Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

Practice patterns using minimally invasive surgery for the treatment of ovarian cancer: A survey of physician members of the Society of Gynecologic Oncologists.

Retrospective studies suggest that minimally-invasive surgery may be safe and effective for the treatment of early-stage ovarian cancer as well as interval cytoreduction after neoadjuvant chemotherapy. Adoption rates and attitudes towards its use remain largely unknown. We aimed to determine the current use of minimally-invasive surgery for the treatment of ovarian cancer and identify perceived barriers towards further adoption of this method. Electronic survey was administered to physician members of the Society of Gynecologic Oncology. Chi-square analysis was used to determine if any correlation existed between variables and the current use of minimally invasive surgery in general practice and, specifically, for the treatment of ovarian cancer. There was a survey response rate of 15.1%. Sixty-five percent of respondents practiced in an academic setting, and 32.1% of respondents had completed fellowship training within the past 5 years. Ninety percent of respondents were performing >50% of their current procedures using minimally invasive surgery. Over seventy percent of respondents said that they performed minimally invasive surgery for primary staging and interval cytoreductive surgery for the treatment of ovarian cancer. Concern for residual disease and lack of scientific validation were the most frequently cited barriers to the implementation of minimally invasive surgery for the treatment of ovarian cancer. A majority of respondents have adopted the use of MIS for the management of early stage ovarian cancer. Advances in imaging to detect occult tumor deposits and a randomized trial to study and promote the use of minimally invasive surgery in ovarian cancer is warranted.

Non-indicated use of prophylactic antibiotics in gynaecological surgery at an academic tertiary medical centre.

Surgical site infections (SSI) are the most common surgical complication. Perioperative antibiotics can reduce SSI when used properly. Despite guidelines from The American College of Obstetrics and Gynecology, non-indicated antibiotic use is widespread which exposes women to unnecessary risks. This study represents a quality improvement analysis assessing surgeon compliance with established guidelines regarding antibiotic use in gynaecological surgery. This is a single centre, retrospective study examining gynaecological procedures over two years. Cases were identified using Current Procedure Terminology codes. Perioperative antibiotics were used contrary to published guidelines in 199 of 1046 cases. Three variables were independently associated with inappropriate administration of perioperative antibiotics: entrance into abdominal cavity, higher EBL, and longer procedures. Impact statement Overuse of antibiotics has unintended consequences including allergic sequelae, extended length of hospital stay, increased healthcare costs, and the formation of antibiotic-resistant organisms. Antibiotic stewardship programmes have been shown to reduce the number of resistant pathogens, decrease incidence of Clostridium difficile colitis, and decrease length of hospital stay without increasing infection rates. Further outcomes-based research is needed regarding the use of antibiotic stewardship programmes in gynaecological surgery.

Uterine Clostridium perfringens infection related to gynecologic malignancy.

Uterine gas gangrene caused by Clostridium perfringens is a serious, often life-threatening infection that is rarely encountered in the practice of gynecologic oncology. However, the hypoxic nature of gynecologic cancers due to necrosis and/or prior radiation therapy creates a microenvironment optimal for proliferation of anaerobic bacteria such as the Clostridium species. Early recognition and aggressive treatment with IV antibiotics and surgical debridement remain the cornerstones of management in order to decrease morbidity and mortality. Here we present the case of a 52 year-old woman with a remote history of cervical cancer who was previously treated at our institution with primary chemotherapy and radiation and was then admitted decades later with Clostridium perfringens bacteremia and CT evidence of intrauterine abscess. The patient received a prolonged course of IV antibiotic therapy and subsequently underwent definitive surgical management with a total abdominal hysterectomy, bilateral salpingo-oophorectomy, small bowel resection with anastomosis for a utero-ileal fistula identified intraoperatively. Pathology from the uterine specimen demonstrated a primary poorly differentiated uterine adenocarcinoma. The patient recovered fully from her Clostridium perfringens infection and was discharged from the hospital shortly after surgical intervention.