掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Endometriosis is known to be associated with an increased risk of endometrioid and clear cell ovarian cancer. However, the association between endometriosis and endometrial cancer is controversial. Therefore, we retrospectively analyzed the medical records of women with endometrial cancer who had undergone surgery at our institution to evaluate the clinicopathological relationship between endometrial cancer and endometriosis. The study included 720 women pathologically diagnosed with endometrial cancer at our hospital between 2000 and 2020. The participants were allocated to two groups of patients with endometrial cancer: patients with endometriosis (n = 101) and patients without endometriosis (n = 619). Endometrial cancer patients with endometriosis were significantly younger (median age 54.0 vs. 58.0; p = 0.002). In addition, endometrial cancer patients with endometriosis had fewer pregnancies and deliveries (median pregnancy 1.58 vs. 1.99; p = 0.019, median delivery 1.25 vs. 1.56; p = 0.012). The percentage of patients classified as stage IA was significantly higher in those with endometrial cancer with endometriosis (68.3% vs. 56.4%; p = 0.029). In the analysis of synchronous ovarian cancer, the percentage of dual primary cancer was higher in patients with endometriosis (14.9% vs. 1.6%; p < 0.001). The association of young-onset early-stage endometrial cancer with endometriosis is an important finding that cannot be ignored clinically.

DOI： 10.3390/cancers15235635

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

DOI： 10.1080/01443615.2023.2283162

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared to high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by immunohistochemistry across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer while the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

DOI： 10.1158/1535-7163.MCT-23-0257

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IMPORTANCE: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied. OBJECTIVE: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy. EXPOSURES: Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group). MAIN OUTCOMES AND MEASURES: Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score. RESULTS: A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas. CONCLUSIONS AND RELEVANCE: Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

DOI： 10.1001/jamanetworkopen.2023.18602

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記述言語：英語  

INTRODUCTION AND IMPORTANCE: Squamous cell carcinoma (SCC) arising from mature cystic teratoma of the ovary (MCT-SCC) has a poor prognosis at advanced stages. Although the relationship between homologous recombination deficiency (HRD) and platinum-based chemotherapy sensitivity or poly (ADP ribose) polymerase (PARP) inhibitor efficacy in epithelial ovarian cancer has been demonstrated in clinical trials, the significance of HRD status in MCT-SCC has not previously been described. CASE PRESENTATION: A 73-year-old woman underwent emergency laparotomy due to ovarian tumor rupture. The ovarian tumor was strongly adherent to the surrounding pelvic organs and could not be completely resected. The postoperative diagnosis was stage IIIB MCT-SCC (pT3bNXM0) of the left ovary. After surgery, we conducted the myChoice CDx. The genomic instability (GI) score of 87 was remarkably high, and there was no BRCA1/2 pathogenic mutation. After six courses of combination therapy with paclitaxel and carboplatin, the residual tumors had shrunk by 73 %. We performed interval debulking surgery (IDS), and the residual tumors were completely resected. Subsequently, the patient underwent two courses of the combination of paclitaxel, carboplatin, and bevacizumab, followed by maintenance therapy with olaparib and bevacizumab. Twelve months after IDS, no recurrence has been observed. CLINICAL DISCUSSION: The present case suggests that there are some HRD cases among MCT-SCC patients and that IDS and maintenance therapy with PARP inhibitors may be effective in such cases, as in epithelial ovarian cancer. CONCLUSION: Although the frequency of HRD-positive status in MCT-SCC remains unknown, HRD testing may provide appropriate treatment options for advanced MCT-SCC.

DOI： 10.1016/j.ijscr.2023.108329

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the gross and microscopic features of squamous cell carcinoma arising from ovarian mature cystic teratoma (MCT-SCC) vary from case to case, the spatial spreading of genomic alterations within the tumor remains unclear. To clarify the spatial genomic diversity in MCT-SCCs, we performed whole-exome sequencing by collecting 16 samples from histologically different parts of two MCT-SCCs. Both cases showed histological diversity within the tumors (case 1: nonkeratinizing and keratinizing SCC and case 2: nonkeratinizing SCC and anaplastic carcinoma) and had different somatic mutation profiles by histological findings. Mutation signature analysis revealed a significantly enriched apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) signature at all sites. Intriguingly, the spread of genomic alterations within the tumor and the clonal evolution patterns from nonmalignant epithelium to cancer sites differed between cases. TP53 mutation and copy number alterations were widespread at all sites, including the nonmalignant epithelium, in case 1. Keratinizing and nonkeratinizing SCCs were differentiated by the occurrence of unique somatic mutations from a common ancestral clone. In contrast, the nonmalignant epithelium showed almost no somatic mutations in case 2. TP53 mutation and the copy number alteration similarities were observed only in nonkeratinizing SCC samples. Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT-SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC-mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT-SCC.

DOI： 10.1111/cas.15754

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J03271&link_issn=&doc_id=20230517600024&doc_link_id=10.57291%2Fjsgo.41.2_242&url=https%3A%2F%2Fdoi.org%2F10.57291%2Fjsgo.41.2_242&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ovarian clear cell carcinoma (OCCC) is associated with chemotherapy resistance and poor prognosis, especially in advanced cases. Although comprehensive genomic analyses have clarified the significance of genomic alterations such as ARID1A and PIK3CA mutations in OCCC, therapeutic strategies based on genomic alterations have not been confirmed. On the other hand, OCCC is clinically characterized by a high incidence of thromboembolism. Moreover, OCCC specifically shows high expression of tissue factor and interleukin-6, which play a critical role in cancer-associated hypercoagulation and may be induced by OCCC-specific genetic alterations or the endometriosis-related tumor microenvironment. In this review, we focused on the association between cancer-associated hypercoagulation and molecular biology in OCCC. Moreover, we reviewed the effectiveness of candidate drugs targeting hypercoagulation, such as tissue factor- or interleukin-6-targeting drugs, anti-inflammatory drugs, anti-hypoxia signaling drugs, anticoagulants, and combined immunotherapy with these drugs for OCCC. This review is expected to contribute to novel basic research and clinical trials for the prevention, early detection, and treatment of OCCC focused on hypercoagulation.

DOI： 10.3390/cancers14092125

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.

DOI： 10.1038/s41467-022-28568-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND Vulvar extramammary Paget disease (EMPD) with abnormal cervical cytology is extremely rare. We encountered a case of secondary EMPD derived from urothelial carcinoma diagnosed after cytological examination for cervical cancer screening. We diagnosed the case promptly owing to suspicion based on the patient's medical history and vulvar appearance. We report the case and present a review of published cases of EMPD with abnormal cervical cytology. CASE REPORT A 77-year-old Japanese woman visited a hospital because cervical cancer screening raised the suspicion of adenocarcinoma. Findings of the cytological examinations of the cervix, endometrium, and urethral meatus corresponded to those of other malignant neoplasms of the Bethesda system. The patient had undergone total urethral cystectomy for urothelial carcinoma 5 years earlier. In our hospital, we found erythema extending from the urethral meatus to the vulva and performed a vulvar biopsy based on the suspicion of recurrence of the urothelial carcinoma. We diagnosed secondary EMPD derived from the urothelial carcinoma based on the findings of Paget cells in the epithelium and immunohistochemistry. CONCLUSIONS A review of all the reported cases of EMPD with abnormal cervical cytology shows that the frequency of primary lesions is high in primary EMPD and secondary EMPD derived from urothelial carcinoma. These cases demonstrated the difficulty of suspecting EMPD based on cervical cytology alone. It should be considered that the cells derived from vulvar EMPD can be observed in cervical cytology, particularly in patients with a history of primary EMPD or urothelial carcinoma and with vulvar symptoms.

DOI： 10.12659/AJCR.933655

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear. MATERIALS AND METHODS: We retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status. RESULTS: In the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways. CONCLUSIONS: CCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation.

DOI： 10.1016/j.ygyno.2021.08.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The histology of the endometrium has traditionally been established by observation of two-dimensional (2D) pathological sections. However, because human endometrial glands exhibit coiling and branching morphology, it is extremely difficult to obtain an entire image of the glands by 2D observation. In recent years, the development of three-dimensional (3D) reconstruction of serial pathological sections by computer and whole-mount imaging technology using tissue clearing methods with high-resolution fluorescence microscopy has enabled us to observe the 3D histoarchitecture of tissues. As a result, 3D imaging has revealed that human endometrial glands form a plexus network in the basalis, similar to the rhizome of grass, whereas mouse uterine glands are single branched tubular glands. This review summarizes the relevant literature on the 3D structure of mouse and human endometrium and discusses the significance of the rhizome structure in the human endometrium and the expected role of understanding the 3D tissue structure in future applications to systems biology.

DOI： 10.3390/jpm11080713

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation-specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin-fixed paraffin-embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild-type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild-type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild-type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.

DOI： 10.1111/cas.14871

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as "endometriosis-associated ovarian cancer" (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.

DOI： 10.3390/cancers13061439

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable in vitro 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).

DOI： 10.1016/j.xpro.2021.100354

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

骨盤臓器脱に対して2018年6月〜2020年2月に腹腔鏡下仙骨腟固定術を行った31例のうち、直腸脱の同時手術を行った2例を除く29例を対象とし、「手術時間」「術中出血量」「術中・術後合併症」「再発の有無」「術前後の排尿機能」などについて検討した。手術時間は128〜256分(中央値199分)、出血量は5〜10mL(中央値5mL)であった。術中合併症は認めなかった。術後合併症として腹腔内感染を1例に認めたが保存的治療で改善した。再発は1例に認め、再発部位はメッシュ固定部位以外の後壁であり、追加手術は要しなかった。排尿機能はOABSSとIPSSで評価し、術前のOABSSは軽症(5点以下)5例、中等症(6〜11点)6例、術後のOABSSは軽症1例、中等症1例、重症(12点以上)1例であった。術前のIPSSは軽症(0〜7点)50%、中等症(8〜19点)35%、重症(20〜35点)15%、術後のIPSSは軽症81%、中等症15%、重症4%であった。

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

セプラフィルムは優れた癒着防止効果が報告されているが、腹腔鏡下手術での体腔内搬入や貼付操作に難渋することが多い。今回、セプラフィルムの操作にEndoロールを用いた方法を試行し、その有効性について従来法(リデューサーを用いる方法)と比較検討した。腹腔鏡下単純子宮全摘出術3例にEndoロールを使用した結果、3例とも充填が比較的簡便に途中で破損することなく可能であった。最も優れていた点は、5mmポートから挿入可能なため、カメラで確認しながら安全に体腔内搬入でき、周囲臓器にセプラフィルムが付着する前に、広がったままの状態で受け取ることにより貼付が容易な点であった。

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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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：Springer Science and Business Media LLC  

ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

DOI： 10.1038/s41598-020-71273-7

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その他リンク： http://www.nature.com/articles/s41598-020-71273-7

記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本産科婦人科内視鏡学会  

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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：Cold Spring Harbor Laboratory  

<title>Summary</title>The histological basis of the human uterine endometrium has been established by 2D observation. However, the fundamental morphology of endometrial glands is not sufficiently understood because these glands have complicated winding and branching patterns. To construct a big picture of endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and 3D layer analyses revealed that endometrial glands formed a plexus network in the stratum basalis, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of adenomyosis, a representative “endometrium-related disease”, and observed 3D morphological features including direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, 3D analysis of the human endometrium and endometrium-related diseases will be a promising approach to better understand the pathologic physiology of the human endometrium.

DOI： 10.1101/2020.05.29.118034

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

DOI： 10.1038/s41388-020-1237-0

PubMed

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記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

DOI： 10.1038/s41598-019-54116-y

PubMed

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記述言語：英語  

Levonorgestrel is used worldwide as an emergency oral contraceptive. There have been occasional reports of ectopic pregnancy after oral levonorgestrel use. We present a case of ectopic tubal pregnancy after the use of oral levonorgestrel as an emergency contraceptive in a 37-year-old woman with a history of treatment for Chlamydia trachomatis infection. She conceived after sexual intercourse on menstrual day 14 of the first menstrual cycle following a normal delivery. After salpingectomy for this right tubal pregnancy, her following pregnancy was an ectopic pregnancy in the contralateral tube, which was treated with laparoscopic salpingectomy. Histopathological examination revealed endometriosis. We should be aware of ectopic pregnancy even after emergency contraceptive use, especially in patients with risk factors, such as Chlamydia infection and endometriosis. Because the efficacy of levonorgestrel decreases after ovulation, we should check the stage of the cycle before prescription.

DOI： 10.1111/jog.13815

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1. Most NUTM1 exons were retained in the MXD4-NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

DOI： 10.1002/gcc.22668

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

DOI： 10.1016/j.celrep.2018.07.037

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

DOI： 10.1038/s41389-017-0018-2

PubMed

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DOI： 10.1158/1538-7445.AM2017-529

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

DOI： 10.1111/cas.13196

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.

DOI： 10.1038/srep18657

PubMed

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：北海道産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The differential diagnosis between uterine sarcoma and benign leiomyoma is difficult when made only by magnetic resonance imaging (MRI); it usually requires an additional preoperative diagnostic procedure. We report our results using ultrasound-guided needle biopsy for these types of uterine tumors. METHODS: Ultrasound-guided needle biopsy was performed on 63 patients with uterine smooth muscle tumors suspected of malignancy by MRI. We compared the results of presurgical biopsy against the postsurgical pathology of the tumor. RESULTS: Among 63 patients with a high signal intensity of the uterine tumor on T2-weighted MRI (1 case was undetermined), 12 cases (19.3%) were diagnosed by the needle biopsy as malignant, and 51 cases (80.6%) were benign. Among the 12 diagnosed as malignant tumors, 11 had surgery performed, and one was treated with chemotherapy. Among the 51 patients diagnosed with a benign tumor, 27 had surgery performed, and 24 were put on a wait-and-see clinical follow-up schedule. One of the 27 surgical patients with a benign tumor had a postsurgical diagnosis of a low-grade endometrial stromal sarcoma. In the 38 cases where surgery was performed, we found the sensitivity, specificity, and the positive and negative predictive values of the needle biopsy were 91.7%, 100%, 100%, and 96.2%, respectively. CONCLUSIONS: Ultrasound-guided needle biopsy may be a reliable preoperative diagnostic procedure for uterine tumors with suspected malignancy.

DOI： 10.1097/IGC.0000000000000189

PubMed

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5180/jsgoe.29.313

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記述言語：日本語   出版者・発行元：東北連合産科婦人科学会・北日本産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：英語  

We have reported good control of atypical genital bleeding when using a cyclic administration of dienogest (repeated 4-week cycles, each consisting of the administration of 2 mg/day of dienogest for 3 weeks, followed by 1 week of drug withdrawal) in patients with endometriosis. Herein, we report the effectiveness of the long-term cyclic administration (22 months) of dienogest in a case of pathological disappearance of intestinal endometriosis diagnosed by endoscopy and histology of the lower gastrointestinal tract. There is no recurrent sign after 16 months of the treatment being stopped. Atypical genital bleeding during treatment was 3-5 days a month in each cycle. Compliance was good, so we could continue the therapy. The long-term cyclic administration of dienogest in patients with intestinal endometriosis may have significant merit.

DOI： 10.2147/IJWH.S43567

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：東北連合産科婦人科学会・北日本産科婦人科学会  

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

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記述言語：日本語  

The subject was a 75-year-old female who was receiving paclitaxel and carboplatin(TC)chemotherapy every other week after surgery for ovarian cancer. She greatly complained of taste disorders after four cycles(of every other week administration) of TC chemotherapy. To understand how the taste disorder was caused by chemotherapy objectively, taste examinations were conducted for the patient in our department. These examinations were conducted after receiving the informed consent from the patient. The authors conducted taste examinations for the patient using serum zinc measurement, tongue cell culture, electrogustometry, and filter paper disc tests(before and after starting chemotherapy), and found that her serum zinc level fell significantly after four cycles of chemotherapy. Orally disintegrating tablets of polaprezinc were then administered to the patient, after which the subjective symptom of taste disorder improved. Her serum zinc level increased, and the electrogustometric threshold rapidly fell(an improvement). The filter paper disc test showed some improvement, particularly in the glossopharyngeal nerve and the greater petrosal nerve field.

PubMed

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記述言語：日本語  

Calcium transfer from the mother to the infant during pregnancy and lactation plays an extremely important role in the bone health of the mother and neonate. Calcium aids in bone health through all ages but is especially crucial during pregnancy and lactation. Changes in the structure and metabolism of bone during pregnancy and the early stage of postpartum are evaluated by investigating bone mineral density (BMD), bone histomorphometry and bone markers of human or animal models. The bone resorption increased at the end of pregnancy and lactation, and the bone formation increases and the bone structure is almost recovered after cessation of lactating in postpartum. Puerperal BMD remained static over the subsequent 5-10 years. If the women have a low BMD at this stage of their reproductive life, it tends not to improve over this time. Perhaps identification of this at-risk group may lead to effective interventions to reduce fracture risk in later life.

PubMed

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2018235919

記述言語：英語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：新潟産科婦人科学会  

完全型アンドロゲン不応症(AIS)に対し腹腔鏡下性腺摘出術を施行した4例について検討した。年齢は16歳が2例、19歳が2例であった。性腺が鼠径管内に存在した1例も含めて、全例で腹腔鏡下に性腺摘出が可能であった。全例、術後経過は良好で、外来通院にてエストロゲン補充療法中である。今回の検討から、術前画像診断(特にMRI所見)により性腺の存在位置を予測し、鼠径管内に存在が疑われる場合には開腹手術への移行に備えることで、腹腔鏡下手術をAISに対する予防的性腺摘出術に適応することが可能であると考えられた。

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1158/1538-7445.AM2016-1504

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1158/1538-7445.AM2016-99

Web of Science

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記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

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記述言語：日本語   出版者・発行元：日本産科婦人科学会  

CiNii Article

CiNii Books

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その他リンク： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=453999

記述言語：日本語   出版者・発行元：日本産科婦人科学会  

CiNii Article

CiNii Books

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その他リンク： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=450428

記述言語：日本語   出版者・発行元：日本産科婦人科学会  

CiNii Article

CiNii Books

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その他リンク： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=450113