log-rank: P=0.0076) and OS (log-rank: P=0.0078), respectively]. Multivariable analysis showed that CTGF expression was a significant predictor of poorer PFS and OS [PFS: HR (high vs. low): 1.837, 95% CI: 1.023-3.289 (P=0.0418); OS: HR: 2.141, 95% CI: 1.077-4.296 (P=0.0300)]. In in vitro studies, in acquired paclitaxel (PTX)-resistant EOC cells, the silencing of CTGF expression led to the restoration of PTX sensitivity. Furthermore, we confirmed that the TGF‑β‑dependent migration‑promoting effect on these CTGF‑depleted cells was completely inhibited. In conclusion, the results of the present study suggest the possible involvement of CTGF in the migration‑promoting effect and chemoresistance of EOC, suggesting that it may be a target for overcoming the malignant properties of EOC.

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  63. Unique miRNA profiling of squamous cell carcinoma arising from ovarian mature teratoma: comprehensive miRNA sequence analysis of its molecular background 国際誌

    Yoshida, K; Yokoi, A; Kagawa, T; Oda, S; Hattori, S; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Utsumi, F; Niimi, K; Suzuki, S; Shibata, K; Kajiyama, H; Yokoi, T; Kikkawa, F

    CARCINOGENESIS   40 巻 ( 12 ) 頁: 1435 - 1444   2019年12月

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

    Owing to its rarity, the carcinogenesis and molecular biological characteristics of squamous cell carcinoma arising from mature teratoma remain unclear. This study aims to elucidate the molecular background of malignant transformation from the aspects of microRNA (miRNA) profiling. We examined 7 patients with squamous cell carcinoma and 20 patients with mature teratoma and extracted their total RNA from formalin-fixed paraffin-embedded tissues. Then we prepared small RNA libraries and performed comprehensive miRNA sequencing. Heatmap and principal component analysis revealed markedly different miRNA profiling in cancer, normal ovarian and mature teratoma tissues. Then we narrowed down cancer-related miRNAs, comparing paired-cancer and normal ovaries. Comparisons of cancer and mature teratoma identified two markedly upregulated miRNAs (miR-151a-3p and miR-378a-3p) and two markedly downregulated miRNAs (miR-26a-5p and miR-99a-5p). In addition, these findings were validated in fresh cancer tissues of patient-derived xenograft (PDX) models. Moreover, several miRNAs, including miR-151a-3p and miR-378a-3p, were elevated in the murine plasma when tumor tissues were enlarged although miR-26a-5p and miR-99a-5p were not elucidated in the murine plasma. Finally, we performed target prediction and functional annotation analysis in silico and indicated that targets genes of these miRNAs markedly correlated with cancer-related pathways, including 'pathway in cancer' and 'cell cycle'. In conclusion, this is the first study on miRNA sequencing for squamous cell carcinoma arising from mature teratoma. The study identified four cancer-related miRNAs that were considered to be related to the feature of malignant transformation. Moreover, miRNAs circulating in the murine plasma of the PDX model could be novel diagnostic biomarkers.

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  64. The usefulness of bevacizumab for relief from symptomatic malignant ascites in patients with heavily treated recurrent ovarian cancer 国際誌

    Shimizu, Y; Kajiyama, H; Yoshida, K; Tamauchi, S; Nakanishi, T; Kikkawa, F

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   45 巻 ( 12 ) 頁: 2435 - 2439   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aim: Accumulation of ascites fluid is a major obstacle in the late phase of epithelial ovarian cancer. However, there is no consensus on a specific treatment for malignant ascites. The present study evaluated the clinical benefit of half-dose bevacizumab therapy (7.5 mg/kg every 3–4 weeks). Methods: This was a single-arm interventional study performed at Aichi Cancer Center Hospital. Four patients with platinum-resistant epithelial ovarian cancer and symptomatic malignant ascites were no longer considered candidates for standard chemotherapy. As a palliative approach, half-dose bevacizumab therapy (7.5 mg/kg every 3–4 weeks) was used with informed consent. The clinical data of these patients were retrospectively reviewed. Results: All patients had been heavily pretreated and showed progressive disease. Thus, standard chemotherapy was no longer feasible, and palliative paracentesis for malignant ascites was clinically needed. Among the four patients, three did not require additional paracentesis after bevacizumab therapy, and there were no adverse events. One patient needed paracentesis owing to lymphorrhea. Conclusion: The use of bevacizumab therapy as a palliative approach for malignant ascites might be an option in patients with terminal-stage ovarian cancer. However, further evaluation is needed with regard to the possibility of severe side effects and medical expenses.

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  65. COMPREHENSIVE MIRNA SEQUENCING OF SQUAMOUS CELL CARCINOMA ARISING FROM OVARIAN MATURE TERATOMA

    Yoshida, K; Yokoi, A; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kajiyama, H; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   29 巻   頁: A544 - A545   2019年11月

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    記述言語:日本語  

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  66. REDUCED RESPONSE TO CONTROLLED OVARIAN STIMULATION AFTER RADICAL TRACHELECTOMY

    Tamauchi, S; Kajiyama, H; Osuka, S; Moriyama, Y; Yoshihara, M; Iyoshi, S; Yoshida, K; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   29 巻   頁: A269 - A270   2019年11月

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    記述言語:日本語  

    DOI: 10.1136/ijgc-2019-ESGO.469

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  67. Prognostic factors and effects of fertility-sparing surgery in women of reproductive age with ovarian clear-cell carcinoma: a propensity score analysis 国際誌

    Yoshihara, M; Kajiyama, H; Tamauchi, S; Suzuki, S; Takahashi, K; Matsui, S; Kikkawa, F

    JOURNAL OF GYNECOLOGIC ONCOLOGY   30 巻 ( 6 ) 頁: e102   2019年11月

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

    Objective: The aim of this study was to investigate the clinical characteristics of young patients with stage I clear-cell carcinoma (CCC) and evaluate the prognostic factors and effects of fertility-sparing surgery (FSS) using propensity score (PS) adjustment. Methods: We conducted a regional multi-institutional study between 1986 and 2017. Among 4,277 patients with ovarian tumor, clinical and pathological data of 103 fertile women with stage I unilateral CCC were collected. We evaluated survival and reproductive outcomes in these patients. Additionally, to analyze the effects of FSS, baseline imbalance between patients with and those without FSS was adjusted with an inverse probability of treatment weighting using PSs involving independent clinical variables. Results: The mean patient age was 39.4 years, and the median follow-up period for surviving patients was 55.6 months. In multivariate analysis, stage IC2/IC3 (vs. IA/IC1) was the only independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS). FSS was not associated with poorer prognosis when compared to the prognosis with non-preserving surgery with regard to both RFS and OS. No statistical difference in survival outcomes between FSS and other approaches was confirmed after PS adjustment. Among patients who underwent FSS, four deliveries with healthy neonates were noted without any gestational complications. Conclusion: FSS can be considered in stage I CCC, specifically in stage IA and IC1 patients who strongly desire to have children in the future. Further clinical research is needed to clarify the optimal application of FSS for CCC.

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  68. Fertility-Sparing surgery for young women with ovarian endometrioid carcinoma: a multicenteric comparative study using inverse probability of treatment weighting. 国際誌

    Kajiyama H, Yoshihara M, Tamauchi S, Yoshikawa N, Suzuki S, Kikkawa F

    European journal of obstetrics & gynecology and reproductive biology: X   4 巻   頁: 100071 - 100071   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:European Journal of Obstetrics and Gynecology and Reproductive Biology: X  

    Introduction: The aim of this study was to evaluate the oncologic outcome of women with stage I ovarian endometrioid carcinoma (EC) who underwent fertility-sparing surgery (FSS). Materials and nethods: Between 1986 and 2017, a total of 3227 patients with epithelial ovarian carcinoma were retrospectively evaluated based on a central pathological review and search of the medical records from multiple institutions. We identified 24 and 54 patients with stage I EC who underwent FSS and conventional radical surgery (CRS), respectively. Inverse probability of treatment weighting (IPTW)–adjusted Kaplan-Meier and Cox regression analyses were employed to compare OS between the two groups. Results: With follow-up of a total of 78 patients, 9 patients (11.5%) developed recurrence. In addition, 5 patients (6.4%) died of the disease. Recurrence was noted in 3 (10.7%) patients in the FSS group and 6 (11.1%) patients in the CRS group. Death was noted in 2 (8.3%) patients in the FSS group and 3 (5.6%) patients in the CRS group. In the original cohort, there was no significant difference in overall survival (OS) or recurrence-free survival (RFS) between the FSS and RS groups {Log-rank: OS (P = 0.630), RFS (P = 0.757)}. In the IPTW-adjusted cohort, the 5-year OS rates were 96.6 and 92.4% in patients with FSS and CRS, respectively (P = 0.319). Furthermore, the 5-year RFS rate was 88.6% for the FSS group and 88.1% for the CRS group (Log-rank: P = 0.556). Conclusions: Young women with stage I EC undergoing FSS showed a relatively satisfactory prognosis, equal to those receiving CRC.

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  69. Relationship between preexisting mental disorders and prognosis of gynecologic cancers: A case-control study 国際誌

    Tamauchi, S; Kajiyama, H; Moriyama, Y; Yoshihara, M; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   45 巻 ( 10 ) 頁: 2082 - 2087   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aim: Cancer treatment involves long-term therapy and follow-up, with mental disorders (MD) often affecting the treatment process. Hence, in this study, we retrospectively analyze cases involving gynecologic cancer with MD and clarify the relationship between psychosis and cancer prognosis. Methods: Patients with both gynecologic cancer and MD from January 2003 to August 2016 were recruited in this study. Cases were limited to those whose MD had been diagnosed before their cancer. Control patients without MD were also analyzed. Both cases and controls were adjusted for age, cancer type, and cancer stage. Results: A total of 54 patients with gynecologic cancer and MD, as well as 108 controls without MD, were included. The median age of the patients was 52 years. Details regarding cancer type were as follows: 11 ovarian cancers, 26 uterine corpus cancers and 17 cervical cancers. Among these, 25 schizophrenia cases, 15 depressive disorders, 4 bipolar disorders and 10 other MD were recorded. No significant differences in the 5-year survival rate were found between patients and controls. In advanced-stage cervical cancer, however, the prognosis was significantly poor given the low rate of initial treatment completion. Moreover, patients with advanced-stage cervical cancer had significantly lower chemotherapy completion rates compared to those with other gynecologic malignancies. Conclusion: Mental disorders do not affect the prognosis of gynecologic cancers, except for advanced cervical cancer. Accordingly, improving the low rate of initial treatment completion seems to be a focal point for better prognosis in advanced cervical cancer.

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  70. Oncologic and reproductive outcomes of cystectomy as a fertility-sparing treatment for early-stage epithelial ovarian cancer

    Kajiyama, H; Suzuki, S; Niimi, K; Tamauchi, S; Kawai, M; Nagasaka, T; Shibata, K; Kikkawa, F

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   24 巻 ( 7 ) 頁: 857 - 862   2019年7月

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    記述言語:英語   出版者・発行元:International Journal of Clinical Oncology  

    Background: Fertility-sparing surgery (FSS) has mainly been chosen for young women with ovarian-confined/well-differentiated epithelial ovarian cancer (EOC). In general, FSS consists of at least conservation of contralateral ovary and the uterus with a staging surgery. However, information on the clinical outcome in women who underwent cystectomy as a fertility-preserving option is lacking. Methods: After a central pathological review and search of the medical records from multiple institutions between 1987 and 2015, a total of eight early-stage EOC patients treated with cystectomy as FSS were retrospectively evaluated. Diagnosis and staging were based on International Federation of Gynecology and Obstetrics criteria (2014). Surgery consisted of uni- or bilateral cystectomy. The oncologic and reproductive outcomes were assessed. Results: The median age was 29 years (range 26–38 years). The median follow-up time was 103.6 months (range 42.2–218.3 months). The stage was IA in 3, IC1 in 4, and IC3 in one patient. Five patients received adjuvant chemotherapy. After cystectomy, two patients experienced recurrence in the pelvic cavity and bilateral ovaries, respectively. The former patient died of the disease 42 months after cystectomy, and conversely, the latter one was rescued by subsequent radical surgery. Four full-term childbirths were observed in three patients. Conclusions: Although oophorectomy is considered as an appropriate fertility-preserving operation, cystectomy may be an unavoidable option when it is the only surgical procedure available. It is desirable to verify the utility by accumulating larger numbers of patients through a future registry system.

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  71. Endometriosis and cancer 国際誌

    Kajiyama, H; Suzuki, S; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Niimi, K; Shibata, K; Kikkawa, F

    FREE RADICAL BIOLOGY AND MEDICINE   133 巻   頁: 186 - 192   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    Endometriosis, characterized by the presence of extra-uterine endometrium, is a common gynecologic disorder in reproductive-age women. Although the detailed molecular mechanism of etiology remains unelucidated, recent studies have gradually revealed both genetic and epigenetic backgrounds of the development of endometriosis. In clinical practice, endometriosis has been recognized as a precursor lesion of several types of malignancies and endometriosis-associated carcinoma. An imbalance between reactive oxygen species and local antioxidants has been reported to contribute to the development of endometriosis-associated carcinoma as well as the pathophysiology of this disease through a systemic inflammatory response in the peritoneal cavity. This review mainly presents an epidemiology, possible etiology of endometriosis, precursor lesions, molecular features, and the association between the microenvironmental accumulations of oxidative stress in endometriosis-associated ovarian cancer progression.

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  72. Reproductive outcomes of 105 malignant ovarian germ cell tumor survivors: a multicenter study 国際誌

    Tamauchi, S; Kajiyama, H; Yoshihara, M; Ikeda, Y; Yoshikawa, N; Nishino, K; Utsumi, F; Niimi, K; Suzuki, S; Kikkawa, F

    AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY   219 巻 ( 4 ) 頁: 385.e1 - 385.e7   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Journal of Obstetrics and Gynecology  

    Background: Malignant ovarian germ cell tumors usually occur in young women. Until the 1970s, before establishment of systemic chemotherapy, malignant ovarian germ cell tumors had a very poor prognosis. Recently, prognosis has improved, and fertility-sparing treatment is being adopted in patients who desire to become pregnant. However, the number of malignant ovarian germ cell tumor survivors who actually became pregnant remains unknown. Objective: The present study aimed to clarify the reproductive outcomes in malignant ovarian germ cell tumor survivors by using data from a multicenter database and an additional survey on reproductive outcomes. Study Design: The study used the Tokai Ovarian Tumor Study Group database on ovarian cancer patients. We assessed the database from 1986 through 2016 and selected malignant ovarian germ cell tumor patients <40 years of age who received fertility-sparing treatment. Questionnaires on reproductive outcomes were sent to the registered facilities. The following data were collected and used in this study: age, date of onset, surgical procedure, chemotherapy regimen, tumor type, International Federation of Gynecology and Obstetrics stage, survival outcome and period, number of pregnancies and childbirths, marital status, childbearing desire, method of pregnancy, gestational weeks at delivery, birthweight of the baby, obstetric complications, and menstrual status after fertility-sparing treatment. Results: A total of 110 malignant ovarian germ cell tumor patients who received fertility-sparing treatment were identified. The median follow-up period was 10.4 years. Five patients were excluded because of death or loss of fertility after treatment for recurrence. Thus, 105 patients were finally included. The additional survey revealed that 42 of 45 patients who desired childbirth became pregnant. The total number of pregnancies was 65, and 56 babies were born to 40 malignant ovarian germ cell tumor survivors. Conclusion: The reproductive outcomes of malignant ovarian germ cell tumor survivor are promising with fertility-sparing treatment. Malignant ovarian germ cell tumor survivors can become pregnant and give birth if they desire.

    DOI: 10.1016/j.ajog.2018.07.021

    Web of Science

    Scopus

    PubMed

  73. Efficacy of medroxyprogesterone acetate treatment and retreatment for atypical endometrial hyperplasia and endometrial cancer

    Tamauchi, S; Kajiyama, H; Utsumi, F; Suzuki, S; Niimi, K; Sakata, J; Mizuno, M; Shibata, K; Kikkawa, F

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   44 巻 ( 1 ) 頁: 151 - 156   2018年1月

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    記述言語:英語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    Aim: Medroxyprogesterone acetate (MPA) is used to preserve fertility in patients with Grade 1 endometrial cancer without myometrial invasion (G1EA) and those with atypical endometrial hyperplasia (AEH). However, the efficacy of retreatment with MPA has not been sufficiently established for patients who experience recurrence but wish to retain their fertility. This study aimed to show the effectiveness of MPA treatment and retreatment for AEH and G1EA. Methods: A total of 39 patients received MPA treatment between 2005 and 2015, including nine with G1EA and 30 with AEH. The patients received high-dose (600 mg/day) MPA for 26 weeks. If a complete response was not achieved, MPA treatment was continued. After complete remission, if there was a recurrence, the patient was offered a choice of a hysterectomy or retreatment with MPA. The gynecologic and obstetric outcomes were retrospectively analyzed. Results: The median age was 34 years, and the median body mass index was 23.3 kg/m2. The median follow-up period was 52 months. Complete response rates for the initial treatment were 89% for G1EA and 93% for AEH. Recurrence occurred in 88% of patients with G1EA (7/8) and 50% of those with AEH (14/28). Seven patients with G1EA and 11 with AEH received MPA retreatment, and 100% and 92% of these achieved a complete response. During the study period, a total of 14 pregnancies were recorded with 10 live births. Conclusion: MPA can be effective for G1EA and AEH treatment even when they recur.

    DOI: 10.1111/jog.13473

    Web of Science

    Scopus

    PubMed

  74. ESTABLISHMENT AND CHARACTERISATION OF PATIENT-DERIVED XENOGRAFT MODELS FOR MALIGNANT GYNECOLOGIC TUMORS

    Suzuki S, Tamauchi S, Shimizu Y, Yoshihara M, Nakamura K, Yoshikawa N, Kajiyama H, Kikkawa F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   27 巻   頁: 1382 - 1382   2017年11月

  75. EVALUATING THE LONG TERM PROGNOSTIC FACTOR AND THE ROLE OF CYTOREDUCTION IN THE OVERALL POPULATION OF PATIENTS WITH CLINICAL AND SURGICAL STAGE IV ENDOMETRIAL CARCINOMA

    Shimizu Y, Kajiyama H, Suzuki S, Yoshikawa N, Nakamura K, Yoshihara M, Tamauchi S, Yoshida K, Kikkawa F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   27 巻   頁: 1213 - 1213   2017年11月

  76. ESTABLISHMENT AND CHARACTERISATION OF PATIENT-DERIVED XENOGRAFT MODELS FOR MALIGNANT GYNECOLOGIC TUMORS

    Suzuki S, Tamauchi S, Shimizu Y, Yoshihara M, Nakamura K, Yoshikawa N, Kajiyama H, Kikkawa F

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   27 巻   頁: 494 - 494   2017年11月

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科研費 3

  1. CRISPR-Cas9スクリーニングによる卵巣奇形腫悪性転化の新規治療の開発

    研究課題/研究課題番号:22K16831  2022年4月 - 2024年3月

    日本学術振興会  科学研究費助成事業  若手研究

    玉内 学志

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    担当区分:研究代表者 

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    卵巣成熟嚢胞性奇形腫悪性転化は非常に難治性の疾患である。これまで動物モデルや細胞株が存在しなかったため新規治療研究が行われてこなかったが、申請者は世界で初めて動物モデルと細胞株を樹立した。本研究では、この細胞株を用いて遺伝子の網羅的ノックアウトスクリーニングを行い、新規治療標的分子を探索し、その効果を動物モデルを用いて実証することを目的としている。
    【ノックアウトスクリーニングの進捗状況】 当研究室で樹立した卵巣奇形腫悪性転化の細胞株NOSCC1を用いて、CRISPR-Cas9ノックアウトスクリーニングを実施した。NOSCC1に対してCas9タンパクを導入後、sgRNAライブラリを発現するレンチウィルスをインフェクションさせた多様な遺伝子プロファイルを持つ細胞集団を作成し、スクリーニングの選択圧としてシスプラチン添加を行った。セレクション完了後にgDNAを抽出し、生存細胞に取り込まれたsgRNA配列のアンプリコンシーケンスを行い、リファレンス細胞との比較を行った。ネガティブスクリーニングの結果、25個の遺伝子が見出された。創薬可能性の観点から絞り込みを行い、10個の遺伝子が新規治療標的遺伝子として見出された。10個の遺伝子について、細胞株を用いたノックダウン実験を行い、さらに4種類の遺伝子へと選別を行った。
    【薬効試験の準備状況】当研究室では卵巣奇形腫悪性転化の患者腫瘍由来モデル (PDX) も樹立しており、PDXマウス腫瘍を分割して多数のヌードマウスに再移植することで、多数の擬似的な担癌患者集団を作成することが可能であり、これらのマウスへの投薬によってヒトの腫瘍に対する抗腫瘍効を検証できる。新たに1種のPDXが樹立され、腫瘍増大の自然史を含めた予備的データ取得を完了しており、新規標的遺伝子に対する阻害剤投与試験のフェーズを速やかに実行する体制が構築されつつある。
    予定通りスクリーニングを完了し、新規治療標的遺伝子を選別できている。
    選別された新規治療標的遺伝子について、細胞株を用いたノックダウン実験を行い、抗腫瘍効果の確認を行う。また、標的遺伝子を阻害する化合物を調査し、細胞株及び患者腫瘍由来マウスモデルを用いて、効果を実証する予定である。

  2. 細胞分裂期キナーゼ阻害との合成致死性に基づいた新しい卵巣癌治療法の開発

    研究課題/研究課題番号:20K18162  2020年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業  若手研究

    玉内 学志

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    担当区分:研究代表者 

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    卵巣癌は婦人科領域において最も予後不良な癌種の一つであり、抗癌剤への容易な耐性獲得がその主因である。BRCA遺伝子変異との合成致死性に基づき開発されたPARP阻害剤オラパリブが使用可能になったが、より広く適応可能且つ治療効果の高い分子標的薬の開発が望まれている。VRK1は卵巣癌細胞株における網羅的ノックダウンスクリーニングによって見いだされた新規治療のターゲット遺伝子であり、本研究では、VRK1を高発現する卵巣癌PDXモデルを用いて、VRK1阻害剤による腫瘍増殖抑制効果や、卵巣癌におけるVRK1阻害の合成致死性への関与と、それを引き起こす分子メカニズムを解明することを目的とする。
    VRK1は細胞分裂に関与するセリントレオニンキナーゼの一つであり、多くの癌種で高発現している。ルテオリンはVRK1の発現を抑制するフラボノイドであり、卵巣癌に対するルテオリンの抗腫瘍効果とそのメカニズムを検証した。
    ルテオリンの投与によって卵巣癌細胞株の増殖が抑制された。また、卵巣癌患者の腫瘍を移植したマウスモデルにおいても、ルテオリン投与によって腫瘍の増殖が抑制された。
    遺伝子変化の網羅的解析などによって、ルテオリンの抗腫瘍効果メカニズムは、癌抑制遺伝子であるTP53経路の活性化であることが示された。
    ルテオリンは緑黄色野菜に含まれるフラボノイドの一つで、癌を抑制する作用が知られているが、卵巣癌での効果を検証した報告はなかった。本研究では卵巣癌患者の腫瘍を用いた動物モデルにおいて、ルテオリンの経口摂取によって癌の増殖を抑制できることを示した。また、なぜルテオリンが癌を抑制するかのメカニズムも検証し示した。
    既存の抗がん剤などに比べて、ルテオリンというより自然な成分を用いて、新しいがん治療戦略の可能性を示した。

  3. 難治性卵巣癌の微小環境が誘導する抗癌剤ホルミシスとその克服へ向けての新展開

    研究課題/研究課題番号:19K23884  2019年8月 - 2021年3月

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

    玉内 学志

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    担当区分:研究代表者 

    配分額:2860000円 ( 直接経費:2200000円 、 間接経費:660000円 )

    卵巣癌は婦人科領域において最も予後不良な癌種の一つであり、抗癌剤への容易な耐性獲得がその主因である。再発卵巣癌は多発的な病変を形成するが、抗癌剤治療によって縮小する病変と増大する病変とがしばしば混在し、この病態は近年では腫瘍内の遺伝子多様性(heterogeneity)の観点で論じられてきたが、腫瘍周辺の微小環境の違いがエピジェネティックに誘導する悪性形質である可能性がある。本研究では、これら微小環境が関与する抗癌剤耐性メカニズムを解明し、再発卵巣癌に対する新規治療戦略への布石を作ることを目的とする。
    【目的】多発的な病変を形成する再発卵巣癌では、抗癌剤によって縮小する病変と増大する病変とがしばしば混在し、これは微小環境の違いによって腫瘍にデリバリーされる酸素量と抗癌剤量に偏りが生じると、かえって癌の増殖を促進させてしまうという仮説に基づき検証を行った。
    【成績】NOS3は、IC50量の1/10~1/100量のCDDPを投与することで細胞増殖が有意に亢進した。この濃度帯の細胞増殖亢進は20%酸素培養に比して1%酸素培養で顕著だった。メタボローム解析では、抗癌剤からの保護作用を持つとされる還元型グルタチオン及びグルタチオン総量が、IC501/100量の細胞で増加していた。
    低濃度の抗癌剤投与は、かえって癌細胞の増殖を亢進させ (抗癌剤ホルミシス)、低酸素状態によってこの作用が増強することが判明した。卵巣癌の腹膜微小環境においては、酸素や抗癌剤のデリバリーに不均衡が生じることは十分あり得、抗癌剤ホルミシスを念頭において治療に当たる必要があると考えられる。