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Epithelial ovarian cancer is characterized by aggressive peritoneal dissemination. Neutrophils are mobilized to peritoneal cavity in some patients with ovarian cancer dissemination; however, its pathological significance remains unknown. This study aimed to investigate the role of neutrophil extracellular traps (NETs) in ovarian cancer dissemination. We conducted a retrospective analysis of clinical data and samples from 340 patients with ovarian cancer who underwent primary surgery between 2007 and 2016 at the Osaka University Hospital. In vitro, NETs formation was induced by stimulating human peripheral neutrophils. The human ovarian cancer cell line, OVCAR8, was cocultured with NETs. For an ovarian cancer dissemination mouse model, we performed an intraperitoneal injection of OVCAR8 cells into nude mice. The association between NETs and peritoneal dissemination was explored, and model mice were treated with the PAD4 inhibitor GSK484 to assess antitumor efficacy. Neutrophilia (neutrophil count >7000/mm3) correlated with shorter survival, advanced peritoneal dissemination, elevated granulocyte colony-stimulating factor (G-CSF) levels, increased neutrophil count in ascites, and augmented NETs foci in peritoneal dissemination sites. In vitro assays revealed that G-CSF stimulated neutrophils to form NETs, promoting cancer cell adhesion. In vivo investigations revealed that G-CSF–producing tumor-bearing mice had accelerated peritoneal dissemination and poor prognosis. NETs formation was pathologically observed at the peritoneal dissemination sites. Inhibition of NETs formation by GSK484 significantly delayed peritoneal dissemination in vivo. In conclusion, G-CSF was associated with intra-abdominal NETs formation and increased peritoneal dissemination. NETs represent potential therapeutic targets for ovarian cancer, particularly in patients with neutrophilia. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical cancer is the most common frequent gynecological malignancy. The incidence has decreased owing to screening programs and human papillomavirus vaccination; however, the incidence of adenocarcinoma has recently increased in some countries, especially in the young population. Adenocarcinoma treated with definitive radiotherapy, the recommended approach for treating locally advanced cervical cancer, has a lower response and survival rate than squamous cell carcinoma. Our study aimed to assess the response to definitive radiotherapy by histological subtype and to investigate prognostic factors of adenocarcinoma according to the uniform staging system and histological classification. We confirmed that 52 patients with adenocarcinoma responded significantly less to definitive radiotherapy and had shorter survival times than 275 patients with squamous cell carcinoma. In the adenocarcinoma population, univariate and multivariate analyses showed that gastric-type adenocarcinoma was an independent poor prognostic factor associated with response to definitive radiotherapy. The pathogenesis of gastric-type adenocarcinoma must be investigated to overcome its poor response to treatment and establish novel therapeutic strategies for it. We aimed to evaluate the response to definitive radiotherapy (RT) for cervical cancer based on histological subtypes and investigate prognostic factors in adenocarcinoma (AC). Of the 396 patients treated with definitive RT between January, 2010 and July, 2020, 327 patients met the inclusion criteria, including 275 with squamous cell carcinoma (SCC) and 52 with AC restaged based on the 2018 International Federation of Gynecology and Obstetrics staging system. Patient characteristics, response to RT, and prognoses of SCC and AC were evaluated. The complete response (CR) rates were 92.4% and 53.8% for SCC and AC, respectively (p < 0.05). Three-year overall survival and progression-free survival (PFS) rates of SCC were significantly higher than those of AC (88.6% vs. 74.1%, p < 0.05 and 76.3% vs. 59.3%, p < 0.05, respectively). Among the AC population, univariate and multivariate analyses were performed to examine prognostic factors associated with non-complete response (CR). In the multivariate analysis, gastric-type adenocarcinoma (GAS) was associated with non-CR in AC (adjusted odds ratio, 12.2; 95% confidence interval 1.0–145.6; p < 0.05). The 3-year PFS rate in patients with GAS was significantly lower than that in patients with other histological types of AC (44.4% vs. 66.7%, p < 0.05). Definitive RT for cervical cancer was significantly less effective for AC than for SCC. GAS was the only independent prognostic factor associated with non-CR in AC. [ABSTRACT FROM AUTHOR]

Ovarian clear cell carcinoma (OCCC), particularly advanced or recurrent settings, is generally resistant to platinum-based chemotherapy, warranting novel therapeutic strategies. Mutations in the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin kinase (PI3K/AKT/mTOR) pathway are frequently reported in OCCC. Therefore, we hypothesized that the PI3K/mTOR dual inhibitor, GSK458, and arsenic trioxide may exert synergistic anti-tumor effects on OCCC. We investigated the effects of GSK458, arsenic trioxide, and the combination of GSK458 and arsenic trioxide on cell viability, colony formation, and apoptosis in seven OCCC cells. Mechanistically, transcriptomic differences were assessed among the groups. Additionally, their anti-tumor effects were evaluated on the three-dimensional cultures of OCCC patient-derived xenografts as well as in vivo. Low-dose combination of GSK458 and arsenic trioxide exerted synergistic anti-tumor effects in vitro. Viability of the three-dimensional OCCC patient-derived xenograft cultures treated with the combination of GSK458 and arsenic trioxide decreased to 23.8% of that of the control. RNA sequencing revealed that the mechanism was associated with cell cycle and DNA damage repair. The combination of GSK458 and arsenic trioxide synergistically inhibited the PI3K/AKT/mTOR pathway and angiogenesis and increased apoptosis. Compared to any monotherapy, the combination treatment significantly suppressed tumor growth in vivo, thereby enhancing survival. Overall, our findings highlight the potential of the novel combination of GSK458 and arsenic trioxide combination for OCCC treatment.

Aim: The aim of this study was to retrospectively analyze the efficacies of uterine artery embolization (UAE) using gelatin sponge for symptomatic uterine fibroids., Methods: A series of 60 consecutive premenopausal women underwent UAE using gelatin sponge particles or porous gelatin particles. Patients were routinely followed up at 1, 3, 6, and 12 months after the procedure and asked to report any procedure-related complications. At each follow-up, an original clinical questionnaire was completed by the patients to evaluate changes in fibroid-related symptoms. Pelvic magnetic resonance imaging was performed before and at 3 and 12 months after the procedure, and the changes in volume of the dominant fibroid were calculated., Results: Bilateral UAE was successfully performed in all the patients. Median age was 45 years (range 34-53 years), and median follow-up period was 25.2 months (range 1-116 months). At the 3- and 12-month follow-up, the dominant fibroid volumes were found to be significantly decreased by 33.4% (95% confidence interval [CI]: 24.9-41.1) and 48.4% (95% CI: 40.7-56.1) compared to baseline volumes, respectively. Excluding patients not having menorrhagia or bulk-related symptoms, at 12 months 49 of 50 (98%) women showed improvement in menorrhagia, and 45 of 47 (95.7%) women showed improvement in bulk-related symptoms. During the follow-up period, ten patients (16.7%) required further interventions including two patients who had undergone hysterectomy. No sequelae were experienced by any of the patients., Conclusion: UAE using gelatin sponge was associated with a high clinical success rate and good fibroid volume reduction compared to UAE using other embolic agents.