Th17 cells target the metabolic miR-142-5p-succinate dehydrogenase subunit C/D (SDHC/SDHD) axis, promoting invasiveness and progression of cervical cancers.

During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse; however, the underlying Th17-driven mechanisms are not fully understood. Here, using microarrays, we found that Th17 cells induced an epithelial-to-mesenchymal transition (EMT) phenotype of cervical cancer cells and promoted migration and invasion of 2D cultures and 3D spheroids via induction of microRNA miR-142-5p. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR-142-5p and provided evidence that Th17-miR-142-5p-dependent reduced expression of SDHC and SDHD mediated enhanced migration and invasion of cancer cells using small interfering RNAs (siRNAs) for SDHC and SDHD, and miR-142-5p inhibitors. Consistently, patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patient biopsies correlated with increased numbers of Th17 cells. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4+ T cells > 43.90% in situ was associated with reduced recurrence-free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.

Chemoradiotherapy-induced increase in Th17 cell frequency in cervical cancer patients is associated with therapy resistance and early relapse.

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post-therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer.

Urogynecology in obstetrics: impact of pregnancy and delivery on pelvic floor disorders, a prospective longitudinal observational pilot study.

PURPOSE: To assess changes in the pelvic floor anatomy that cause pelvic floor disorders (PFDs) in primigravidae during and after pregnancy and to evaluate their impact on women's quality of life (QoL). METHODS: POP-Q and translabial ultrasound examination was performed in the third trimester and 3 months after delivery in a cohort of primigravidae with singleton pregnancy delivering in a tertiary center. Results were analyzed regarding mode of delivery and other pre- and peripartal factors. Two individualized detailed questionnaires were distributed at 3 months and at 12 months after childbirth to determinate QoL. RESULTS: We recruited 45 women, of whom 17 delivered vaginally (VD), 11 received a vacuum extraction delivery (VE) and 17 a Cesarean section in labor (CS). When comparing third-trimester sonography to 3 months after delivery, bladder neck mobility increased significantly in each delivery group and hiatal area increased significantly in the VD group. A LAM avulsion was found in two women after VE. Connective tissue weakness (p = 0.0483) and fetal weight at birth (p = 0.0384) were identified as significant risk factors for the occurrence of PFDs in a multivariant regression analysis. Urinary incontinence was most common with 15% and 11% of cases at 3, respectively, 12 months after delivery. 42% of women reported discomfort during sexual intercourse, 3 months after delivery and 24% 12 months postpartum. Although 93% of women engage a midwife after delivery, only 56% participated in pelvic floor muscle training. CONCLUSION: Connective tissue weakness and high fetal weight at birth are important risk factors for the occurrence of PFDs. Nevertheless, more parturients should participate in postpartal care services to prevent future PFDs.

Jejunal obstruction due to rare internal hernia between skeletonized external iliac artery and vein as late complication of laparoscopic hysterectomy with pelvic lymphadenectomy-case report and review of literature.

BACKGROUND: Internal herniation of small intestine in the lesser pelvis alongside iliac vasculature is a rare occurrence. Skeletonization of iliac vessels during pelvic lymph node dissection (LND), as part of surgical staging or treatment of patients with uterine, ovarian or urogenital cancer, is a strict prerequisite for orifice formation. CASE PRESENTATION: A 68-year-old woman presented at the emergency department with complaints of constipation for the last 3 days and acute-onset abdominal pain, nausea and vomiting since few hours. She had a history of laparoscopic hysterectomy, bilateral salpingo-oophorectomy and para-aortic and pelvic LND 7 years ago. A distended abdomen with diffuse tenderness on palpation was noted. A CT scan demonstrated bowel obstruction secondary to an incarcerated hernia underneath an elongated right external iliac artery. During an emergency exploratory laparotomy, the incarcerated bowel was reduced and the hernial orifice closed with a running suture. The patient had an uneventful postoperative period and was discharged on the fifth postoperative day. DISCUSSION: This rare internal hernia can manifest with non-specific symptoms of small bowel obstruction at any given point after index surgery, sometimes even after several years free of complaints. Contrast-enhanced computed tomography is the method of choice for fast and reliable diagnosis and helps in planning the necessary emergency laparotomy. CONCLUSION: This life-threatening complication adds to the current controversy of pelvic and para-aortic lymphadenectomy in patients with endometrial cancer. Primary closure of peritoneal defects should be considered to potentially prevent internal hernias, especially when elongated iliac vessels are present.

Oncostatin M treatment increases the responsiveness toward cisplatin-based chemoradiotherapy in cervical cancer cells in a STAT3-dependent manner.

Cervical cancer stage-dependent therapies include surgery, chemotherapy, radiotherapy and chemoradiotherapy. Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard therapy for locally advanced cervical carcinoma (FIGO>IIB), however therapy resistance in a subset of patients is still a major clinical challenge. The present study aimed to analyze the impact of Oncostatin M (OSM) stimulation on CCRT-induced cell death. The present study used cells derived from cervical squamous cell carcinomas (SW756, 808, CaSki and 879) and adenocarcinoma (HeLa). The cervical carcinoma cells were HPV18-positive (HeLa, SW756, 808) or HPV16-positive (CaSki, 879). In addition to the established cell lines HeLa, SW756 and CaSki, the more recently generated cervical cancer cells 808 and 879 were also used. To analyze their radiosensitivity, cells were treated with increasing doses of irradiation (0-8 Gy). To mimic chemotherapy, radiotherapy or CCRT in vitro, the cells were challenged with 0.975 µg/ml cisplatin, irradiated with 6 Gy or a combination. A total of 10 ng/ml OSM was applied for 2 h prior to the respective therapy. The responsiveness toward radiation alone varied among the cervical carcinoma cells. CaSki, 808 and 879 cells were resistant to irradiation up to 8 Gy. OSM pre-treatment sensitized two out of five cell lines (HeLa and 879) to irradiation. Notably, all tested cells were sensitized by OSM for CCRT-treatment, particularly in the less radiosensitive cells. Cell death enhancement was dependent on phosphorylated signal transducer and activator of transcription 3 (STAT3; Tyr705) signaling activation as demonstrated with a dominant-negative version of STAT3 interfering with phosphorylation at Tyr705 (dnSTAT3-Y705F). In conclusion, OSM pre-treatment was able to override resistance to CCRT via the STAT3 signaling pathway.