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A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9-10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.

DOI： 10.1038/s41467-018-06434-4

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Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

DOI： 10.1038/ncomms14470

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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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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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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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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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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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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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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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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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Poly(ADP-ribose) polymerase inhibitors (PARPis) have improved the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC). However, PARPis are not effective for all HGSOC patients. Spatial transcriptomics is a powerful tool for characterizing the tumor microenvironment. We used Visium to analyze eight tumor samples from HGSOC patients with clinical information on PARPi sensitivity. Two complementary analyses were performed: an integrated analysis across all samples, without considering spatial information, and an analysis with spatial information within each sample. Both approaches indicated that midkine (MDK) signaling is involved in PARPi resistance. Furthermore, we identified receptors that enhance MDK signaling in cancer cells. To assess the generalizability of this finding, we deconvolved bulk RNA-sequencing data using single-cell RNA-sequencing data as a reference to examine the relationship between receptor expression levels and overall survival (OS). This analysis revealed that high SDC4 expression in cancer cells is associated with poor OS in HGSOC patients.

DOI： 10.1038/s41698-025-01122-1

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Other Link： https://www.nature.com/articles/s41698-025-01122-1

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.heliyon.2025.e44099

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

ABSTRACT

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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Language：English   Publisher：Pediatric Pulmonology  

Objectives: Respiratory management is crucial for patients with congenital diaphragmatic hernia (CDH). This prospective study aimed to assess the optimal initial ventilatory mode for CDH by comparing conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation (HFO). Methods: Fifteen participating institutes used CMV or HFO as the initial ventilation mode for CDH, we thus divided them into two groups (CMV and HFO). Clinical data were prospectively collected from patients with isolated left CDH born at a gestational age ≥ 34 weeks between 2017 and 2021. The primary outcome was mortality to discharge, with non-inferiority analysis. We also performed analyses stratified by disease severity. Results: Of the 247 patients, 124 received CMV, and 123 received HFO. The mortality rates for CMV and HFO were 11.3% and 15.4%, respectively, which met the definition of non-inferiority. We observed no significant differences in BPD (CMV, 41% vs. HFO, 42%) or the combined outcome of mortality or BPD (48% vs. 51%). Among patients with mild and moderate disease, CMV was associated with less frequent switching of the ventilation mode, shorter mechanical ventilation time, lower use of inhaled nitric oxide (iNO) therapy, and a shorter duration of iNO. In severe cases, HFO was associated with less frequent switching of the ventilation mode and a reduced need for ECMO. Conclusions: The initial ventilation mode in CDH patients does not influence mortality or BPD outcomes. However, this study suggests that CMV may be more beneficial for mild-to-moderate cases, while HFO may be more advantageous for severe cases.

DOI： 10.1002/ppul.71316

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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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Publisher：American Chemical Society (ACS)  

Targeted molecular capture from complex biological fluids remains a critical challenge in extracellular vesicle (EV) analysis. Here we develop a nanowire-based microfluidic platform functionalized via a single-step click conjugation using N-hydroxysuccinimide-functionalized polyketones (pKNHSs) with discrete chain lengths. Tetrameric pKNHS enabled efficient and stable antibody immobilization on ZnO nanowires while minimizing non-specific adsorption. This chemically defined interface facilitated the selective capture of EVs from both cultured cells and serum, preserving membrane proteins and encapsulated miRNAs. Using antibody-modified nanowires, we identified distinct miRNA signatures associated with specific membrane markers in serum samples from patients with high-grade serous ovarian carcinoma. These results highlight the ability of discrete, chain-engineered polyketones to enable robust and tunable bioconjugation chemistry. The discrete-length polymer design also offers a generalizable strategy for precision surface engineering. Our approach offers a modular strategy for EV enrichment and molecular profiling with potential applications in liquid biopsy and precision diagnostics.

DOI： 10.26434/chemrxiv-2025-n859x

DOI： 10.1016/j.ygyno.2025.04.280

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DOI： 10.1016/j.ygyno.2025.04.335

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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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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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Publisher：Pediatric Blood and Cancer  

Background: Complete resection of the primary tumor is critical for the survival of children with hepatoblastomas (HBs). This prospective clinical study aimed to clarify the outcome of a chemotherapy regimen comprising cisplatin and doxorubicin (PLADO) followed by definitive surgery conducted at the appropriate time in patients with intermediate-risk HB. Methods: Intermediate-risk HB was defined as patients without evidence of metastatic disease who met any of the following criteria: age ≥3 years; PRETEXT IV disease; presence of more than one PRETEXT annotation factor. The study protocol consisted of four preoperative and two postoperative courses of PLADO. The appropriate surgeries were conducted at optimized timings via real-time central surgical reviews. Results: The 3-year progression-free and overall survivals of the 33 intermediate-risk patients included were 78.7% and 87.9%, respectively. Preoperative PLADO resulted in a partial response in 83.9% of the patients. Microscopic complete resection was ultimately obtained in 31 (94%) patients. No patient required more than six preoperative courses before surgery or liver transplantation (LTx). Two patients never had surgery due to tumor progression. Conclusions: The outcome for patients with intermediate-risk HB was satisfactory. PLADO, combined with surgery (including LTx) conducted at the optimal time, appeared to cure most patients in this study.

DOI： 10.1002/pbc.31770

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Medical Association  

Extracellular vesicles (EVs) play various roles in cancer progression, mediating intercellular signaling. EVs carry bioactive substances such as ribonucleic acid, deoxyribonucleic acid, and proteins, each providing important functions in whole biological fields, not only in cancer. Particularly in clinical oncology, EVs have attracted much attention owing to their promising potential as new diagnostic and therapeutic targets. Ovarian cancer is one of the major causes of gynecologic cancer deaths and is often asymptomatic in the early stages; therefore, biomarkers that enable early diagnosis are critical to improving patient survival. Ovarian cancer cells easily spread through the abdominal cavity rather than through the bloodstream, forming direct metastatic foci in organs such as peritoneal membranes or omentum. The disease is treated multimodally with surgery and chemotherapy, even in advanced stages, and a certain degree of response to treatment is observed. However, most relapsed cancer gradually acquired resistance to chemotherapies. We have investigated various EV molecules in ovarian cancer and shown their clinical utility. In addition, the heterogeneity of EVs has emerged as a recent topic, and we have developed and used novel techniques to understand them. Applying these findings to clinical practice, EV-based approaches have the potential to revolutionize ovarian cancer management, enabling early detection, personalized monitoring, and targeted therapy. Continued innovation and interdisciplinary collaboration will be key to realizing the full potential of EV translational research to improve outcomes for patients with ovarian cancer.

DOI： 10.31662/jmaj.2025-0086

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Language：English   Publisher：Journal of Pediatric Surgery  

Purpose: Owing to advances in prenatal diagnoses, the overall outcome of congenital diaphragmatic hernia (CDH) can be estimated; however, practical clinical information among CDH survivors for counselling families were lacking. The present study analyzed the overall outcome of prenatally diagnosed left isolated CDH, using a Japanese CDH Study Group (JCDHSG) database. Methods: Prenatally diagnosed patients with left isolated CDH (n = 511), registered in our JCDHSG database from 2006 to 2021 were retrospectively reviewed. Prenatal diagnoses were divided into three categories depending on the observed-to-expected lung-to-head circumference ratio and liver herniation (extremely severe + severe [ES + S], n = 94; moderate [Mo], n = 156, and Mild [Mi], n = 261). The primary outcomes were the survival and intact discharge rates. Intact discharge was defined as CDH survivors without home-based medical care at discharge. The secondary outcomes included the operation timing, ventilation duration, and hospitalization duration. Results: The overall survival rate at discharge was 86.9 % (444/511). Among survivors at discharge, the intact discharge rate was 80.6 % (358/444). The survival and intact discharge rates varied significantly by disease severity. Among CDH survivors, the median operation timing was consistent across severity grades, however, the median duration of ventilation (26, 20, and 10 days for ES + S, Mo, and Mi, respectively, p < 0.001) and length of hospitalization duration (83, 65, and 39 days for ES + S, Mo, and Mi, respectively, p < 0.001) differed significantly. Conclusions: Prenatal diagnoses, categorized by disease severity correlated well with the stratified clinical outcomes. These data support accurate prenatal family counselling with prognostic prediction in prenatally diagnosed left isolated CDH patients. Type of Study: Original Research, Clinical Research. Levels of Evidence: LEVEL Ⅲ Retrospective Comparative Study.

DOI： 10.1016/j.jpedsurg.2025.162442

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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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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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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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Language：English   Publisher：Journal of Pediatric Surgery  

Background: This study aimed to examine the incidence of undescended testis (UDT) in congenital diaphragmatic hernia (CDH) and clinical risk factors for developing UDT. Methods: Male patients with CDH born between 2006 and 2021 were retrospectively assessed for UDT using the database of the Japanese CDH study group. The UDT risk factors were examined by comparing patients with and without UDT. Results: Of the 605 boys with CDH, 408 were followed for at least one year and were included in this study. A total of 50 (12.3 %) of the 408 patients experienced UDT and orchidopexy was performed in 41 (10.2 %) patients. Twenty-four cases developed UDT on the same side of CDH, whereas only 6 cases developed UDT on the contralateral side of CDH; the remaining 20 cases were bilateral UDT. Comparison between the patients with and without UDT revealed significantly lower birth weight and lower Apgar Score in the patients with UDT. Furthermore, patients with UDT demonstrated a significantly higher rate of non-isolated, “liver-up”, defect with C/D type, and patch closure. Multivariate analysis showed that the C/D type defect was deemed an independent risk factor for developing UDT. Conclusions: The incidence of UDT and the need for orchidopexy are elevated in boys with CDH. In patients with CDH, UDT may tend to occur on the same side as that affected by CDH. The diaphragmatic large defect was considered to be an independent risk factor for UDT in CDH although different factors are thought to be involved in testicular descent.

DOI： 10.1016/j.jpedsurg.2025.162297

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Language：English   Publisher：Pediatrics International  

Background: Vitamin K (VK) prophylaxis refers to the administration of VK to newborns to prevent neonatal VK deficiency bleeding (VKDB), which is characterized by intracranial hemorrhage (ICH). This study investigated the relationship between VK prophylaxis methods and VKDB in biliary atresia (BA). Methods: The survey targeted 497 cases in the Japanese Biliary Atresia Registry between 2015 and 2019, of which 395 (79.5%) returned the questionnaire. Of the 395 patients, 289 were selected after excluding cases in which the gestational age was <36 weeks or the VK prophylaxis methods/feeding contents were unknown. The patients were categorized into two groups according to VK prophylaxis methods. We conducted a comparative study using propensity score matching. The prognosis of patients with or without ICH was also investigated. Results: In the analysis, no VKDB occurred in patients using the 3-month method. In the propensity score matching analysis, age at first visit and age at surgery were later in the three-times method (p = 0.018 and p = 0.022, respectively); VKDB was higher in the three-times method than in the 3-month method (p = 0.029). ICH, jaundice disappearance, cholangitis, and native liver survival rates (NLSRs) were not significantly different between groups. When examining the prognosis based on ICH occurrence, the two groups showed no significant differences in jaundice disappearance, cholangitis, and NLSRs. The ICH group had a greater number of cases of delayed mental and/or motor development. Conclusions: In BA, the 3-month method is effective in preventing VKDB, and early diagnosis is crucial.

DOI： 10.1111/ped.70075

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DOI： 10.1016/j.jdermsci.2025.02.004

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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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMED iD3 Catalyst Unit  

<p>My research group recently developed a novel method for isolating extracellular vesicles (EVs) using cellulose nanofiber (CNF) sheets, termed as EV sheets, which are designed with tunable pore sizes. EVs, including exosomes, play a crucial role in cellular communication and are key targets of disease mechanisms. EV sheets capture intact EVs from minimal volumes of biofluid, such as the surfaces of organs, and store them under dry conditions until analysis. These EV sheets addressed the current limitations of EV research. CNF Sheets provide a breakthrough by effectively isolating and preserving EVs from as little as 10 µL of biofluid. In ovarian cancer models and patient samples, EV sheets revealed spatial heterogeneity in the EV profiles and identified unique miRNA signatures based on their location. This technique detects cancer-associated miRNAs at an early stage before visible symptoms such as ascites develop. Importantly, the miRNA profiles obtained from tumor surfaces differed from those obtained from the surrounding fluids, providing a better understanding of tumor-derived EVs. The EV sheet isolation method has a high EV recovery efficiency and compatibility with small RNA sequencing, demonstrating its potential to advance cancer diagnosis, staging, and treatment planning. EV sheets also offer advantages in EV preservation and transport, making them practical for clinical and research applications. In addition, this method is promising for elucidating EV biology, particularly its role in cancer progression and intercellular communication. Future studies will aim to refine this method for wider clinical use and maximize its potential.</p>

DOI： 10.33611/trs.2025-001

CiNii Research

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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.

DOI： 10.1038/s42003-025-07511-3

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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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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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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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

High-grade serous ovarian carcinoma (HGSOC) is a deadly subtype of ovarian cancer (OC), often diagnosed at late stages due to nonspecific symptoms and lack of effective markers for early detection. Aberrant protein N-linked glycosylation has been reported in HGSOC, holding a potential for improving the diagnosis and prognosis of affected patients. Building on our recent observation documenting that HGSOC-derived extracellular vesicles (EVs) exhibit aberrant protein expression patterns, we here explore the protein N-glycosylation displayed by EVs isolated from HGSOC cell lines and patient ascites relative to those from matching controls to unveil candidate markers for HGSOC. Comparative glycoproteomics of small EVs (sEVs, <200 nm) and medium/large EVs (m/lEVs, >200 nm) isolated from HGSOC and non-cancerous cell lines revealed lower overall N-glycosylation of EV proteins and a decreased protein expression of oligosaccharyltransferase (OST) subunits from HGSOC compared to non-cancerous cell lines. Increased α2,6-sialylation was also observed in m/lEVs from HGSOC cell lines and patient ascites by lectin blotting, which correlated with increased gene expression of ST6GAL1 and decreased gene expression of ST3GAL3/4 in HGSOC compared to normal ovary tissues. Our study provides insights into the EV glycoproteome of HGSOC and the underlying changes in the glycosylation machinery in HGSOC tissues, opening new avenues for the discovery of novel markers against HGSOC.

DOI： 10.1016/j.bbadva.2025.100140

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Publisher：Yakugaku Zasshi  

In this study, we assessed the information sharing practices between pharmacists and multidisciplinary healthcare professionals such as doctors, care managers, and nurses, and others. We evaluated the effectiveness of“home medical care management guidance reports”and“home-visit drug management guidance reports”prepared by pharmacists. We also identified factors that could enhance collaborative practices. To improve the reports, we introduced a new report form with an overview column and a reply column. We used the SOAP format in the new reports. We found that the response rate for reports from X pharmacy was significantly higher than that of Y pharmacies. A survey revealed that X’s reports contained more categories (median of 3 versus 1 in Y’s reports). Pharmacy X’s reports had a smaller proportion of pharmacotherapy details, and a larger proportion of information regarding patients’living and health conditions, as well as environmental factors. We also found that the character count in X’s assessment column was significantly greater (168.5 versus 60), and notably less in the overview sections (12 versus 22) when compared to Y’s reports. Suggestions and guidance constituted a significantly larger portion of X’s reports (29.8% compared to 10.8% in Y’s). Questionnaire feedback from other healthcare professionals to whom the subject pharmacies send reports highlighted the importance of pharmacist-provided information on health and living conditions, based on pharmacological knowledge. Based on these results, to enhance health information sharing, pharmacists should integrate assessments of pharmacotherapy with health and living conditions and effectively communicate this information to other professionals.

DOI： 10.1248/yakushi.24-00102

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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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OBJECTIVE: To examine the efficacy and safety of minimally invasive surgery (MIS) and conventional abdominal surgery for epithelial ovarian cancer (EOC), stratified by treatment type. METHODS: A systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Ovarian Cancer Committee. Several academic databases, including PubMed/MEDLINE, Cochrane Database, and Ichushi were searched by the Japan Medical Library Association on November 11, 2023, using the keywords "epithelial ovarian cancer", "minimally invasive surgery", "laparoscopic", and "robot-assisted". Articles describing MIS treatment for EOC compared with conventional abdominal surgery were independently assessed by two authors. The primary outcomes were survival and perioperative adverse events. RESULTS: After screening 1114 studies, 35 articles were identified, including primary staging surgery (PSS) for early-stage EOC EOC (n = 20) and neoadjuvant chemotherapy following interval debulking surgery (NACT-IDS; n = 10) and upfront primary debulking surgery (PDS; n = 5) for advanced-stage EOC. These studies included 29,888 patients (7661 undergoing MIS and 22,227 undergoing abdominal surgery). Patients receiving MIS and abdominal surgery had similar overall survival (PSS: odds ratio [OR] 1.02, 95% confidence interval [CI] 0.75-1.37; NACT-IDS: OR 0.93, 95%CI 0.25-3.44 and PDS: OR 0.66, 95%CI 0.36-1.22, all P > 0.05). MIS showed perioperative complication rates comparable to those of abdominal surgery (intraoperative and postoperative, all treatment types P ≥ 0.05). However, the rate of lymph node dissection in early-stage EOC (PSS: OR 0.49, 95%CI0.26-0.91) and multivisceral resections in advanced-stage EOC (NACT-IDS: OR 0.27 95%CI 0.16-0.44 and PDS: OR 0.27, 95%CI 0.16-0.44) was lower in MIS than in abdominal surgery (all P < 0.05). CONCLUSION: MIS did not negatively impact the survival and perioperative complications of patients with EOC compared to abdominal surgery. While MIS is a viable option, varied case selection and surgical procedures suggest potential bias, requiring further validation studies.

DOI： 10.1016/j.ygyno.2024.08.011

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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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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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.celrep.2024.114517

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Language：English   Publisher：Pediatric Surgery International  

Purpose: This study aimed to clarify surgical complications associated with open surgery for congenital diaphragmatic hernia (CDH). Methods: We performed an exploratory data analysis of the clinical characteristics of surgical complications of neonates with CDH who underwent laparotomy or thoracotomy between 2006 and 2021. Data of these patients were obtained from the database of the Japanese CDH Study Group. Results: Among 1,111 neonates with left or right CDH, 852 underwent open surgery (laparotomy or thoracotomy). Of these 852 neonates, 51 had the following surgical complications: organ injury (n = 48; 6% of open surgeries); circulatory failure caused by changes in the organ location (n = 2); and skin burns (n = 1). Injured organs included the spleen (n = 30; 62% of organ injuries), liver (n = 7), lungs (n = 4), intestine (n = 4), adrenal gland (n = 2), and thoracic wall (n = 2). Fourteen of the patients who experienced organ injury required a blood transfusion (2% of open surgeries). The adjusted odds ratio of splenic injury for patients with non-direct closure of the diaphragm was 2.2 (95% confidence interval, 1.1–4.9). Conclusion: Of the patients who underwent open surgery for CDH, 2% experienced organ injury that required a blood transfusion. Non-direct closure of the diaphragmatic defect was a risk factor for splenic injury.

DOI： 10.1007/s00383-024-05826-6

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.device.2024.100363

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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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Publisher：Advanced Powder Technology  

A sequential particle assembling process was developed to fabricate composite particles with multiple components. Cobalt sintering aids and carbon nanotube (CNT) conductive additives were sequentially and electrostatically absorbed on Li<inf>1.3</inf>Al<inf>0.3</inf>Ti<inf>1.7</inf>(PO<inf>4</inf>)<inf>3</inf> (LATP) electrolyte particles under various dispersion conditions. The effect of the particle assembling conditions on the composite body's sintering ability and conductive properties was investigated. By optimizing the microstructure of the composite particle and its particle charging conditions, it became possible to obtain a sintered composite electrode with a finely connected path of each LATP and CNT phase.

DOI： 10.1016/j.apt.2024.104430

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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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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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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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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Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

DOI： 10.1002/jev2.12404

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

DOI： 10.1111/jog.15828

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The pathogenesis of endometriosis is a complex process, and recent research has introduced novel hypotheses in this field. This review summarizes recent studies on the pathogenesis of endometriosis. We focused on several classical hypotheses, as well as their interactions with the microenvironment of hormonal dependence and immunosuppression. Furthermore, we highlighted the emergence of bacterial factors associated with endometriosis. Recent advances in next-generation sequencing (NGS) have revealed the presence and detailed distribution of these bacteria as well as the involvement of specific bacteria in pathogenesis. These factors alter the microenvironment in the early stages of endometriosis development, leading to lesion formation. Understanding the mechanisms underlying the early development of endometriosis from a new perspective would be helpful for the development of novel therapeutic agents for endometriosis.

DOI： 10.1016/j.isci.2023.108739

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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 |log2FC | >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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Publisher：Japanese Journal of Gastroenterological Surgery  

The patient was a 63-year-old woman who was diagnosed with a pancreatic tumor in an abdominal ultrasound examination. CT showed a 33-mm low density mass anterior to the tail of the pancreas. The lesion showed incremental and heterogeneous contrast. MRI showed a low intensity signal on T1WI, a low intensity signal in the center and a mildly high intensity signal in the margins on T2WI, and a high intensity signal in the margins and a low intensity signal in the center on DWI. Based on these findings, solid pseudopapillary neoplasm (SPN) or desmoid tumor was suspected as the differential diagnosis. Considering the risk of seeding, we decided not to conduct a biopsy and to perform laparoscopic pancreatectomy. Intraoperative findings suggested invasion of the gastric wall. Therefore, distal pancreatectomy with partial resection of the stomach wall and splenectomy was performed. The pathological diagnosis was desmoid tumor. Reports of laparoscopic pancreatic resection for intra-abdominal desmoid tumor are rare, and we report our findings including a literature review.

DOI： 10.5833/jjgs.2022.0100

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

DOI： 10.1007/s10147-023-02417-8

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Publisher：Scientific Reports  

Remote ischemic preconditioning (RIPC) protects organs from ischemia–reperfusion injury. Recent trials showed that RIPC improved gas exchange in patients undergoing lung or cardiac surgery. We performed a systematic search to identify randomized controlled trials involving RIPC in surgery under general anesthesia. The primary outcome was the P<inf>a</inf>O<inf>2</inf>/F<inf>I</inf>O<inf>2</inf> (P/F) ratio at 24 h after surgery. Secondary outcomes were A-a DO<inf>2</inf>, the respiratory index, duration of postoperative mechanical ventilation (MV), incidence of acute respiratory distress syndrome (ARDS), and serum cytokine levels. The analyses included 71 trials comprising 7854 patients. Patients with RIPC showed higher P/F ratio than controls (mean difference [MD] 36.6, 95% confidence interval (CI) 12.8 to 60.4, I² = 69%). The cause of heterogeneity was not identified by the subgroup analysis. Similarly, A-a DO<inf>2</inf> (MD 15.2, 95% CI − 29.7 to − 0.6, I² = 87%) and respiratory index (MD − 0.17, 95% CI − 0.34 to − 0.01, I² = 94%) were lower in the RIPC group. Additionally, the RIPC group was weaned from MV earlier (MD − 0.9 h, 95% CI − 1.4 to − 0.4, I² = 78%). Furthermore, the incidence of ARDS was lower in the RIPC group (relative risk 0.73, 95% CI 0.60 to 0.89, I² = 0%). Serum TNFα was lower in the RIPC group (SMD − 0.6, 95%CI − 1.0 to − 0.3 I² = 87%). No significant difference was observed in interleukin-6, 8 and 10. Our meta-analysis suggested that RIPC improved oxygenation after surgery under general anesthesia. Clinical trial number: This study protocol was registered in the University Hospital Medical Information Network (registration number: UMIN000030918), https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035305.

DOI： 10.1038/s41598-023-44833-w

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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-Prkdcscid1l2rgtm1Wjl/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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Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25-50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

DOI： 10.1038/s41598-023-44365-3

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

DOI： 10.1093/jjco/hyad086

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

DOI： 10.1007/s43032-023-01230-y

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/or.2023.8523

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本癌学会  

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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Stress granules (SGs) are dynamic, non-membranous structures composed of non-translating mRNAs and various proteins and play critical roles in cell survival under stressed conditions. Extensive proteomics analyses have been performed to identify proteins in SGs; however, the molecular functions of these components in SG formation remain unclear. In this report, we show that ubiquitin-associated protein 2-like (UBAP2L) is a crucial component of SGs. UBAP2L localized to SGs in response to various stresses, and its depletion significantly suppressed SG organization. Proteomics and RNA sequencing analyses found that UBAP2L formed a protein-RNA complex with Ras-GTP-activating protein SH3 domain binding protein 1 (G3BP1) and small nucleolar RNAs (snoRNAs). In vitro binding analysis demonstrated that snoRNAs were required for UBAP2L association with G3BP1. In addition, decreased expression of snoRNAs reduced the interaction between UBAP2L and G3BP1 and suppressed SG formation. Our results reveal a critical role of SG component, the UBAP2L/snoRNA/G3BP1 protein-RNA complex, and provide new insights into the regulation of SG assembly.

DOI： 10.1038/s42003-023-04754-w

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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 1,271 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 anti-tumor 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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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DOI： 10.3802/jgo.2023.34.e34

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Language：English   Publisher：Pediatric Pulmonology  

Background: Mortality prediction of congenital diaphragmatic hernia (CDH) is essential for developing treatment strategies, including fetal therapy. Several researchers have reported prognostic factors for this rare but life-threatening condition; however, the optimal combination of prognostic factors remains to be elucidated. Objectives: This study aimed to develop the most discriminative prenatal and postnatal models to predict the mortality of infants with an isolated left-sided CDH. Methods: This multi-institutional retrospective cohort study included infants with CDH born at 15 tertiary hospitals of the Japanese CDH Study Group between 2011 and 2016. We developed multivariable logistic models with every possible combination of predictors and identified models with the highest cross-validated area under the receiver operating characteristic curve (AUC) for prenatal and postnatal predictions. Results: Among 302 eligible infants, 44 died before discharge. The prenatal mortality prediction model was based on the observed/expected lung area to head circumference ratio (O/E LHR), liver herniation, and stomach herniation (AUC, 0.830). The postnatal mortality prediction model was based on O/E LHR, liver herniation, and the lowest oxygenation index (AUC, 0.944). Conclusion: Our models can facilitate the prenatal and postnatal mortality prediction of infants with isolated left-sided CDH.

DOI： 10.1002/ppul.26172

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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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Language：English   Publisher：Pediatric Surgery International  

Purpose: This study aimed to evaluate prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia (CDH). Methods: A systematic literature search was performed to identify relevant observational studies that evaluated the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e-LHR), observed-to-expected total fetal lung volume (o/e-TFLV), lung-to-thorax transverse area ratio (L/T ratio), intrathoracic herniation of the liver and the stomach, and side of diaphragmatic hernia, using a threshold for the prediction of mortality in fetuses with CDH. Study quality was assessed using the QUADAS-2 tool. Hierarchical summary receiver operating characteristic curves were constructed. Results: A total of 50 articles were included in this meta-analysis. The QUADAS-2 tool identified a high risk of bias in more than one domain scored in all parameters. Among those parameters, the diagnostic odds ratio of mortality with o/e-LHR < 25%, o/e-TFLV < 25%, and L/T ratio < 0.08 were 11.98 [95% confidence interval (CI) 4.65–30.89], 11.14 (95% CI 5.19–23.89), and 10.28 (95% CI 3.38–31.31), respectively. The predictive values for mortality were similar between the presence of liver herniation and retrocardiac fetal stomach position. Conclusions: This systematic review suggests that o/e-LHR, o/e-TFLV, and L/T ratio are equally good predictors of neonatal mortality in fetuses with isolated CDH.

DOI： 10.1007/s00383-022-05232-w

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

DOI： 10.1371/journal.pone.0273876

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Language：Japanese   Publisher：公益社団法人 日本婦人科腫瘍学会  

DOI： 10.57291/jsgo.40.3_159

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.3802/jgo.2022.33.e40

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Language：English   Publisher：Children  

Background: Treatment modalities for neonates with congenital diaphragmatic hernia (CDH) have greatly improved in recent years, with a concomitant increase in survival. However, long-term outcomes restrict the identification of optimal care pathways for CDH survivors in adolescence and adulthood. Therefore, we evaluated the long-term outcomes within the Japanese CDH Study Group (JCDHSG). Methods: Participants were born with CDH between 2006 and 2018 according to the JCDHSG. Participants were enrolled in the database at 1.5, 3, 6, and 12 years old. Follow-up items included long-term complications, operations for long-term complication, and home medical care. Results: A total of 747 patients were included in this study, with 626 survivors (83.8%) and 121 non-survivors (16.2%). At 1.5, 3, 6, and 12 years old, 45.4%, 36.5%, 34.8%, and 43.6% developed complications, and 20.1%, 14.7%, 11.5%, and 5.1% of participants required home care, respectively. Recurrence, pneumonia, pneumothorax, gastroesophageal reflux disease, and intestinal obstruction decreased with age, and thoracic deformity increased with age. Conclusions: As CDH survival rates improve, there is a need for continued research and fine-tuning of long-term care to optimize appropriate surveillance and long-term follow-up.

DOI： 10.3390/children9060856

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates. EXPERIMENTAL DESIGN: Transcriptome analysis was performed using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis was used to identify potential therapeutic target genes for uterine leiomyosarcoma. Afterward, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using SK-UT-1, SK-LMS-1, and SKN cell lines. RESULTS: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The Ingenuity Pathway Analysis revealed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI-2536 or prexasertib) were found to exert a superior anti-cancer effect against cell lines at low nanomolar concentrations and induce cell cycle arrest. In SK-UT-1 tumor-bearing mice, BI-2536 monotherapy remarkably suppressed tumorigenicity. Moreover, the prexasertib and cisplatin combination therapy inhibited tumor proliferation and prolonged the time to tumor progression. CONCLUSIONS: We identified upregulated expressions of PLK1 and CHEK1; their kinase activity was activated in uterine leiomyosarcoma. BI-2536 and prexasertib demonstrated a significant anti-cancer effect. Therefore, cell cycle-related kinases may present a promising therapeutic strategy for the treatment of uterine leiomyosarcoma.

DOI： 10.1158/1078-0432.CCR-22-0100

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: We investigated the impact of cystectomy for borderline ovarian tumor (BOT) on tumor recurrence in comparison with those receiving salpingo-oophorectomy using the inverse probability of treatment weighting (IPTW). METHODS: Between 1986 and 2017, 4,708 women with a malignant ovarian neoplasm were collected after a central pathological review and search of the medical records from 14 collaborating institutions. Among them, a total of 285 young women with stage I BOT were extracted. To compare recurrence-free survival (RFS) between the surgery groups, Cox regression analyses and IPTW-adjusted Kaplan-Meier method were employed. RESULTS: During a median follow-up of 62.0 (1.2-270.4) months, 10 patients (3.5%) developed recurrence. In multivariate analysis, the practice of cystectomy was not a significant prognostic indicator of RFS {hazard ratio (95% confidence interval): 1.276 (0.150-10.864), P=0.823}. In the IPTW-adjusted cohort, the 5-year RFS rates were 95.8 and 96.0% in patients receiving cystectomy and salpingo-oophorectomy, respectively (P=0.378). CONCLUSION: If patients are selected appropriately, cystectomy in itself may not increase tumor recurrence in young women with early-stage BOT. A large-scale prospective clinical study is necessary to validate this finding.

DOI： 10.1002/ijgo.13844

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

DOI： 10.1016/j.matbio.2022.03.003

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1186/s12905-022-01642-z

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1038/s41598-022-08503-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

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

DOI： 10.1007/s10147-021-02075-8

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Other Link： https://link.springer.com/article/10.1007/s10147-021-02075-8/fulltext.html

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DOI： 10.18999/nagjms.80.3.417

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Language：Japanese   Publisher：Japan Society of Gynecologic Oncology  

<p>Adenocarcinoma of the vulva is rare. Lesions of the posterior vaginal vestibule are often assumed to be primary lesions of the Bartholin's glands. We report a case where vulvar adenocarcinoma in a Crohn's disease patient was diagnosed as cancer arising from an anal fistula following resection. A 48-year-old woman received treatment for Crohn's disease. Six months prior, she had a tumor of the left vulvar area, close to the vaginal vestibule. Adenocarcinoma was confirmed based on biopsy results. Upper and lower gastrointestinal endoscopy performed was negative. Accordingly, Bartholin's adenocarcinoma was suspected. On the first visit, a 4 cm mass was found in the left Bartholin's gland area. CT revealed mild bilateral inguinal lymph node hypertrophy. We performed simple vulvectomy and bilateral inguinal lymph node sampling for biopsy. The pathological diagnosis was moderately different from adenocarcinoma. A continuity was observed between the colonic mucosal epithelium and the adenocarcinoma. Accordingly, anal fistula cancer was confirmed. The excision margin was positive on the deep exfoliated surface of the left vaginal wall. Subsequently, robot-assisted laparoscopic abdominal perineal resection, vaginal perineal resection, colon stoma construction, and inguinal lymph node dissection were performed. Capecitabine plus oxaliplatin (CAPOX) chemotherapy is currently being administered to the patient. Vulvar adenocarcinoma with Crohn's disease should be scrutinized with suspicion of anal fistula cancer.</p>

DOI： 10.57291/jsgo.40.1_10

Open Access

CiNii Research

Publisher：Cold Spring Harbor Laboratory  

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

DOI： 10.1101/2022.01.06.22268775

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

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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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15154

Language：English   Publishing type：Research paper (scientific journal)  

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.

DOI： 10.1016/j.celrep.2021.109549

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Language：English   Publishing type：Research paper (scientific journal)  

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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(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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1038/s41388-020-01595-3

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Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.

DOI： 10.1016/j.celrep.2021.108726

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

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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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVE: To establish and characterize cell lines derived from human endometrial epithelial cells (ECs) and mesenchymal cells (MCs) from patients with and without endometriosis. DESIGN: In vitro experimental study. SETTING: University and national cancer center research institute. PATIENT(S): Two women with endometriosis and two women without endometriosis. INTERVENTION(S): Sampling of endometrial ECs and MCs. MAIN OUTCOME MEASURE(S): Establishing immortalized endometrial ECs and MCs with quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunocytochemical analysis, and RNA sequence profiling performed to characterize the immortalized cells and a cell proliferation assay, three-dimensional culture, and assays for hormone responses performed to characterize the features of ECs. RESULT(S): The qRT-PCR, immunocytochemical analysis, and Western blot analysis revealed that the ECs and MCs maintained their original features. Moreover, the immortalized cells were found to retain responsiveness to sex steroid hormones. The ECs formed a gland-like structure in three-dimensional culture, indicating the maintenance of normal EC phenotypes. The RNA sequence profiling, principal component analysis, and clustering analysis showed that the gene expression patterns of the immortalized cells were different from those of cancer cells. Several signaling pathways that were statistically significantly enriched in ECs and MCs with endometriosis were revealed. CONCLUSION(S): We successfully obtained four paired immortalized endometrial ECs and MCs from patients with and without endometriosis. Using these cells could help identify diagnostic and therapeutic targets for endometriosis. The cell lines established in this study will thus serve as powerful experimental tools in the study of endometriosis.

DOI： 10.1016/j.xfss.2020.09.001

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

DOI： 10.1002/ijgo.13244

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Publisher：Journal of Clinical Oncology  

PURPOSE We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). PATIENTS AND METHODS From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. RESULTS The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. CONCLUSION The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

DOI： 10.1200/JCO.19.01067

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Language：English   Publishing type：Research paper (scientific journal)  

Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

DOI： 10.1002/ijc.32854

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

DOI： 10.1093/jjco/hyz163

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Uterine leiomyosarcoma (ULMS) is the major subtype of uterine sarcoma (US) and contributes to uterine cancer deaths. Although preoperative diagnosis of US remains challenging, frequent application of laparoscopic surgery for benign uterine leiomyomas (ULM) requires precise exclusion of US. MicroRNAs are stably present in the bloodstream, and the application of circulating miRNAs as disease biomarkers has been recognized. In the present study, we aimed to identify diagnostic biomarkers for distinguishing US from ULM by focusing on circulating miRNAs. All serum samples were collected preoperatively between 2009 and 2017, and all cases were histopathologically diagnosed. Whole miRNA profiles were obtained using a miRNA microarray. By analyzing expression levels of the miRNAs, candidate miRNAs were selected based on diagnostic performance in discriminating US from ULM, and a diagnostic model was then constructed. A total of 90 serum samples were analyzed, and clustering analyses revealed that the profiles of ULMS were distinct from those of controls. Based on leave-one-out cross-validation, seven miRNAs were selected as biomarker candidates. Based on model construction, the optimal model consisted of two miRNAs (miR-1246 and miR-191-5p), with an area under the receiver operating characteristic curve (AUC) for identifying ULMS of 0.97 (95% confidence interval [CI], 0.91-1.00). In contrast, serum lactate dehydrogenase had an AUC of only 0.64 (95% CI, 0.34-0.94). Seven serum miRNAs with high diagnostic performance for preoperative US screening were detected, and a promising diagnostic model for ULMS was generated.

DOI： 10.1111/cas.14215

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

DOI： 10.1093/carcin/bgz135

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/ijgc-2019-ESGO.1079

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Cancer-associated fibroblasts (CAFs), one of the major components of a tumour microenvironment, comprise heterogeneous populations involved in tumour progression. However, it remains obscure how CAF heterogeneity is governed by cancer cells. Here, we show that cancer extracellular vesicles (EVs) induce a series of chemokines in activated fibroblasts and contribute to the formation of the heterogeneity. In a xenograft model of diffuse-type gastric cancer, we showed two distinct fibroblast subpopulations with alpha-smooth muscle actin (α-SMA) expression or chemokine expression. MicroRNAs (miRNAs) profiling of the EVs and the transfection experiment suggested that several miRNAs played a role in the induction of chemokines such as CXCL1 and CXCL8 in fibroblasts, but not for the myofibroblastic differentiation. Clinically, aberrant activation of CXCL1 and CXCL8 in CAFs correlated with poorer survival in gastric cancer patients. Thus, this link between chemokine expression in CAFs and tumour progression may provide novel targets for anticancer therapy.

DOI： 10.1038/s41388-019-0832-4

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DOI： 10.1038/s41598-019-45001-9

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Language：English   Publishing type：Research paper (scientific journal)  

KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancer (NSCLC). Mutations in KRAS are detected in 30% of NSCLC cases, with most of them occurring in codons 12 and 13 and less commonly in others. Despite intense efforts to develop drugs targeting mutant KRAS, no effective therapeutic strategies have been successfully tested in clinical trials. Here, we investigated molecular targets for KRAS-activated lung cancer cells using a drug library. A total of 1271 small molecules were screened in KRAS-mutant and wild-type lung cancer cell lines. The screening identified the cytotoxic effects of benzimidazole derivatives on KRAS-mutant lung cancer cells. Treatments with two benzimidazole derivatives, methiazole and fenbendazole-both of which are structurally specific-yielded significant suppression of the RAS-related signaling pathways in KRAS-mutated cells. Moreover, combinatorial therapy with methiazole and trametinib, a MEK inhibitor, induced synergistic effects in KRAS-mutant lung cancer cells. Our study demonstrates that these benzimidazole derivatives play an important role in suppressing KRAS-mutant lung cancer cells, thus offering a novel combinatorial therapeutic approach against such cancer cells.

DOI： 10.1016/j.canlet.2019.03.002

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Language：English   Publishing type：Research paper (scientific journal)  

The mesothelium, covered by a continuous monolayer of mesothelial cells, is the first protective barrier against metastatic ovarian cancer. However, mesothelial cells release tumor-promoting factors that accelerate the process of peritoneal metastasis. We identified cancer-associated mesothelial cells (CAMs) that had tumor-promoting potential. Here, we found that plasminogen activator inhibitor-1 (PAI-1) induced the formation of CAMs, after which CAMs increasingly secreted the oncogenic factors interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5), further promoting the metastasis of ovarian cancer cells in a feedback loop. After the formation of CAMs, PAI-1 activated the nuclear factor kappa B (NFκB) pathway in the CAMs, thus transcriptionally upregulating the expression of the downstream NFκB targets IL-8 and CXCL5. Moreover, PAI-1 correlated with peritoneal metastasis in ovarian cancer patients and indicated a poor prognosis. In both ex vivo and in vivo models, after PAI-1 expression was knocked down, the metastasis of ovarian cancer cells decreased significantly. Therefore, targeting PAI-1 may provide a potential target for future therapeutics to prevent the formation of CAMs and alleviate peritoneal metastasis in ovarian cancer patients.

DOI： 10.1016/j.canlet.2018.10.027

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Language：Japanese   Publisher：Japan Academy of Midwifery  

<p><b>Purpose</b></p><p>The authors' birth center is an in-hospital midwifery facility annexed to the Perinatal Medical Center. Even if the course of pregnancy and delivery is uneventful, unexpected massive bleeding can occur after childbirth. Pregnancies conceived via assisted reproductive technology (ART) are said to be a risk factor for <i>placenta accreta</i>; and <i>placenta accreta</i> can cause critical obstetrical hemorrhage. In our facility, if a parturient conceived via ART wishes to give birth in an in-hospital midwifery unit, childbirth is carried out in a birth center with the permission of the obstetrician. We conducted a case-control study about postpartum hemorrhage (PPH) to examine the safety of giving birth of pregnant women conceived via ART (fresh embryo transfer and cryopreserved embryo transfer) in an in-hospital midwifery care.</p><p><b>Subjects and Methods</b></p><p>During the survey period between April 2013 and March 2016, the total number of birth center deliveries was 604, including 567 not conceived through ART and 37 conceived through ART: fresh embryo transfer in 9 cases and cryopreserved embryo transfer (CET) in 28 cases. We carried out a statistical analysis of the amount of postpartum bleeding, the amount of bleeding during the 24 hours following delivery, and the frequency of PPH (postpartum bleeding of 500mL or more, or bleeding of 800mL or more during the 24 hours following delivery) among pregnancies not conceived through ART, pregnancies conceived through fresh embryo transfer, and pregnancies conceived through CET. Multiple linear regression analysis of the amount of postpartum bleeding and the amount of bleeding during the 24 hours following delivery was performed, and the frequency of PPH was determined using multivariate logistic analysis.</p><p><b>Results</b></p><p>The amount of postpartum bleeding and the amount during the 24 hours following delivery were significantly greater among pregnancies conceived through CET than among those not conceived through ART; the frequency of PPH was also significantly higher among pregnancies conceived through CET than among those not conceived through ART. In addition, PPH consisted of critical obstetrical hemorrhage in 4 cases, 3 of which occurred in mothers pregnant with fetuses conceived through ART using CET.</p><p><b>Conclusions</b></p><p>Our study suggested that pregnancy conceived through CET was a risk factor for PPH. Regarding care system and eligibility for giving birth of pregnant women conceived through CET in an in-hospital midwifery unit, further investigations are needed.</p>

DOI： 10.3418/jjam.jjam-2017-0048

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：生命科学系学会合同年次大会運営事務局  

Language：English   Publishing type：Research paper (scientific journal)  

Ovarian cancer is the leading cause of gynecologic cancer mortality, due to the difficulty of early detection. Current screening methods lack sufficient accuracy, and it is still challenging to propose a new early detection method that improves patient outcomes with less-invasiveness. Although many studies have suggested the utility of circulating microRNAs in cancer detection, their potential for early detection remains elusive. Here, we develop novel predictive models using a combination of 8 circulating serum miRNAs. This method was able to successfully distinguish ovarian cancer patients from healthy controls (area under the curve, 0.97; sensitivity, 0.92; and specificity, 0.91) and early-stage ovarian cancer from patients with benign tumors (0.91, 0.86 and 0.83, respectively). This method also enables subtype classification in 4 types of epithelial ovarian cancer. Furthermore, it is found that most of the 8 miRNAs were packaged in extracellular vesicles, including exosomes, derived from ovarian cancer cells, and they were circulating in murine blood stream. The circulating miRNAs described in this study may serve as biomarkers for ovarian cancer patients. Early detection and subtype determination prior to surgery are crucial for clinicians to design an effective treatment strategy for each patient, as is the goal of precision medicine.

DOI： 10.18632/oncotarget.20688

Open Access

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Japanese Society for Molecular Tumor Marker Research  

DOI： 10.11241/jsmtmr.32.27

CiNii Research

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：医歯薬出版(株)  

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Language：Japanese   Publisher：東海産科婦人科学会  

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Language：Japanese   Publisher：(公財)上原記念生命科学財団  

Language：Japanese   Publisher：(公財)上原記念生命科学財団  

Language：Japanese   Publisher：愛知産科婦人科学会  

Language：Japanese   Publisher：愛知産科婦人科学会  

Language：Japanese   Publisher：愛知産科婦人科学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：Japanese   Publisher：愛知産科婦人科学会  

Language：Japanese   Publisher：愛知産科婦人科学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：Japanese   Publisher：東海産婦人科内視鏡手術研究会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：Japanese   Publisher：東海産婦人科内視鏡手術研究会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：Japanese   Publisher：愛知産科婦人科学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：東海産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：English   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：English   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：東海産科婦人科学会  

骨盤内臓全摘術は、周囲臓器に浸潤した進行・再発婦人科悪性腫瘍に対して完全切除を行うことで、長期生存が期待できる方法の一つである。しかし、侵襲が大きい上にストマの造設等でQOLの低下を招くため手術適応が難しい。また、拡大視が可能な腹腔鏡下手術は骨盤手術に有用で術後の早期回復も期待でき、近年腹腔鏡下骨盤内臓全摘術も増えている。今回、当院で2012年から2021年に骨盤内臓全摘術を施行した、骨盤内進行・再発婦人科悪性腫瘍23例を対象として、合併症、予後等を解析した。さらに開腹手術と腹腔鏡下手術を比較検討した。年齢の中央値は54歳で、原発は子宮頸癌8例、腟癌3例、子宮体癌3例、卵巣・卵管癌6例、平滑筋肉腫2例、原発不明癌1例であった。術式は開腹10例、腹腔鏡11例で全例外科および泌尿器科と連携して行った。周術期死亡例はなく、周術期合併症は17例(73.9%)にあり、尿路系合併症が8例(34.7%)で最多であった。開腹と腹腔鏡での手術成績の比較において、手術時間の中央値に差はなく、腹腔鏡で出血量が少なく入院期間が短い傾向にあったが有意差はなかった。観察期間(7.7ヵ月〜105.2ヵ月)における全患者23例の5年生存率は64.2%であった。全生存期間中央値は34.5ヵ月で、無増悪期間中央値は26.7ヵ月であった。予後因子を検討したところ、切除断端陽性では全生存率、無増悪生存率ともに、切除断端陰性より有意に予後不良となった。今回の検討において、骨盤内臓全摘術は、周囲臓器に浸潤した進行・再発婦人科悪性腫瘍に対して、比較的安全に施行できる術式と考えられた。また、腹腔鏡下手術は開腹と比較して低侵襲な可能性があり、合併症や早期回復の点で、腹腔鏡下手術を選択することも可能と考える。(著者抄録)

Language：Japanese   Publisher：東海産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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

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Language：English   Publisher：(一社)日本癌治療学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：Japanese   Publisher：東海産婦人科内視鏡手術研究会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：English   Publisher：(一社)日本癌治療学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：(一社)日本癌学会  

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：English   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：English   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

Language：Japanese   Publisher：(公社)日本産科婦人科学会