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Cisplatin derivatives are first-line chemotherapeutic agents for epithelial ovarian cancer. However, chemoresistance remains a major hurdle for successful therapy and the underlying molecular mechanisms are poorly understood at present. RNA sequencing of organoids (PDO) established from cisplatin-sensitive and -resistant ovarian cancer tissue samples was performed. Glucose metabolism, cell senescence, and chemosensitivity properties were subsequently examined. Immunoprecipitation, mass spectrometry, Fӧrster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM), luciferase reporter assay, ChIP and animal experiments were conducted to gain insights into the specific functions and mechanisms of action of the serine/threonine kinase, Aurora-A, in ovarian cancer. Aurora-A levels were significantly enhanced in cisplatin-resistant PDO. Furthermore, Aurora-A promoted chemoresistance through suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Mechanistically, Aurora-A bound directly to the transcription factor sex determining region Y-box 8 (SOX8) and phosphorylated the Ser327 site, in turn, regulating genes related to cell senescence and glycolysis, including hTERT, P16, LDHA and HK2, through enhancement of forkhead-box k1 (FOXK1) expression. Aurora-A regulates cell senescence and glucose metabolism to induce cisplatin resistance by participating in the SOX8/FOXK1 signaling axis in ovarian cancer. Our collective findings highlight a novel mechanism of cisplatin resistance and present potential therapeutic targets to overcome chemoresistance in ovarian cancer.

PurposeTo evaluate the impact of UAE for postpartum and postabortion hemorrhage on future infertility, especially in patients undergoing infertility treatment, along with angiographic endpoints.Materials and methodsSixty-two sessions performed emergent or prophylactic UAE for postpartum or postabortion hemorrhage between 2008 and 2017 were selected. Subsequent pregnancy outcomes and complications were investigated as primary outcomes. The cases were divided into two groups based on the presence of massive hemorrhage. The relationships between angiographic endpoints and complications were also evaluated as secondary outcomes.ResultsThe mean patient age was 34.1 ± 6.5 years. Fourteen of the 23 patients (60.9%) with desired fertility achieved pregnancy and 10 patients achieved live births (43.5%). In the patients during infertility treatment, three of the four patients had complications of severe adhesion after caesarean section or placenta accreta. In the group of patients with massive hemorrhage, the occurrence of uterine infection was significantly high (p = 0.014), but the angiographic endpoints were not significant, regardless of the occurrence of uterine infection.ConclusionIt was unnecessary to modify embolic endpoint according to seriousness of the hemorrhage. The pregnancy and live birth rates were acceptable, although patients undergoing infertility treatment had a higher rate of delivery complications.

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression‐free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double‐blind, placebo‐controlled KEYNOTE‐826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD‐L1 combined positive score (CPS) ≥1, all‐comers, and PD‐L1 CPS ≥10. Fifty‐seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD‐L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16–0.77]), all‐comers (n = 57; 0.45 [0.22–0.90]), and patients with PD‐L1 CPS ≥10 (n = 25; 0.36 [0.12–1.07]). HRs (95% CI) for OS were 0.38 (0.14–1.01), 0.41 (0.17–1.00), and 0.37 (0.10–1.30), respectively. Incidence of grade 3–5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE‐826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer. Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression‐free survival and overall survival compared with chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3 KEYNOTE‐826 study. In this subset analysis of patients enrolled in Japan in the KEYNOTE‐826 study, pembrolizumab plus chemotherapy with or without bevacizumab was associated with prolonged progression‐free survival and overall survival in this setting.

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012‐2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2‐3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type‐specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type‐specific RCs between CIN1 and CIN2‐3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type‐specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2‐3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2‐3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01‐4.98), followed by HPV31 (2.51, 1.54‐5.24), HPV18 (2.43, 1.59‐4.32), HPV35 (1.56, 0.43‐8.36), HPV33 (1.01, 0.49‐3.31), HPV52 (0.99, 0.76‐1.33), and HPV58 (0.97, 0.75‐1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71‐2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14‐0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9‐valent vaccine contributed to 89.7% (95% CI, 88.7‐90.7) of CIN2‐3/AIS and 93.8% (95% CI, 92.4‐95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9‐valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women. We updated HPV type‐specific risks of and contributions to cervical cancer and precancer in Japan, using a large dataset from young Japanese women with cervical abnormalities. The relative risk for progression to cervical cancer and precancer was the highest for HPV16, followed by HPV31, HPV18, HPV35, HPV33, HPV52 and HPV58. The new 9‐valent vaccine is estimated to provide over 90% protection against invasive cervical cancer among Japanese women up to an age of 40 years.

This study evaluated the influence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. We retrospectively analyzed the data of patients with stage IA endometrial cancer admitted in our hospital between 2005 and 2015. Among 989 patients who underwent peritoneal cytology, 135 (13.7%) had PPC. Multivariate analysis extracted several independent risk factors for recurrence in stage IA patients, including those with PPC. Adjuvant chemotherapy did not cause a significant difference in the 5-year relapse-free survival rate in patients with PPC (p = 0.78). Similarly, the 5-year recurrence-free survival rate with or without chemotherapy was not different among type II cancer patients (p = 0.11). However, the baseline risk of 5-year relapse-free survival without chemotherapy in patients with PPC and type II was very low (66.7%). While PPC was an independent risk factor for recurrence in stage IA endometrial cancer, adjuvant chemotherapy did not influence the survival rate in patients with PPC. While it is controversial whether adjuvant chemotherapy should be administered in stage IA uterine cancer with only PPC as a prognostic factor, it should be considered for early-stage patients who have multiple risk factors for recurrence.

We previously identified suppressyn (SUPYN), a placental protein that negatively regulates the cell fusion essential for trophoblast syncytialization via binding to the trophoblast receptor for syncytin-1, ASCT2, and hypothesized that SUPYN may thereby regulate cell-cell fusion in the placenta. Here, we redefine in vivo SUPYN localization using specific monoclonal antibodies in a rare early placental sample, showing SUPYN localization in villous and extravillous trophoblast subtypes, the decidua and even in placental debris in the maternal vasculature. In human trophoblast cell lines, we show SUPYN alters ASCT2 glycosylation within the secretory pathway and that this binding is associated with inhibition of cell fusion. Using newly-optimized trophoblast isolation protocols that allow tracking of ex vivo cell fusion, we present transcription and translation dynamics of fusion-related proteins over 96 hours in culture and the effects of changes in ambient oxygen levels on these processes. We report converse syncytin-1 and SUPYN transcriptional and translational responses to surrounding oxygen concentrations that suggest both are important in the effects of hypoxia and hyperoxia on placental syncytialization. Our results suggest that SUPYN’s anti-fusogenic properties may be exerted at several sites in the maternal body and its dysregulation may be associated with diseases of abnormal placentation.

The second edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine cervical cancer was published in 2011. The guidelines comprise eight chapters and five algorithms. They were prepared by consensus among the members of the Japan Society of Gynecologic Oncology Guidelines Formulation Committee and Evaluation Committee and are based on a careful review of the evidence obtained from the literature, health insurance system, and actual clinical settings in Japan. The highlights of the 2011 revision are (1) the recommended grades have been changed to five stages—A, B, C1, C2, and D; (2) the revisions are consistent with the new International Federation of Gynecology and Obstetrics staging system; (3) the roles are shared between the ‘Japanese classification of cervical cancer’ and the new guidelines; (4) clinical questions related to adenocarcinoma have been revised; and (5) a clinical question regarding cervical cancer in pregnant patients has been added. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. Each recommendation is accompanied by a classification of recommendation categories. The objective of these guidelines is to update the standard treatment strategies for cervical cancer, thus eliminating unnecessary and insufficient treatment.

Background: The optimal timing of cytoreductive surgery for advanced high-grade serous carcinoma (HGSC) remains a critical unmet question in the modern era of platinum-based chemotherapy and PARP inhibitor (PARPi) maintenance. To address this gap, we compared outcomes following primary debulking surgery (PDS) versus interval debulking surgery (IDS) in a uniformly treated, contemporary cohort. Methods: Patients with FIGO stage IIIB–IVB HGSC treated between 2019 and 2023 were retrospectively analyzed. Baseline tumor burden was assessed using detailed radiologic and laparoscopic evaluations, including both presurgical and intraoperative assessments. Progression-free survival (PFS) and overall survival (OS) were examined using multivariable Cox proportional hazards models and reported as adjusted hazard ratios (aHRs). Subgroup analyses were rigorously conducted according to residual disease status and BRCA mutation status. Results: Among 221 patients (PDS, n = 60; IDS, n = 151), the median follow-up was 40 months. In the overall cohort, adjusted PFS and OS did not differ significantly between the PDS and IDS groups (PFS: aHR, 1.15; 95%CI, 0.67–1.98; OS: aHR, 1.24; 95%CI, 0.54–2.83). Outcomes were comparable among patients achieving R0 resection. Notably, BRCA-mutated patients demonstrated a substantial survival advantage with PDS (BRCA-mutated PFS: aHR, 3.34; 95%CI, 1.06–16.67; OS: aHR, 6.07; 95%CI, 2.13–∞), whereas BRCA wild-type patients showed no significant difference between surgical strategies. Conclusions: The findings suggest that BRCA-mutated patients may derive a survival benefit from PDS, whereas surgical timing had a limited impact on BRCA wild-type disease. This result underscores the importance of integrating molecular profiling, particularly BRCA mutation status, with surgical assessment to guide optimal and personalized treatment strategies in the PARPi era.

PurposeFractures are known to shorten life expectancy and worsen the quality of life. The risk of fractures after radiation therapy in cervical cancer patients is known to be multifactorial. In this study, we examined risk factors for fractures in cervical cancer patients, especially by evaluating bone densities and DVH parameters for fractured bones.Materials and MethodsFor 42 patients, clinical characteristics, pretreatment CT bone densities, and radiation dose were compared between patients with and without fractures.ResultsPosttreatment fractures occurred in 25 bones among ten patients. Pretreatment CT bone densities were significantly lower in patients with fractures (P < 0.05–0.01 across sites, except for the ilium and the ischium). Although DVH parameters were also significantly associated with fractures in univariate analysis, only CT densities were significantly associated with fractures in multivariate analysis.ConclusionPretreatment CT densities of spinal and pelvic bones, which may reflect osteoporosis, have a significant impact on the risk for posttreatment fractures.

Purpose To investigate the relationship between the microbiome of the female genital tract and endometriosis. Methods This prospective cohort study included 36 women who underwent laparoscopic surgery for ovarian tumor from July 2019 to April 2020. Of them, 18 had endometriosis, and 18 did not have endometriosis. Vaginal secretions, endometrial fluid, peritoneal fluid, and ovarian cystic fluid were collected during surgery. Next‐generation sequencing of bacterial 16S rRNA was performed to characterize the microbiome. Results Specific microbiomes were not detected in either peritoneal fluid or ovarian cystic fluid regardless of the presence or absence of endometriosis and the type of cyst. When the cutoff value of infectious bacterial abundance in the vagina was set as 64.3%, there were many cases more than a cutoff value in the endometriosis group significantly (p = 0.01). When the cutoff value of infectious bacterial abundance in the endometrium was set as 18.6%, there were many cases more than a cutoff level in the endometriosis cases significantly (p = 0.02). Conclusion Peritoneal fluid and ovarian cystic fluid are almost sterile, although dysbiosis may occur in the vaginal and endometrial microbiome in women with endometriosis.