記述言語：英語   出版者・発行元：Science Advances  

Patients with epithelial ovarian cancer (EOC) are often diagnosed with peritoneal metastasis and ascites, the accumulation of intraperitoneal fluid containing nonmalignant cells. However, the interactions between EOC and nonmalignant cells before peritoneal metastasis remain unclear. To investigate this, whole EOC spheroids were observed using a multiphoton microscope, and their invasion ability was assessed. Mesothelial cells were identified as notable components of ascites through morphological assessment, immunohistochemical/immunofluorescence staining, and single-cell RNA sequencing analyses. Almost all EOC cells were spheroids, with 60% containing mesothelial cells. EOC cells quickly generate aggregated spheroids with mesothelial cells, and these aggregated cancer-mesothelial spheroids (ACMSs) invade collagen or mesothelial layers. Mesothelial cells forming ACMSs initiated the invasion. RNA sequencing analysis revealed marked RNA expression changes in mesothelial cells, whereas the changes in EOC cells were minor. Transforming growth factor–β1–stimulated mesothelial cells showed increased invadopodium formation along with fascin-1 up-regulation. These findings suggest that EOC cells alter mesothelial cells through ACMSs, thereby elucidating the rapid spread of EOC in the abdominal cavity.

DOI： 10.1126/sciadv.adu5944

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記述言語：英語   出版者・発行元：Placenta  

Objective: Choriocarcinoma is a rare cancer associated with antecedent pregnancy. Therefore, its development may be influenced by an immune-evasive tumor microenvironment. In this study, we focused on natural killer (NK) cells to elucidate the immune microenvironment of choriocarcinoma. Methods: Peripheral blood and intratumoral NK cells were isolated from six samples of four patients with choriocarcinoma. Flow cytometry was used to analyze the NK cell proportion. Immunohistochemistry was performed to assess the expression of NK cell inhibitory ligands using choriocarcinoma tissues from 17 patients. In addition, choriocarcinoma cell lines (JAR, BeWo, and JEG-3) were cocultured with interleukin-2-stimulated NK cells, and loss-of-function analyses of HLA-E were conducted to investigate the impact of NK cells on choriocarcinoma cells. Results: Flow cytometry revealed that NK cells were more abundant in choriocarcinoma tissues than in the peripheral blood. Immunohistochemistry confirmed the expression of NK cell inhibitory ligands, including HLA-E. Moreover, JAR cells were cocultured with NK cells, and viable JAR cells were isolated by flow cytometry. Subsequent mRNA sequencing showed that HLA-E was upregulated, and multiple cytokine-related pathways were activated in the cocultured JAR cells compared with monocultured JAR cells. Functional assays demonstrated that HLA-E knockdown enhanced NK-cell-mediated cytotoxicity, whereas interferon-gamma treatment increased HLA-E expression and promoted tumor cell survival. Conclusion: These findings suggest that NK cells may play an important role in the tumor immune microenvironment of choriocarcinoma through HLA-E expression.

DOI： 10.1016/j.placenta.2025.11.012

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

Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have significantly improved outcomes in ovarian cancer. However, therapy-related myeloid neoplasms (t-MNs) have emerged as rare but serious late complications. Although an increased incidence of t-MNs has been reported following PARPi exposure, clinical predictors remain poorly understood. Methods: This retrospective study analyzed 181 patients with ovarian cancer treated with PARPi at two Japanese institutions. Clinical characteristics and routine hematologic parameters were compared between patients with and without t-MNs. Hematological values were assessed at initial diagnosis, PARPi initiation, 4 weeks after initiation, and at nadir within 12 weeks. Relative changes from initial diagnosis and from PARPi initiation to nadir were also evaluated. Results: t-MNs developed in 6 (3.3%) patients. All patients in the t-MN group had received multiple platinum-containing regimens, and in five of the six cases, t-MN was diagnosed more than 5 years after initial diagnosis. No definitive clinical predictors were identified, although the t-MN group tended to have higher body mass index. Median white blood cell (WBC), hemoglobin, and platelet counts, as well as their relative changes from initial diagnosis or PARPi initiation to nadir, did not differ significantly between the groups. However, the t-MN group exhibited a larger reduction in WBC count from PARPi initiation to nadir, not statistically significant. Conclusions: This real-world study highlights the importance of survivorship care in the era of improved outcomes for ovarian cancer. Continued long-term hematologic monitoring, along with the collection of more cases, is essential to elucidate risk factors for t-MNs in patients receiving PARPi therapy.

DOI： 10.3389/fonc.2026.1728766

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記述言語：英語   出版者・発行元：Science Advances  

Preeclampsia (PE) is a major pregnancy complication characterized by hypertension and multiple end-organ dysfunctions; however, its detailed pathogenesis remains unclear. Extracellular vesicles (EVs) play diverse and critical roles in intercellular communication, and we have demonstrated interaction between EVs and vascular endothelial cells. Through serum proteomic analysis, we identified LIM and calponin homology domain-containing protein 1 (LIMCH1) as a PE-associated EV protein that is highly expressed in PE placentas, particularly in syncytiotropho-blasts, which release EVs into the maternal circulation. LIMCH1-enriched EVs (LIMCH1-EVs) increased endothelial permeability in vitro. Transcriptome analysis revealed that LIMCH1-EVs disrupted endothelial cell-cell junction assembly by suppressing the expression of the tight junction protein ZO-1. Furthermore, administration of LIMCH1-EVs promoted pulmonary vascular permeability in vivo. These findings suggest a role of LIMCH1-EVs in EV-associated vascular endothelial dysfunction, a central pathology of PE. In addition, this study provides insights into mechanisms that may contribute to PE-associated pulmonary edema, which have not yet been clarified.

DOI： 10.1126/sciadv.aeb8806

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記述言語：英語   出版者・発行元：BMC Cancer  

Background: Uterine sarcoma has an inferior prognosis and high recurrence rate among gynecological malignancies, even in early-stage cases with complete resection. However, the risk factors for recurrence remain poorly understood. This study aimed to identify risk factors associated with recurrence in early-stage uterine sarcoma. Methods: Among 97 patients with uterine sarcoma treated at our institution between January 2007 and June 2023, we retrospectively investigated 55 patients of the following five histological types: uterine leiomyosarcoma (ULMS), low- or high-grade endometrial stromal sarcoma (LG-ESS or HG-ESS), adenosarcoma, and smooth muscle tumor of uncertain malignant potential (STUMP). Risk factors were compared between the recurrence and non-recurrence groups using univariate analysis, and recurrence rates, time to recurrence, progression-free survival (PFS), and overall survival (OS) were examined. Results: The median age of 55 patients was 48 years, and the most common initial symptom was abdominal pain or abdominal mass awareness (29.4%), followed by abnormal bleeding in 25.5% of the patients. The median tumor size was 9.7 cm, and stage I cases were 64.8% of the total. Histological types were 28 ULMS, 13 LG-ESS, 8 STUMP, 5 HG-ESS, and one adenosarcoma. Among stage I cases, ULMS had a recurrence rate of 81.3% with a median time to recurrence of 12.4 months, while LG-ESS had a recurrence rate of 30% with a median time to recurrence of 41.1 months. A high mitotic count was significantly associated with recurrence in stage I ULMS (p = 0.044). Other surgical pathological findings, such as lymphovascular space invasion, MIB-1 positive rate, and necrosis, and surgical factors, such as myomectomy and ovarian preservation, showed no statistically significant differences but were higher in the recurrence cases. The 5-year PFS rates in stage I ULMS and LG-ESS groups were 31.3% and 75%, and the 5-year OS rates were 68.5% and 100%, respectively. Conclusions: In stage I ULMS, a high mitotic count was associated with an increased risk of recurrence after complete surgical resection.

DOI： 10.1186/s12885-026-15618-x

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記述言語：英語   出版者・発行元：Cancer Science  

Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare but aggressive malignancy for which no standardized chemotherapy or effective targeted therapies currently exist. To identify therapeutic vulnerabilities in MTMCT, we performed a genome-wide CRISPR-Cas9 knockout screen using the MTMCT-derived NOSCC1 cell line. Two parallel selective pressures were applied: in vivo tumorigenicity in immunodeficient mice and cisplatin exposure in vitro. From this screen, 67 negatively selected genes were identified, among which SOD1 and NDUFB4 emerged as top candidates based on high basal expression levels and clinical relevance. Integration with spatial transcriptomic data from three independent MTMCT patient tumors further supported the prioritization of these targets. SOD1 was selected for further investigation due to the availability of known pharmacological inhibitors. Both siRNA-mediated knockdown and small-molecule inhibition of SOD1 using LCS-1 significantly suppressed MTMCT cell proliferation in vitro by inducing oxidative stress and impairing cell cycle progression. This antiproliferative effect was reversed by co-treatment with N-acetylcysteine, a reactive oxygen species scavenger. In vivo validation using patient-derived xenograft models demonstrated that oral administration of LCS-1 led to significant tumor growth suppression and increased expression of apoptotic and DNA damage markers, including cleaved caspase-3 and γH2AX. These findings establish SOD1 as a critical vulnerability in MTMCT and provide preclinical evidence supporting redox modulation as a therapeutic strategy for this highly chemoresistant and understudied ovarian cancer subtype. Our integrative approach combining functional genomics, spatial transcriptomics, and pharmacologic validation offers a framework for the discovery of novel targets in rare gynecologic malignancies.

DOI： 10.1111/cas.70315

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

Objective: Mucinous ovarian cancer (MOC) is a rare epithelial ovarian cancer subtype with poor prognosis, particularly in advanced stages. Differentiating MOC from mucinous borderline ovarian tumor (MBT) remains clinically challenging, often leading to delayed or inadequate treatment. Accurate preoperative diagnosis is crucial for guiding surgical strategies and improving patient outcomes. This study evaluated preoperative clinical factors that can distinguish MOC from MBT. Methods: We retrospectively analyzed 46 ovarian mucinous tumors diagnosed between 2017 and 2021, including 15 MOC and 31 MBT cases confirmed by histopathology. Patient age, tumor laterality, tumor size, tumor markers (CA125, CA19-9, CA72-4, CEA), and tumor volume were assessed. Tumor size was measured as the maximum magnetic resonance imaging diameter, whereas volume was calculated using three-dimensional imaging. Statistical analyses included the Mann–Whitney U test and receiver operating characteristic curve analysis, with AUC as a measure of diagnostic accuracy. Results: Among the tumor markers, CA72-4 exhibited the highest diagnostic accuracy (area under the curve [AUC]: 0.834), with significantly higher levels in MOC than in MBT (p < 0.001). Tumor size alone was an unreliable discriminator (AUC: 0.42). The tumor volume tended to be larger in MBT than in MOC (median: 2 362 878 cm³ vs. 1 262 436 cm³; p = 0.77). However, the combination of CA72-4 and tumor volume improved the diagnostic performance (AUC: 0.875). Conclusion: The combination of CA72-4 levels and tumor volume enhances preoperative differentiation between MOC and MBT. This combined approach may optimize surgical planning and improve patient outcomes.

DOI： 10.1111/jog.70177

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

The malignant transformation of ovarian mature cystic teratoma (MTMCT) is a rare and aggressive condition often diagnosed at advanced stages with limited treatment options. Leveraging cancer genomic profiling (CGP), this study evaluated the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in a patient-derived xenograft (PDX) model of MTMCT with high loss of heterozygosity (LOH). Tumor samples from a patient with MTMCT were used to establish the PDX model. CGP revealed high LOH and actionable mutations, including STK11 (E256*) and EMSY amplification, suggesting potential sensitivity to PARP inhibitors. Mice treated with PARP inhibitors exhibited significantly reduced tumor volumes compared to controls. Whole-exome sequencing (WES) performed on control and post-treatment residual tumors demonstrated that while total LOH levels remained stable, copy-neutral LOH (CN-LOH) increased significantly, indicating treatment-induced genomic instability. Notably, STK11 (E256*) underwent CN-LOH in residual tumors, suggesting a role in acquired resistance. Furthermore, EMSY amplification, initially observed in the tumor and associated with PARP inhibitor sensitivity, was absent after treatment, reflecting clonal selection or adaptive resistance. These findings underscore the therapeutic potential of PARP inhibitors in high-LOH MTMCT while highlighting the emergence of resistance mechanisms, including CN-LOH and loss of EMSY amplification. They emphasize the importance of considering tumor evolution and treatment timing when interpreting CGP results, providing a foundation for further research into predictive biomarkers and resistance mechanisms in rare gynecologic malignancies.

DOI： 10.1016/j.bbrc.2025.152979

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記述言語：英語   出版者・発行元：Cancer Science  

Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease-specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin-fixed, paraffin-embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR-517a-3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG-3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR-517a-3p, which was validated by dual-luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR-517a-3p functions as a tumor suppressor by directly regulating SRSF1 expression.

DOI： 10.1111/cas.70207

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出版者・発行元：Heliyon  

Extracellular vesicles (EVs) are secreted from mammalian cells and bacteria and are involved in disease pathogenesis. Recently, bacterial factors have been linked to the pathogenesis of endometriosis. Therefore, identifying host-bacterial interactions is crucial for a better understanding of endometriosis. Here, we isolated bacterial EVs (BEVs) from six species of common vaginal bacteria and analyzed their components by comprehensive small RNA sequencing. We then examined the influence of these BEVs on host cells. We showed that BEVs from Fusobacterium nucleatum (F. nuc.), an endometriosis-associated bacterium, significantly stimulated the migration ability of endometrial mesenchymal cells ( P  < 0.01). Exposure of dTHP-1 cells to BEVs form F. nuc. enhanced cytokine secretion and may induce the polarization of M2 macrophages over the M1 phenotype. We also investigated the potential of BEVs as biomarkers. We detected 40 specific RNA sequences that are both expressed in over 0.01 % of BEVs from F. nuc. and that were detected in >10 read counts in the serum of patients with endometriosis, but not in tissue samples. Serum samples from patients with endometriosis (n = 14) showed aberrant expression of six specific genes compared to patients without endometriosis (n = 34), and the receiver operating characteristic curve indicated that a combination of these six genes was most accurate for the diagnosis of endometriosis (area under the curve = 0.91). Small RNAs in BEVs may serve as novel biomarkers to detect endometriosis-related bacterial factors.

DOI： 10.1016/j.heliyon.2025.e44099

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

Malignant ovarian tumors (MOTs) and borderline ovarian tumors (BOTs) differ in treatment strategies and prognosis. However, accurate preoperative diagnosis remains challenging, and improving diagnostic accuracy is crucial. We developed and validated a system using artificial intelligence (AI) to integrate machine learning (ML) models based on blood test data and deep learning (DL) models based on magnetic resonance imaging (MRI) findings to distinguish between MOT and BOT. We analyzed 78 patients with malignant serous ovarian tumors and 31 with borderline serous ovarian tumors treated at our institution. A classification model was developed using ML for blood test data, and a DL model was constructed using MRI data. By integrating these models, we developed three fusion models as multimodal diagnostic AI and compared them with standalone models. The performance was evaluated using precision, recall, and accuracy. The classification model using Light Gradient Boosting Machine achieved an accuracy of 0.825, and the DL model using Visual Geometry Group 16-layer network achieved an accuracy of 0.722 for discriminating BOT from MOT. The intermediate, late, and dense fusion models achieved accuracies of 0.809, 0.776, and 0.825, respectively. Integrating multimodal information such as blood test and imaging data may enhance learning efficiency and improve diagnostic accuracy.

DOI： 10.1038/s41598-025-21128-w

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記述言語：英語   出版者・発行元：Proteomics  

Diverse extracellular vesicles (EVs) are present in all body fluids; however, knowledge of large EVs (lEVs) remains limited. Molecular EV profiles vary depending on EV size and the physiological circulatory system, even within the same patient. In this study, we aimed to characterize the proteomic profile of IEVs in ovarian cancer patients and identify lEV-protein biomarkers. We collected tissue, serum, and ascites from patients with high-grade serous ovarian cancer and concurrently separated small EVs (sEVs) and lEVs through sequential multistep centrifugation. Proteomic analysis of tissues and EVs revealed distinct EV profiles in serum and ascites, identifying 11 lEV-specific proteins in serum and 14 in ascites that were absent in sEV. Of these, seven serum-specific and 10 ascites-specific proteins were further analyzed using transcriptomic databases, revealing candidate diagnostic and prognostic lEV-protein biomarkers. Our findings underscore the importance of size-based EV separation, as particle size influences biosynthetic mechanisms, in identifying lEV-specific proteins with potential diagnostic and prognostic values. Summary: This study underscores the importance of distinguishing extracellular vesicle (EV) subtypes and considering body fluid specificity in biomarker discovery. By isolating EVs based on size and stepwise separation and analyzing their proteomic profiles in ovarian cancer, we identified potential large EV (lEV)-specific biomarkers that reflect disease pathology. These findings provide a foundation for lEV-protein–based liquid biopsy approaches that could enhance the accuracy of early detection and patient stratification. Further validation in clinical settings may pave the way for more precise and personalized ovarian cancer diagnostics.

DOI： 10.1002/pmic.70054

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記述言語：英語   出版者・発行元：Journal of Extracellular Biology  

Extracellular vesicles (EVs) are present in body fluids and act as disease biomarkers. Emerging evidence has proven that EVs are released not only from mammalian cells but also from bacteria. Ovarian cancer has a dismal prognosis because of difficulties in early detection. This study aimed to identify bacterial EV (BEV) proteins associated with ovarian cancer. Fifteen patients with ovarian cancer or non-cancer were recruited, and EVs were isolated from the ascites. BEVs were recovered from seven in vitro-cultured strains of bacteria present in the vaginal microbiota, and LC-MS/MS analysis was performed. The detected peptide data were annotated to both human and bacterial references, and the human data showed that the profiles of cancer EVs were distinct from those of patients with non-cancer. As analysed by bacterial proteins, P15636_Protease1 was found as the BEV-associated protein highly expressed in patients with cancer. To distinguish patients with cancer, the area under the curve was 0.88 (95% CI, 0.64–1.00). In addition, homology analysis showed that P15636_Protease1 is a unique protein only detected in bacteria. In this study, ovarian cancer-specific bacterial proteins were identified on EVs, and BEVs in bodily fluids are promising in the discovery of disease biomarkers.

DOI： 10.1002/jex2.70073

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記述言語：英語   出版者・発行元：Human Cell  

Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare and aggressive subtype of cervical adenocarcinoma characterized by intrinsic resistance to chemotherapy and poor clinical outcomes due to the lack of effective treatment options. To address this critical unmet need, we established a novel GAS-derived cell line, KGAS, from ascitic fluid collected from a patient with recurrent GAS. Short tandem repeat (STR) analysis confirmed the genetic identity between the primary tumor and the cell line. Upon transplantation into immunocompromised mice, KGAS cells formed tumors that expressed Claudin-18 and MUC6, clinically recognized markers of GAS. Furthermore, KGAS cells exhibited marked resistance to paclitaxel and carboplatin, showing significantly reduced growth inhibition compared to HeLa cells. We also established a paclitaxel- and carboplatin-resistant subline, rKGAS, and performed microRNA (miRNA) sequencing to explore the molecular basis of acquired chemoresistance. Seventeen differentially expressed miRNAs were identified between KGAS and rKGAS cells. Upregulated miRNAs in rKGAS were predicted to target oncogenes such as BCL2, MET, SIRT1, and VEGFA, whereas downregulated miRNAs were associated with tumor suppressor genes, including IGF1R, TNFAIP3, and MTOR. The KGAS and rKGAS cell lines represent valuable preclinical models for elucidating the molecular mechanisms of chemoresistance and malignant progression in cervical GAS, and may contribute to the development of novel therapeutic strategies for this challenging cancer subtype.

DOI： 10.1007/s13577-025-01286-9

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

Background: Complete hydatidiform moles coexisting with a fetus (CHMCF) are uncommon. Although CHMCF is associated with perinatal complications and post-molar gestational trophoblastic neoplasia (GTN), necessitating post-delivery chemotherapy, live birth remains feasible. This report presents 14 cases of CHMCF in Japan. Methods: We reviewed medical records of patients with CHMCF treated at our hospital from 2000 to 2020 and summarized clinical data, including maternal age, pregnancy details, delivery outcomes, fertility treatments, serum human chorionic gonadotropin (hCG) levels, and ultrasonography findings. Results: Fourteen cases of CHMCF were diagnosed. The average age of the mothers was 30.6 years, with the majority conceiving following fertility treatment. The mean gestational age at diagnosis was 12 weeks. Six patients maintained their pregnancies, leading to two live births through emergency cesarean section. Eight patients exhibited spontaneous regression following treatment and pregnancy interruption, achieving negative serum hCG levels within 17.4 weeks. Six patients experienced post-molar GTN, including the two who had live births. One patient presented with FIGO stage I disease, while five patients had stage III lung metastases. All patients received chemotherapy, averaging nine courses, achieving remission within 13.7 weeks. Conclusion: The occurrence of GTN was higher after CHMCF than after typical complete hydatidiform moles. Despite the heightened risk of premature birth, some patients with CHMCF who maintain their pregnancies can successfully deliver live babies. Informed consent is essential for patients with CHMCF when considering pregnancy continuation. A team approach involving gynecological oncologists, obstetricians, and neonatologists is essential for effective diagnosis and treatment.

DOI： 10.1007/s10147-025-02815-0

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記述言語：英語   出版者・発行元：Communications Biology  

Platinum-resistant ovarian cancer (PROC) is a clinically severe unresolved issue, and it remains unclearly defined by molecular biology. Extracellular vesicles (EVs) play an essential role in cell-to-cell communication in the tumor microenvironment. This study aimed to investigate the molecular mechanisms of PROC, focusing on the unique ascites environment of ovarian cancer. Multi-transcriptome analyses using clinical samples revealed that PROC exhibited an activated Janus kinase (JAK)/signal transducer and activator of transcription pathway with high JAK1 expression in cancer cells. Immunohistochemistry for patient tissues confirmed the negative association between JAK1 expression and platinum response. JAK inhibitors were effective in PROC cell lines and cell- and patient-derived xenograft models, as well as synergistic with platinum. Furthermore, small RNA sequencing indicated that activated peritoneal mesothelial cell-derived EVs enriched in miR135a-5p increased JAK expression and platinum resistance in cancer cells. Collectively, EVs in ascites regulated platinum sensitivity in ovarian cancer cells, and JAK targeting therapeutic strategy overcomes PROC.

DOI： 10.1038/s42003-025-08771-9

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記述言語：英語   出版者・発行元：Cancer Medicine  

Background: The precision management of ovarian clear cell carcinoma (OCCC) faces limitations due to the absence of personalized prognostic tools. This study aimed to establish predictive risk scores to enable effective stratification and tailored treatment of OCCC. Methods: Retrospective data from 206 OCCC patients treated between 2004 and 2019 at two hospitals were analyzed. Penalized regression models were utilized to develop three risk scores based on preoperative laboratory results and intraoperative findings. These scores underwent internal and external validation. Results: The median follow-up periods were 65.7 and 44.0 months for the derivation and validation cohorts, respectively. In internal validation with the derivation cohort, all three risk scores effectively identified the high-risk group for tumor recurrence. Upon validation with the external cohort, Risk Score 3, which incorporated variables selected in most cross-validations by the penalized regression (Elastic Net), distinctly differentiated the high- and low-risk groups (p = 0.03). Risk Score 2, consisting solely of preoperatively available variables, also demonstrated marginal significance (p = 0.08). Conclusion: Our findings underscore the significance and utility of the developed risk scores in tailoring personalized treatments for patients with OCCC.

DOI： 10.1002/cam4.71118

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

The impact on prognosis of neutrophil infiltration in the microenvironment of ovarian cancer remains to be elucidated. In this study, we analyzed the association between neutrophil infiltration in peritoneal metastasis and prognosis. Furthermore, we analyzed the correlation between neutrophil infiltration in peritoneal metastasis and the number of peripheral blood neutrophils, the degree of neutropenia, vascular endothelial area, and the number of stromal cells. Thirty-four specimens each of primary and metastatic advanced ovarian cancer with high-grade serous carcinoma histology were taken. Staining for MPO, CD31, and αSMA was performed on all specimens. We investigated the correlation among tissue neutrophil infiltration, prognosis, and neutrophil indicators from blood tests. Survival analysis showed that neutrophil infiltration in the primary tumor had no impact on prognosis, whereas high neutrophil infiltration in the disseminated tumor significantly shortened progression-free survival and overall survival. No correlation was found between neutrophil infiltration and the number of peripheral blood neutrophils, the degree of neutropenia, area of vascular endothelial cells, and number of stromal cells. Neutrophil infiltration into disseminated lesions of the omentum has a significant impact on prognosis. The results of the present study may provide insights for refining clinical approaches.

DOI： 10.1038/s41598-025-05010-3

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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  

Background In ovarian cancer (OvCa), achieving complete resection (RO) in initial surgery is crucial for improving prognosis. However, patients with undetected microscopic metastasis post-RO surgery often have poorer outcomes. This study explores prognostic factors for OvCa patients who underwent RO surgery, focusing on the role of ascites cytology as an indicator of microscopic peritoneal metastasis. Methods We analyzed data from 975 OvCa cases in the Tokai Ovarian Tumor Study Group database (1986-2019). Excluding patients without chemotherapy or with distant metastasis, we examined prognostic factors using Cox regression analysis. Propensity score (PS) methods balanced the cytology-positive and -negative groups, with subgroup analysis for clinical stage and ascites volume. Results Multivariate analysis identified FIGO stage III and positive ascites cytology as poor prognostic factors for overall and progression-free survival. After PS adjustment, positive ascites cytology also shortened progression-free intervals post-recurrence, especially in cases with peritoneal or lymph node metastasis. Subgroup analysis revealed a more substantial prognostic impact of positive ascites cytology in early-stage cases. Conclusion The present results suggest that in OvCa patients with the R0 status, the presence of tumor cells in ascites is an independent negative prognostic factor and may be an indicator of peritoneal micro-metastasis.

DOI： 10.1093/jjco/hyaf046

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

Objective: To identify preoperative imaging features associated with retroperitoneal growth of large uterine fibroids and evaluate their impact on surgical outcomes. Methods: This retrospective study included 20 patients who underwent hysterectomy for uterine fibroids measuring ≥10 cm between 2014 and 2024. Preoperative CT or MRI was evaluated for four features: bladder displacement, sigmoid colon deviation, cecal displacement, and hydronephrosis. Tumor growth direction (intraperitoneal vs. retroperitoneal) was determined intraoperatively. Operative time, blood loss, and complications were compared between groups. Results: Eight tumors exhibited retroperitoneal growth. Bladder displacement, cecal shift, sigmoid colon deviation, and hydronephrosis were significantly more common in retroperitoneal cases (all p < 0.05). Retroperitoneal tumors were associated with significantly greater median blood loss (1591 mL vs. 651 mL, p = 0.043), although operative time did not differ significantly (301 vs. 232 min, p = 0.237). Organ injury or resection occurred only in the retroperitoneal group. A bubble plot illustrated the trend of increased surgical burden in retroperitoneal cases. Conclusion: Retroperitoneal growth of large uterine fibroids is associated with increased intraoperative blood loss and surgical complexity. Four simple imaging features may serve as reliable indicators of growth direction and help guide preoperative planning.

DOI： 10.1111/jog.70013

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出版者・発行元：診断と治療社  

DOI： 10.34433/og.0000001187

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

Squamous cell carcinoma arising from mature teratoma (SCC-MT) is a rare ovarian malignancy. The detailed molecular pathology of SCC-MT is not well understood. Moreover, the prognosis of the patients remains poor because no standard treatment has been established. In this study, we performed single-nucleus RNA sequencing and spatial transcriptomics using clinical SCC-MT samples to identify novel therapeutic candidates. snRNA-seq revealed three epithelial cell clusters, of which one was significantly associated with epidermis and keratinocyte development. Moreover, spatial transcriptomics revealed that the epithelial-mesenchymal transition was significantly inhibited, and the MYC and E2F targets were significantly activated in cancer spots on specimen sections. We focused on KLF5, which was one of the upregulated genes in cancer cells, and performed a functional analysis using NOSCC-1, a cell line derived from an SCC-MT. KLF5 downregulation significantly decreased cell proliferation and increased apoptosis. Furthermore, we previously identified miR-145-5p as a downregulated miRNA in SCC-MT. We demonstrated that miR-145-5p overexpression attenuated cell proliferation and decreased KLF5 expression. In conclusion, through multi-omics analyses, we identified unique gene expression profiles of SCC-MT and determined a role for KLF5 in SCC-MT development. Therefore, KLF5-related factors may be novel therapeutic targets, and further studies are needed to improve the diagnosis and treatment of SCC-MT.

DOI： 10.1111/cas.70022

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記述言語：英語   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2025.02.004

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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：Communications Biology  

Histological chorioamnionitis (HCA) is a form of maternal immune activation (MIA) linked to an increased risk of neurodevelopmental disorders in offspring. Our previous study identified neurodevelopmental impairments in an MIA mouse model mimicking HCA. Thus, this study investigated the role of CD11c⁺ microglia, key contributors to myelination through IGF-1 production, in this pathology. In the mouse model, the CD11c⁺ microglial population was significantly lower in the MIA group than in the control group on postnatal day 3 (PN3d). Furthermore, myelination-related protein levels significantly decreased in the MIA group at PN8d. In humans, preterm infants with HCA exhibited higher IL-6 and IL-17A cord-serum levels and lower IGF-1 levels than those without HCA, followed by a higher incidence of delayed myelination on magnetic resonance imaging at the term-equivalent age. In silico analysis revealed that the transient induction of CD11c⁺ microglia during early development occurred similarly in mice and humans. Notably, a lack of high CD11c⁺ microglial population has been observed in children with neurodevelopmental disorders. This study reports impaired induction of CD11c⁺ microglia during postnatal development in a mouse model of MIA associated with delayed myelination. Our findings may inform strategies for improving outcomes in infants with HCA. (Figure presented.)

DOI： 10.1038/s42003-025-07511-3

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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：Frontiers in Endocrinology  

Introduction: Endometriosis can cause of infertility, and evaluation methods for predicting clinical pregnancy outcomes are desired. Extracellular vesicles (EVs) exist in blood and it contains small non-coding RNAs (ncRNAs) that may reflect disease severity. In this study, we investigated small ncRNAs in serum EVs to identify specific biomarkers for predicting clinical pregnancy. Methods: Serum samples were collected from 48 patients who underwent assisted reproductive technology (ART). EVs were successfully isolated from serum samples and characterized using nanoparticle tracking assays, electron microscopy, and western blotting of EV’s markers. We performed small RNA sequencing and analyzed microRNA (miRNA) profiles in the infertility patients with and without endometriosis to detect pregnancy-predicting biomarkers. Results: Candidate miRNAs in serum EVs were selected by comparing patients without endometriosis who became pregnant (n = 13) with those who did not (n = 21). A total of 241 miRNAs were detected; however, no trends separated the two groups. Next, EVs from patients with endometriosis were analyzed and divided into pregnant (n = 4) and non-pregnant (n = 10) cases. Among the 224 candidate miRNAs, miRNA profiles of pregnant women with endometriosis were separated from those of non-pregnant women by receiver-operating characteristics (ROC) curve analysis (area under the curve [AUC] > 0.8). In patients with endometriosis, serum EVs may be useful for predicting possible pregnancy before infertility treatment. Finally, we used small RNA sequencing of the tissue to demonstrate that pregnancy-predicting miRNAs in serum EVs were produced from endometriosis lesions. Although no predictors were found from miRNAs in serum EVs without endometriosis, miRNAs in serum EVs of patients with endometriosis could provide novel noninvasive biomarkers to predict pregnancy and have potential clinical applicability in ART. Discussion: Further studies are required to examine the functional importance of these miRNAs to elucidate the pathological mechanisms of endometriosis and pregnancy.

DOI： 10.3389/fendo.2024.1442684

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

Aim: While manual vacuum aspiration (MVA) is commonly employed for early first-trimester abortions, its effectiveness in treating hydatidiform mole is still unclear. This study sought to evaluate the efficacy and safety of MVA in comparison to dilation and curettage (D&C) for managing hydatidiform mole. Methods: We conducted a retrospective review of medical records for 198 patients with hydatidiform mole treated at Nagoya University Hospital between 2004 and 2023. After excluding cases with incomplete data, we compared 106 patients who underwent D&C with 60 patients treated with MVA followed by curettage. We evaluated the surgical duration, intraoperative blood loss, and the occurrence of post-molar gestational trophoblastic neoplasia (GTN) in both groups. Results: The surgical duration and blood loss were similar between the MVA and D&C groups. The average surgical time was 13.2 min for D&C and 11.8 min for MVA (p = 0.145). Most cases in both groups experienced blood loss of less than 10 mL, with no significant difference (p = 0.066). Over a median follow-up period of 33.4 months, 25 cases developed post-molar GTN. All GTN cases originated from complete hydatidiform mole (25 of 132 cases, 18.9%), and none were from partial hydatidiform mole. Kaplan–Meier analysis, focusing only on patients with complete hydatidiform mole, indicated no significant difference in the time to onset of GTN between the D&C and MVA groups (p = 0.632). Conclusions: MVA followed by curettage is a viable approach for treating molar pregnancy.

DOI： 10.1111/jog.16210

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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：Cancer Immunology Immunotherapy  

Objectives: We focused on how the immunophenotypes based on the distribution of CD8-positive tumor-infiltrating lymphocytes (TILs) relate to the endometrial cancer (EC) molecular subtypes and patients’ prognosis. Patients and methods: Two cohorts of EC patients (total n = 145) were analyzed and categorized using the Molecular Risk Classifier for Endometrial cancer (ProMisE): POLEmut (POLE mutation), MMRd (mismatch repair deficiency), NSMP (no specific molecular profile), and p53abn (p53 abnormality). CD8-positive TILs, within the central tumor and the invasive margin, were examined by using immunohistochemical staining and advanced image-analysis software. It was investigated whether these immunophenotypes correlate with the molecular subtypes and patients' survival. RNA-sequencing (RNA-seq) was used to explore tumor-derived factors influencing these immunophenotypes. Results: Three distinct immunophenotypes (inflamed, excluded, and desert) based on the CD8-positive TIL patterns were identified in EC patients. Notably, the inflamed phenotype was most frequently observed in the POLEmut and MMRd subtypes, while the desert phenotype was predominant in the NSMP subtype; however, other immunophenotypes were also observed. All p53abn subtype showed the non-inflamed (excluded or desert) phenotype. The prognosis was markedly poorer in the patients with the non-inflamed phenotype than in those with the inflamed phenotype. The RNA-seq analysis showed that the expression of MYC target genes and type-1 interferon response genes was enriched in the non-inflamed phenotype in MMRd and NSMP subtypes, respectively. Conclusion: Evaluating not only the molecular classification but also the immunophenotype may lead to more personalized immunotherapy in EC and elucidating the mechanisms that underlie the formation of the three immunophenotypes could lead to the discovery of new immunotherapy targets.

DOI： 10.1007/s00262-024-03919-8

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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  

Advanced ovarian cancer often presents with multiple lesions exhibiting varying responses to chemotherapy, highlighting the critical influence of the tumor microenvironment (TME). This study investigates the phenomenon of chemotherapeutic hormesis, wherein low doses of chemotherapeutic agents, such as cisplatin (CDDP) and paclitaxel (PTX), paradoxically stimulate rather than inhibit cancer cell proliferation. Our findings indicate that NOS3 ovarian cancer cells, particularly drug-resistant variants, exhibit enhanced proliferation when exposed to low concentrations of these drugs. This effect is further amplified under hypoxic conditions, suggesting that the TME plays a pivotal role in modulating chemotherapeutic outcomes. Mechanistically, low-dose CDDP upregulates pathways involved in cell cycle progression, specifically the G2/M checkpoint and mitotic spindle formation, accelerating rather than arresting the cell cycle. Furthermore, the activation of the reactive oxygen species (ROS) pathway and increased glutathione levels indicate increased cellular response to oxidative stress, further contributing to cell survival and proliferation. These findings challenge traditional treatment strategies that prioritize the maximization of drug dosage, suggesting that a more nuanced approach considering the influence of the TME and the potential for hormesis could improve therapeutic outcomes. Understanding the mechanisms driving chemotherapeutic hormesis is essential for developing more effective treatments for refractory ovarian cancer. Future research should focus on mitigating the impact of hormesis to enhance the efficacy of chemotherapy in resistant cancer types.

DOI： 10.1038/s41598-024-84290-7

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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：Cancer Medicine  

Background: Platinum chemotherapy is the cornerstone of treatment for high-grade serous ovarian cancer (HGSOC); however, validated biomarkers that can accurately predict platinum response are lacking. Based on their roles in the underlying pathophysiology, circulating microRNAs are potential, noninvasive biomarkers in cancer. In the present study, we aimed to evaluate the circulating miRNA profiles of patients with HGSOC and to assess their potential utility as biomarkers to predict platinum response. Methods: Pretreatment serum samples collected from patients who received platinum chemotherapy for Stage III–IV HGSOC between 2008 and 2016 were analyzed using miRNA microarray. LASSO logistic regression analysis was used to construct predictive models for treatment-free interval of platinum (TFIp). Results: The median follow-up was 54.6 (range, 3.5–144.1) months. The comprehensive analysis of 2588 miRNAs was performed in serum samples of 153 eligible patients, and predictive models were constructed using a combination of circulating miRNAs with an area under the receiver operating characteristic curve of 0.944 for TFIp >1 month, 0.637 for TFIp ≥6 months, 0.705 for TFIp ≥12 months, and 0.938 for TFIp ≥36 months. Each predictive model provided a significant TFIp classification (p = 0.001 in TFIp >1 month, p = 0.013 in TFIp ≥6 months, p < 0.001 in TFIp ≥12 months, and p < 0.001 in TFIp ≥36 months). Conclusion: Circulating miRNA profiles has potential utility in predicting platinum response in patients with HGSOC and can aid clinicians in choosing appropriate treatment strategies.

DOI： 10.1002/cam4.70251

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

Objective: A complete hydatidiform mole (CHM) is a common disease and is known to develop post-molar gestational trophoblast neoplasia (GTN). However, the molecular mechanisms underlying the progression of CHM to post-molar GTN remain largely unknown. In this study, we investigated the molecular factors associated with the progression using RNA-seq. Methods: We included 13 patients with CHM and performed RNA-seq using freshly frozen samples. We identified differentially expressed genes between patients who developed GTN (GTN group) and those who achieved spontaneous remission after uterine evacuation (SR group), and performed pathway analysis. Then, functional analyses were performed on choriocarcinoma (JAR and JEG-3) and CHM (Hmol1-3B and Hmol1-2C) cells. Moreover, we evaluated the in vivo tumorigenicity of XBP1-overexpressed Hmol1-3B cells. Results: The gene expression profiles were separated into two groups, and an upstream regulator analysis was performed using 281 differentially expressed genes. We focused on transcription factors and identified that 33 transcription factors were activated in the GTN group. Then, excluding those with low expression levels in clinical samples and cell lines, XBP1 was selected for further analysis. Additionally, XBP1 downregulation significantly decreased the migration and invasive abilities of choriocarcinoma cells, whereas XBP1 overexpression significantly increased the migration and invasive abilities of CHM cells. Furthermore, animal experiments showed that tumor weight and blood human chorionic gonadotropin (hCG) levels were significantly higher in the XBP1-overexpressing Hmol1-3B-bearing mice than those in the control mice. Conclusion: RNA-seq identified XBP1 as a key factor in post-molar GTN, suggesting it contributes to the development of post-molar GTN.

DOI： 10.1016/j.ygyno.2024.08.023

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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: Prenatal maternal depression is known to affect the neurodevelopment of offspring. This study aimed to investigate the profile of umbilical cord serum in mothers with major depressive disorder (MDD). Methods: Liquid chromatography–tandem mass spectrometry (LC–MS) was conducted using umbilical cord serum from mothers with MDD (n = 5) and controls (control, n = 5). The levels of several differentially expressed proteins in umbilical cord serum were compared between the MDD (n = 10) and control groups (n = 10) by enzyme-linked immunosorbent assay. Results: The proteomic profiles in the umbilical cord serum were different between the MDD and control groups, including the pathways of regulation of plasma lipoprotein particle levels, and synapse organization. Only apolipoprotein A4 (APOA4) was significantly higher in the cord blood of MDD group. APOA4 levels in maternal serum were also significantly higher in the MDD group than those in the control group. The APOA4 levels in the umbilical cord serum were higher than that in the maternal serum. Conclusions: The levels of APOA4, a biomarker of depression, in the umbilical cord serum at birth were elevated in the neonates of MDD mothers. It is, therefore, likely that fetuses of MDD mothers were exposed to higher APOA4 levels in utero and this could have developmental and mental health implications for the offspring.

DOI： 10.1111/jog.16096

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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  

Aims: To evaluate the safety and effectiveness of high-dose oral medroxyprogesterone acetate (MPA) therapy as a fertility-sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. Methods: We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post-MPA therapy pregnancies were examined. Results: MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post-CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. Conclusions: High-dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.

DOI： 10.1111/jog.16038

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：日本語   出版者・発行元：日本エンドメトリオーシス学会  

卵巣子宮内膜症(OE)は月経血逆流で子宮外に運ばれた子宮内膜細胞が増殖する疾患と考えられる.しかし,月経血逆流はほぼ全ての生殖年齢女性に認められるのに対して,OEの発症率は10%程度であり,逆流血中の子宮内膜細胞が示す性質の違いがOE発症メカニズムに強く関連すると考えられる.我々は子宮内細菌叢に着目し,Fusobacteriumが子宮内微小環境に働きかけ,子宮内膜線維芽細胞の筋線維芽細胞への形質変化を誘導することでOEを発症する可能性を見出した.さらに抗生剤治療の有用性を内膜症モデルマウスにて検証した.また,菌体の放出する細胞外小胞について子宮内膜細胞への直接的影響を検討したので報告する.(著者抄録)

記述言語：日本語   出版者・発行元：(一社)日本妊娠高血圧学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：日本語   出版者・発行元：日本エンドメトリオーシス学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

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  

Background: To investigate the role of CD47 expression and its relationship with tumor-resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. Methods: A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). Results: The study found no direct correlation between CD47 expression levels and overall survival (p = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 (p = 0.047). The negative correlation between CD47 H-score and the density of CD68-positive macrophages at tumor margin was statistically significant (p = 0.049). A high density of CD68-positive macrophages at the tumor margin but a low density of CD163-positive macrophages at the tumor margin were associated with poorer prognosis (p = 0.036). Conclusions: The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer.

DOI： 10.1111/jog.15953

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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 Extracellular Biology  

Congenital diaphragmatic hernia (CDH) is a life-threatening condition with high morbidity and mortality rates. The survival rate of neonates with severe CDH is reportedly only 10%–15%. However, prenatal prediction of severe cases is difficult, and the discovery of new predictive markers is an urgent issue. In this study, we focused on microRNAs (miRNAs) in amniotic fluid-derived small EVs (AF-sEVs). We identified four miRNAs (hsa-miR-127-3p, hsa-miR-363-3p, hsa-miR-493-5p, and hsa-miR-615-3p) with AUC > 0.8 to classify good prognosis group and poor prognosis group in human study. The AUC for hsa-miR-127-3p and hsa-miR-615-3p, for predicting the poor prognosis, were 0.93 and 0.91, respectively. In addition, in the in vivo study, the miRNA profiles of the lung tissues of CDH rats were different from those of control rats. Additionally, two elevated miRNAs (rno-miR-215-5p and rno-miR-148a-3p) in the lung tissues of CDH rats were increased in the AF-sEVs of CDH rats. Our results suggest that severe CDH neonates can be predicted prenatally with high accuracy using miRNAs contained in AF-sEVs. Furthermore, miRNA profile changes in AF-sEVs reflected the lung status in CDH. Our findings may contribute to the development of advanced perinatal care for patients with CDH.

DOI： 10.1002/jex2.160

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Device  

MicroRNAs (miRNAs) are prospective biomarkers for diagnosis and prognosis due to their specific functions. Conventional methods lack the ability to discriminate two main miRNA sources—extracellular vesicle (EV) miRNAs and EV-free miRNAs (i.e., miRNAs not contained in EVs)—in one sample. Here, we demonstrate that a nanowire (NW) thermomicrofluidic device integrated with a Peltier temperature controller can capture EVs and EV-free miRNAs and then preferentially release the EV-free miRNAs by thermal energy and extract the EV miRNAs via a lysis buffer. This leads to discrimination between EV miRNAs and EV-free miRNAs from ovarian cancer serum. Statistical analysis identified a relationship between miRNA source and tumor-related functions of the miRNAs: oncogenesis miRNAs were inside the EVs, and tumor-suppressor miRNAs were outside them. We demonstrate that the NW thermomicrofluidics provides the advantages of a simple, rapid, and effective method for miRNA extraction, accompanied by information from inside or outside the EVs.

DOI： 10.1016/j.device.2024.100363

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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  

Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.

DOI： 10.1038/s41598-024-63600-z

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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  

DOI： 10.57291/jsgo.42.2_75

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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：Cancer Medicine  

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored. Methods: This retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined. Results: High-grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high-grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non-responders. Furthermore, neutrophil counts were significantly higher among responders than among non-responders. Conclusions: Inflammation-related blood data, such as neutrophil count, obtained at the initial pre-treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

DOI： 10.1002/cam4.7149

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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：Biochimica Et Biophysica Acta Molecular Basis of Disease  

Objective: Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. Methods: Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. Results: miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. Conclusion: miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.

DOI： 10.1016/j.bbadis.2024.167103

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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：Reproductive Biology  

Ovarian endometrioma (OE) is a common gynecological disease that is often treated with surgery and hormonal treatment. However, ovarian cystectomy can impair the ovarian reserve (OR). Previously, we showed that perioperative administration of dienogest (DNG) is an effective option for OR preservation. However, there were differences in the extent of OR preservation among patients following perioperative DNG treatment. In the current study, we performed a global examination of serum microRNAs (miRNAs) to identify accurate biomarkers that predict post-operative restoration of OR following perioperative DNG treatment. We also sought to identify specific miRNAs related to the anti-Müllerian hormone (AMH). miRNA sequencing was performed on serum samples obtained from twenty-seven patients who received perioperative DNG treatment. Candidate miRNAs were selected by comparing patients whose ORs were restored postoperatively (responder group, n = 7) with those whose ORs were not (non-responder group, n = 7). miR-370–3p and miR-1307–3p were significantly upregulated in the responder group, whereas miR-27b-3p was upregulated in the non-responder group. The pretreatment value of each miRNA could predict DNG responsiveness for OR following ovarian cystectomy (area under the curve [AUC] > 0.8). The quantitative polymerase chain reaction (qPCR) revealed only miR-1307–3p was found to be significantly upregulated in the responder group (P < 0.05). In addition, we identified miR-139–3p, miR-140–3p, and miR-629–5p as AMH-associated miRNAs. The transition of AMH showed a correlation with miR-139–3p (P < 0.05, r = −0.76). The miRNAs identified herein represent potential serum biomarkers of clinical value in predicting OR prior to DNG treatment.

DOI： 10.1016/j.repbio.2023.100821

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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：Communications Medicine  

Background: Assisted reproductive technology accounts for an increasing proportion of infertility treatments, and assessments to predict clinical pregnancy outcomes are desired. Extracellular vesicles exist in follicular fluid, and small non coding RNAs in extracellular vesicles underline the possibility of reflecting pregnancy potential. Methods: Follicular fluid samples are collected from 20 ovarian follicles of 15 infertile patients undergoing assisted reproductive technology. Extracellular vesicles are isolated by serial centrifugation and small RNA sequencing is performed to investigate the profiles of microRNAs and P-element-induced wimpy testis-interacting RNAs. Results: Small extracellular vesicles with a size range of approximately 100 nm are successfully isolated, and the small non coding RNA profiles of pregnant samples (n = 8) are different from those of non-pregnant samples (n = 12). Fourteen dysregulated small non coding RNAs are selected to identify the independent candidates [mean read count >100, area under the curve >0.8]. Among them, we find that a specific combination of small non coding RNAs (miR-16-2-3p, miR-378a-3p, and miR-483-5p) can predict the pregnant samples more precisely using a receiver operating characteristics curves analysis (area under the curve: 0.96). Furthermore, even in the same patients, the three microRNAs are differentially expressed between pregnant and non-pregnant samples. Conclusions: Our results demonstrate that small non coding RNAs derived from small extracellular vesicles in follicular fluid can be potential non-invasive biomarkers for predicting pregnancy, leading to their probable application in assisted reproductive technology. Further large-scale studies are required to validate the clinical usefulness of these small non coding RNAs.

DOI： 10.1038/s43856-024-00460-8

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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  

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

Background: Increased maternal interleukin (IL)-17A and activated microglia are pivotal factors contributing to the pathological phenotypes of maternal immune activation (MIA), developing neurodevelopmental disorders in offspring. This study aimed to determine whether IL-17A affects the microglial microRNA (miRNA) profiles. Methods: The miRNA expression profiles of primary cultured microglia stimulated with recombinant IL-17A were examined comprehensively using miRNA sequencing and validated through qRT-PCR. The expressions of miRNAs target genes identified using bioinformatics, were investigated in microglia transfected with mimic miRNA. The target gene’s expression was also examined in the fetal brains of the MIA mouse model induced by maternal lipopolysaccharide (LPS) administration. Results: Primary cultured microglia expressed the IL-17A receptor and increased proinflammatory cytokines and nitric oxide synthase 2 upon treatment with IL-17A. Among the three miRNAs with |log<inf>2</inf>FC | >1, only mmu-miR-206-3p expression was significantly up-regulated by IL-17A. Transfection with the mmu-miR-206-3p mimic resulted in a significant decrease in the expression of Hdac4 and Igf1, target genes of mmu-miR-206-3p. Hdac4 expression also significantly decreased in the LPS-induced MIA model. Conclusions: IL-17A affected microglial miRNA profiles with upregulated mmu-miR-206-3p. These findings suggest that targeting the IL-17A/mmu-miR-206-3p pathway may be a new strategy for predicting MIA-related neurodevelopmental deficits and providing preventive interventions. Impact: Despite the growing evidence of interleukin (IL)-17A and microglia in the pathology of maternal immune activation (MIA), the downstream of IL-17A in microglia is not fully known.IL-17A altered microRNA profiles and upregulated the mmu-miR-206-3p expression in microglia. The mmu-miR-206-3p reduced autism spectrum disorder (ASD) related gene expressions, Hdac4 and Igf1.The Hdac4 expression was also reduced in the brain of MIA offspring.The hsa-miR-206 sequence is consistent with that of mmu-miR-206-3p.This study may provide clues to pathological mechanisms leading to predictions and interventions for ASD children born to mothers with IL-17A-related disorders.

DOI： 10.1038/s41390-023-02825-6

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

Systemic sclerosis, an autoimmune disease characterized by fibrosis and vasculopathy of the skin and other multiple organs has been associated with an increased risk of malignancy. We present the case of a 74-year-old woman who had diffused cutaneous systemic sclerosis and uterine cervical cancer. The patient was initially diagnosed with stage IIB squamous cell carcinoma and concurrent chemoradiotherapy was planned. However, cisplatin could not be administered due to acute renal failure, so the patient was treated solely with radiotherapy. However, complications of systemic sclerosis progressed rapidly, and the patient died 63 days later from pulmonary edema. An autopsy later revealed that uterine cervix had primary signet ring cell carcinoma. We suspected that this patient had a combination of signet ring cell carcinoma and squamous cell carcinoma, with squamous cell carcinoma disappearing after radiotherapy. This case highlighted the importance of systemic management for cancers associated with systemic sclerosis.

DOI： 10.1111/jog.15715

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記述言語：英語   出版者・発行元：Frontiers in Pediatrics  

Introduction: To investigate the mechanism underlying the increased risk of subsequent neurodevelopmental disorders in children born to mothers with preeclampsia, we evaluated the neurodevelopment of offspring of a preeclampsia rat model induced by the administration of N-nitro-L-arginine methyl ester (L-NAME) and identified unique protein signatures in the offspring cerebrospinal fluid. Methods: Pregnant rats received an intraperitoneal injection of L-NAME (250 mg/kg/day) during gestational days 15–20 to establish a preeclampsia model. Behavioral experiments (negative geotaxis, open-field, rotarod treadmill, and active avoidance tests), immunohistochemistry [anti-neuronal nuclei (NeuN) staining in the hippocampal dentate gyrus and cerebral cortex on postnatal day 70], and proteome analysis of the cerebrospinal fluid on postnatal day 5 were performed on male offspring. Results: Offspring of the preeclampsia dam exhibited increased growth restriction at birth (52.5%), but showed postnatal catch-up growth on postnatal day 14. Several behavioral abnormalities including motor development and vestibular function (negative geotaxis test: p < 0.01) in the neonatal period; motor coordination and learning skills (rotarod treadmill test: p = 0.01); and memory skills (active avoidance test: p < 0.01) in the juvenile period were observed. NeuN-positive cells in preeclampsia rats were significantly reduced in both the hippocampal dentate gyrus and cerebral cortex (p < 0.01, p < 0.01, respectively). Among the 1270 proteins in the cerebrospinal fluid identified using liquid chromatography-tandem mass spectrometry, 32 were differentially expressed. Principal component analysis showed that most cerebrospinal fluid samples achieved clear separation between preeclampsia and control rats. Pathway analysis revealed that differentially expressed proteins were associated with endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins, which are involved in various nervous system disorders including autism spectrum disorders, schizophrenia, and Alzheimer's disease. Conclusion: The offspring of the L-NAME-induced preeclampsia model rats exhibited key features of neurodevelopmental abnormalities on behavioral and pathological examinations similar to humans. We found altered cerebrospinal fluid protein profiling in this preeclampsia rat, and the unique protein signatures related to endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins may be associated with subsequent adverse neurodevelopment in the offspring.

DOI： 10.3389/fped.2023.1168173

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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：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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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncology Reports  

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In addition, the molecular background of ULMS has not been fully elucidated due to its low incidence. Therefore, no effective treatment strategies have been established based on its molecular back- ground. The present study aimed to investigate the roles of microRNAs (miRNAs/miRs) in the development of ULMS. Comprehensive miRNA sequencing was performed using six ULMS and three myoma samples, and revealed 53 and 11 significantly upregulated and downregulated miRNAs, respectively. One of the most abundant miRNAs in myoma samples was miR-10b-5p. The mean normalized read count of miR-10b-5p was 93,650 reads in myoma, but only 27,903 reads in ULMS. Subsequently, to investigate the roles of miR-10b-5p, gain-of-function analysis was performed using SK-UT-1 and SK-LMS-1 cell lines. The overexpression of miR-10b-5p suppressed cell proliferation and reduced the number of colonies. Moreover, miR-10b-5p increased the number of cells in the G<inf>1</inf> phase. In conclusion, tumor-suppressive miR-10b-5p was significantly downregulated in ULMS compared with in myoma; thus, miR-10b-5p may serve a specific role in sarcoma progression.

DOI： 10.3892/or.2023.8523

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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: Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian carcinoma with poor prognosis. However, no effective biomarkers have been established for predicting unfavorable events, including recurrence and poor prognoses. Serum microRNAs (miRNAs) have been increasingly reported to be useful in predicting a patient’s condition and have been recognized as a potentially less-invasive source for liquid biopsy in cancer. Therefore, this study aimed to evaluate serum miRNA profiles from patients with OCCC and to establish biomarker for predicting the prognoses. Methods: The GSE106817, which included preoperative serum miRNA profiles of patients with ovarian tumors, was used, and clinical information was investigated. In all, 66 patients with OCCC were included, excluding those with other histological subtypes or insufficient prognostic information. Moreover, miRNA profiles of OCCC tissues were also examined. Results: The median follow-up period was 64.3 (8.0–153.3) months. Based on multivariable Cox regression analyses and the expression of miRNAs in OCCC tissues, miR-150-3p, miR-3195, and miR-7704 were selected as miRNA candidates associated with both progression-free survival (PFS) and overall survival (OS). Then, the prognostic index was calculated based on expression values of 3 serum miRNAs. Kaplan-Meier survival analysis indicated that the prognostic index was significantly predictive of PFS and OS (p=0.004 and p=0.012, respectively). Conclusion: Preoperative serum miRNA profiles of miR-150-3p, miR-3195, and miR-7704 can be used to potentially predict the prognosis of patients with OCCC.

DOI： 10.3802/jgo.2023.34.e34

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その他リンク： https://ejgo.org/DOIx.php?id=10.3802/jgo.2023.34.e34

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

Background: Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. Methods: Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. Results: Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model. Conclusion: Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.

DOI： 10.1002/cam4.5243

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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：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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DOI： 10.18999/nagjms.80.3.417

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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  

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

DOI： 10.1038/s41598-021-02635-y

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

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

DOI： 10.1111/cas.15154

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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：Anticancer Research  

Background/Aim: Heat shock protein 105 (HSP105) is overexpressed in various cancers, but not in normal tissues. We investigated the expression levels of HSP105 in cervical cancer and the efficacy of immunotherapy targeting HSP105. Materials and Methods: Previously, we established human leukocyte antigen-A∗02:01 (HLA-A2) restricted HSP105 peptide-specific cytotoxic T lymphocyte (CTL) clones from a colorectal cancer patient vaccinated with an HSP105 peptide. Herein, we evaluated the expression of HSP105 in cervical cancer and cervical intraepithelial neoplasia. Moreover, we tested the effectiveness of an HLAA2-restricted HSP105 peptide-specific CTL clone against cervical cancer cell lines. Results: HSP105 was expressed in 95% (19/20) of examined cervical cancer tissues. Moreover, the HSP105 peptide-specific CTL clone recognized HSP105- and HLA-A∗02:01-positive cervical cancer cell lines and also showed that cytotoxicity against the cervical cancer cell lines depends on HSP105 peptide and HLA class I restricted manners. Conclusion: HSP105 could be an effective target for immunotherapy in patients with cervical cancer.

DOI： 10.21873/anticanres.15289

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer 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.

DOI： 10.1186/s12935-021-02014-7

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Regenerative Therapy  

Cancer stem cells (CSCs) are a small cell subpopulation in many cancer types and are involved in various processes of tumor progression, such as initiation, metastasis and recurrence. The distinguished features of CSCs include a variety of biological properties, including self-renewal, multidifferentiation, stemness marker expression, and resistance to chemotherapy and radiotherapy. Despite their great potential of clinical importance, the CSC signaling pathways are not well understood at the molecular level. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs that play an important role in the regulation of several cellular, physiological, and developmental processes. Aberrant miRNA expression is associated with many human diseases, including cancer. miRNAs have been implicated in the regulation of CSC properties; therefore, a better understanding of miRNA-induced modulation of CSC gene expression could aid in the identification of promising biomarkers and therapeutic targets. In the present review, we summarize the major findings of the impacts of miRNAs on CSC signaling networks; we then discuss the recent advances that have improved our understanding of CSC regulation by miRNA-mediated signaling networks and that may lead to the development of miRNA therapeutics specifically targeting CSCs.

DOI： 10.1016/j.reth.2021.01.004

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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：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.

DOI： 10.3390/curroncol28030155

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Experimental and Clinical Cancer Research  

MicroRNAs (miRNAs) regulate the expression of their target genes post-transcriptionally; thus, they are deeply involved in fundamental biological processes. miRNA clusters contain two or more miRNA-encoding genes, and these miRNAs are usually coexpressed due to common expression mechanisms. Therefore, miRNA clusters are effective modulators of biological pathways by the members coordinately regulating their multiple target genes, and an miRNA cluster located on the X chromosome q27.3 region has received much attention in cancer research recently. In this review, we discuss the novel findings of the chrXq27.3 miRNA cluster in various types of cancer. The chrXq27.3 miRNA cluster contains 30 mature miRNAs synthesized from 22 miRNA-encoding genes in an ~ 1.3-Mb region. The expressions of these miRNAs are usually negligible in many normal tissues, with the male reproductive system being an exception. In cancer tissues, each miRNA is dysregulated, compared with in adjacent normal tissues. The miRNA-encoding genes are not uniformly distributed in the region, and they are further divided into two groups (the miR-506-514 and miR-888-892 groups) according to their location on the genome. Most of the miRNAs in the former group are tumor-suppressive miRNAs that are further downregulated in various cancers compared with normal tissues. miR-506-3p in particular is the most well-known miRNA in this cluster, and it has various tumor-suppressive functions associated with the epithelial–mesenchymal transition, proliferation, and drug resistance. Moreover, other miRNAs, such as miR-508-3p and miR-509-3p, have similar tumor-suppressive effects. Hence, the expression of these miRNAs is clinically favorable as prognostic factors in various cancers. However, the functions of the latter group are less understood. In the latter group, miR-888-5p displays oncogenic functions, whereas miR-892b is tumor suppressive. Therefore, the functions of the miR-888–892 group are considered to be cell type- or tissue-specific. In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression, and the miRNAs themselves, their regulatory mechanisms, and their target genes might be promising therapeutic targets.

DOI： 10.1186/s13046-021-01910-0

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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：Cancers  

Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.

DOI： 10.3390/cancers13030550

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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-Prkdc^scidIl2rg^tm1Wjl/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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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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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Ovarian cancer is the most lethal gynecological cancer due to lack of early screening methods and acquired drug resistance. MicroRNAs (miRNAs) are effective post-transcriptional regulators that are transferred by extracellular vesicles, such as exosomes. Numerous studies have revealed that miRNAs are differentially expressed in epithelial ovarian cancer and act either as oncogenes or tumor suppressor genes. Cancer cells secrete exosomes containing miRNAs, which exert various effects on the components of the tumor microenvironment, including cancer-associated fibroblasts, macrophages, and adipocytes. Conversely, cancer cells also receive exosomes from these cells. As a result of cell-to-cell communication, epithelial ovarian cancer acquires a more aggressive phenotype and resistance to multiple drugs. In addition, some circulating miRNAs are protected from RNase degradation in the peripheral blood and can be potential non-invasive biomarkers. In particular, the combination of several circulating miRNAs enhances the accuracy of cancer screening. Likewise, comprehensive analyses revealed specific miRNA signatures in non-epithelial ovarian tumors and several miRNAs contributing to alterations of carcinogenic pathways. Overall, miRNAs play a crucial role in ovarian cancer progression. In this review, we discuss the emerging roles of intra- and extracellular miRNAs in ovarian cancers. In the near future, miRNAs will be practical biomarkers and computational deep learning will help in the clinical application of miRNAs. Moreover, miRNAs are potential therapeutic targets and agents, and there are ongoing clinical trials of miRNA replacement therapy. Therefore, accelerating research on miRNA might improve the prognosis of patients with ovarian cancer.

DOI： 10.1111/cas.14599

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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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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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.

DOI： 10.1007/s10147-019-01551-6

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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 biological function of non-thermal atmospheric pressure plasma has been widely accepted in several types of cancer. We previously developed plasma-activated medium (PAM) for clinical use, and demonstrated that PAM exhibits a metastasis-inhibitory effect on ovarian cancer through reduced MMP-9 secretion. However, the anti-tumor effects of PAM on endometrial cancer remain unknown. In this study, we investigated the inhibitory effect of PAM on endometrial cancer cell viability in vitro. Our results demonstrated that AMEC and HEC50 cell viabilities were reduced by PAM at a certain PAM ratio, and PAM treatment effectively increased autophagic cell death in a concentration dependent manner. In addition, we evaluated the molecular mechanism of PAM activity and found that the mTOR pathway was inactivated by PAM. Moreover, our results demonstrated that the autophagy inhibitor MHY1485 partially inhibited the autophagic cell death induced by PAM treatment. These findings indicate that PAM decreases the viability of endometrial cancer cells along with alteration of the mTOR pathway, which is critical for cancer cell viability. Collectively, our data suggest that PAM inhibits cell viability while inducing autophagic cell death in endometrial cancer cells, representing a potential novel treatment for endometrial cancer.

DOI： 10.1038/s41598-020-58667-3

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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.

DOI： 10.1007/s10147-019-01550-7

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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.

DOI： 10.21873/invivo.11751

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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.

DOI： 10.1111/jog.14112

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

Objectives: There is increasing evidence that systemic inflammatory response (SIR) markers are prognostic factors for various types of cancers. This is the first study to evaluate the usefulness of SIR markers for the prognosis of early-stage ovarian clear-cell carcinoma (OCCC). Methods: We retrospectively investigated 83 patients diagnosed with stage I–II OCCC who underwent surgery between 2005 and 2017. Initially, receiver operating characteristic curve analysis for overall survival (OS) was used to determine optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Patients were stratified into 2 groups by the cut-off values (NLR=3.26, PLR=160). Univariate and multivariate analyses were performed to elucidate the significance of SIR markers as prognostic factors. Results: In the median follow-up period of 64.1 months, 16 patients experienced recurrence, and nine patients died. The Kaplan-Meier curve showed that OS of the NLR-low group was significantly longer than the NLR-high group (p=0.021). There was no significant difference in progression-free survival between the 2 groups (p=0.668), but the post-recurrence survival of the NLR-low group was significantly longer than the NLR-high group (p=0.019). Furthermore, multivariate analysis showed that increase in NLR is a significant independent prognostic factor for poor prognosis (hazard ratio=7.437, p=0.017). There was no significant difference between PLR-low and PLR-high group. Conclusion: Results suggest that NLR can be a significant independent prognostic factor for early-stage OCCC.

DOI： 10.3802/jgo.2019.30.e85

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DOI： 10.1136/ijgc-2019-ESGO.1079

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

Background: In cervical cancer, para-aortic lymph nodes are common sites of metastasis. The purpose of the study was to evaluate the clinical benefits of prophylactic irradiation as postoperative therapy. Methods: A retrospective cohort study was conducted during 2001–2015 at a single institution. Patients with a high risk of para-aortic lymph nodes recurrence were eligible for this study, and we identified patients who had pelvic lymph node metastasis and underwent radical surgery and concurrent chemo-radiotherapy. As a result, 33 and 46 patients were included in the treatment (prophylactic irradiation) and non-treatment groups, respectively. Baseline differences between the two groups were adjusted with the inverse probability of treatment weighting using propensity scores composed of the independent variables including age, stage, tumor size, pathological findings, lymph node status, and pathological subtypes. Results: In the 68-month median follow-up period (range 6–178 months), 25 patients experienced recurrence, and 17 patients were dead. After adjustment with the inverse probability of treatment weighting, the recurrence rates tended to decrease in the treatment group, but there was no significant difference between the two groups [treatment vs. non-treatment, 29.4% and 44.3%, respectively; hazard ratio, 0.593 (95% CI 0.320–1.099); P = 0.097]. However, adjusted para-aortic lymph nodes recurrence rates were not significantly different [treatment vs. non-treatment, 7.8% and 11.4%, respectively; odds ratio, 0.660 (95% CI 0.187–2.322); P = 0.558]. Moreover, Kaplan–Meier curves showing post-recurrence survival revealed no significant difference between the two groups (P = 0.141). Conclusions: Prophylactic para-aortic lymph nodes irradiation did not reduce the risk of recurrence.

DOI： 10.1007/s10147-018-1376-2

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncology Letters  

Vascular endothelial growth factor (VEGF) inhibitors have been utilized for the treatment against advanced or recurrent cervical carcinoma as a novel therapeutic modality. However, the expression level of VEGF in post-radiotherapy relapsed/persistent cervical cancer remains to be elucidated. The aim of the present study was to investigate the expression of VEGF and associated molecules using tumor samples from patients with post-radiotherapy relapsed/persistent cervical cancer. From a database of 826 patients who were treated at our institution between 2003 and 2015, eight patients with post-radiotherapy relapsed/persistent cervical cancer were identified, and 20 patients who underwent initial surgery alone were used as a control. Using samples from these patients, the expression levels of VEGF-A, VEGF receptor-1 (VEGFR-1) and hypoxia inducible factor-1α (HIF-1α) were immunohisto-chemically categorized as negative or weakly, moderately, or strongly positive according to the size of the staining area, and intensity. In carcinoma cells, the expression levels of VEGF-A, VEGFR-1 and HIF-1α were significantly higher in post-radiotherapy relapsed/persistent cervical cancer compared with control patients (P=0.0003, 0.0003, and 0.0001, respectively). In stroma cells, similar tendencies with statistical significance were observed (P=0.0014 and P<0.0001, respectively). In addition, the expression levels of VEGF-A and VEGFR-1 in carcinoma cells were significantly correlated with each other (P<0.0001). A significantly higher expression of VEGF was identified in post-radiotherapy relapsed/persistent cervical cancer compared with typical specimens from cervical cancer. The findings provide a novel insight into the clinical treatment for recurrent/persistent cervical cancer using a VEGF antagonist.

DOI： 10.3892/ol.2018.8610

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/mco.2017.1530

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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  

記述言語：日本語   出版者・発行元：東海産婦人科内視鏡手術研究会  

記述言語：日本語   出版者・発行元：愛知産科婦人科学会  

記述言語：日本語   出版者・発行元：愛知産科婦人科学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：日本語   出版者・発行元：(一社)日本妊娠高血圧学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：愛知産科婦人科学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：東海産科婦人科学会  

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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  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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)日本産科婦人科学会  

記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

DOI： 10.1101/2022.01.06.22268775

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌学会  

記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：日本語   出版者・発行元：愛知産科婦人科学会  

記述言語：日本語   出版者・発行元：(一社)日本がん・生殖医療学会  

記述言語：日本語   出版者・発行元：(NPO)日本がん・生殖医療学会  

記述言語：日本語   出版者・発行元：東海産科婦人科学会  

開催年月日： 2024年11月

開催年月日： 2024年10月

記述言語：英語  

開催年月日： 2024年10月

記述言語：英語  

開催年月日： 2024年9月

記述言語：英語  

開催年月日： 2024年9月

記述言語：英語  

開催年月日： 2024年9月

記述言語：英語  

開催年月日： 2024年9月

記述言語：英語  

開催年月日： 2024年9月

記述言語：英語  

開催年月日： 2024年9月

記述言語：日本語  

開催年月日： 2024年9月

記述言語：日本語  

開催年月日： 2024年9月

記述言語：日本語  

開催年月日： 2024年9月

記述言語：英語  

開催年月日： 2024年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2024年5月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2024年4月

記述言語：日本語  

開催年月日： 2024年2月

記述言語：日本語   会議種別：ポスター発表  

開催年月日： 2024年2月

記述言語：日本語  

開催年月日： 2024年2月

記述言語：日本語  

開催年月日： 2024年2月

記述言語：日本語  

開催年月日： 2024年2月

記述言語：日本語  

開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2023年10月

記述言語：日本語  

開催年月日： 2023年10月

記述言語：日本語  

開催年月日： 2023年10月

記述言語：日本語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年9月

記述言語：日本語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年9月

記述言語：英語  

開催年月日： 2023年7月

記述言語：日本語  

開催年月日： 2023年7月

記述言語：日本語  

開催年月日： 2023年7月

記述言語：日本語  

開催年月日： 2023年7月

記述言語：日本語  

開催年月日： 2023年7月

記述言語：日本語  

開催年月日： 2023年7月

記述言語：日本語  

開催年月日： 2023年5月

記述言語：日本語   会議種別：口頭発表（基調）  

開催年月日： 2023年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2023年3月

記述言語：日本語  

開催年月日： 2023年2月

記述言語：日本語  

開催年月日： 2022年10月

記述言語：英語  

開催年月日： 2022年9月

記述言語：英語  

開催年月日： 2022年9月

記述言語：英語  

開催年月日： 2022年9月

記述言語：英語  

開催年月日： 2022年9月

記述言語：英語  

開催年月日： 2022年7月

記述言語：日本語  

開催年月日： 2022年7月

記述言語：日本語  

開催年月日： 2022年7月

記述言語：日本語  

開催年月日： 2022年7月

記述言語：日本語  

開催年月日： 2022年2月

記述言語：日本語  

開催年月日： 2022年2月

記述言語：日本語  

開催年月日： 2021年9月

記述言語：英語  

開催年月日： 2021年9月

記述言語：英語  

開催年月日： 2021年9月

記述言語：英語  

開催年月日： 2021年9月

記述言語：英語  

開催年月日： 2021年2月

開催年月日： 2020年10月

記述言語：英語  

開催年月日： 2020年3月

記述言語：日本語  

開催年月日： 2019年11月

DOI： 10.1136/ijgc-2019-ESGO.1079

開催年月日： 2019年10月

記述言語：英語  

開催年月日： 2019年10月

記述言語：英語  

開催年月日： 2019年9月

記述言語：英語  

開催年月日： 2019年6月

記述言語：日本語  

開催年月日： 2019年6月

記述言語：日本語  

開催年月日： 2019年6月

記述言語：日本語  

開催年月日： 2019年1月

記述言語：日本語  

開催年月日： 2019年

記述言語：日本語  

その他リンク： https://search.jamas.or.jp/link/ui/2020114896

開催年月日： 2018年2月

記述言語：日本語  

開催年月日： 2017年3月

記述言語：日本語