Treatment of node-positive endometrial cancer: chemotherapy, radiation, immunotherapy, and targeted therapy.

OPINION STATEMENT: The standard of treatment for node-positive endometrial cancer (FIGO Stage IIIC) in North America has been systemic therapy with or without additional external beam radiation therapy (RT) given as pelvic or extended field RT. However, this treatment paradigm is rapidly evolving with improvements in systemic chemotherapy, the emergence of targeted therapies, and improved molecular characterization of these tumors. The biggest question facing providers regarding management of stage IIIC endometrial cancer at this time is: what is the best management strategy to use with regard to combinations of cytotoxic chemotherapy, immunotherapy, other targeted therapeutics, and radiation that will maximize clinical benefit and minimize toxicities for the best patient outcomes? While clinicians await the results of ongoing clinical trials regarding combined immunotherapy/RT as well as management based on molecular classification, we must make decisions regarding the best treatment combinations for our patients. Based on the available literature, we are offering stage IIIC patients without measurable disease postoperatively both adjuvant chemotherapy and IMRT with carboplatin, paclitaxel, and with or without pembrolizumab/dostarlimab as primary adjuvant therapy. Patients with measurable disease post operatively, high risk histologies, or stage IV disease receive chemoimmunotherapy, and vaginal brachytherapy is added for those with uterine risk factors for vaginal recurrence. In the setting of endometrioid EC recurrence more than 6 months after treatment, patients with pelvic nodal and vaginal recurrence are offered IMRT and brachytherapy without chemotherapy. For measurable recurrence not suitable for pelvic radiation alone, chemoimmunotherapy is preferred as standard of care.

CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival.

OBJECTIVE: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy in the United States, and biomarkers of patient outcomes are limited. Data using immunohistochemical (IHC) analysis are mixed regarding whether and which tumor infiltrating lymphocytes (TILs) impact survival, and IHC does not adequately quantify rare cell populations, including CD137+ (4-1BB) tumor-reactive TILs. Our study investigates if a higher percentage of CD3+ CD137+ TILs is associated with improved overall survival (OS) in OC. METHODS: Flow cytometry was performed on viably banked OC digests. Chart review and statistical analysis were performed. Forty-seven patients were included, 40 of whom were diagnosed with high-grade serous ovarian carcinoma (HGSOC), papillary serous carcinoma, or undifferentiated histology. RESULTS: A high percentage of CD3+ CD137+ TILs correlated with improved OS (n = 40, r = 0.48, P = 0.0016). Subjects were divided into CD3+ CD137+ TIL high and low groups by the median. Subjects with high CD3+CD137+ TIL frequencies (>9.6%) had longer OS (Wilcoxon rank-sum test; P = 0.0032) and improved OS (logrank test; P = 0.007). Differences in CD3+ or CD3+ CD8+ TILs did not impact survival. CD3+ CD137+ TILs were predictive of OS regardless of germline mutation or debulking status. Analysis of subgroups including late stage HGSOC and late stage HGSOC with primary optimal cytoreduction indicated CD3+ CD137+ TILs correlated with improved OS after adjusting for age and PARP inhibitor use (P = 0.034 and P = 0.016, respectively). CONCLUSIONS: Prevalence of CD3+ CD137+ TILs in digested OC specimens is associated with improved OS, while general TIL markers are not. CD137 has the potential to be a novel biomarker for survival in OC.

In the Name of Prevention: Maternal Perspectives on School-Based HPV Vaccination in Rural Southern Chile.

PURPOSE: Since the introduction of the HPV vaccine in Chile in 2014, there have been few studies exploring community perspectives on the vaccine, specifically of parents of adolescents. This study sought to identify maternal factors and family dynamics that affect HPV vaccination behavior. PARTICIPANTS AND METHODS: Participants were recruited at an OB/GYN clinic in Linares, Chile. Participation was voluntary, and eligibility required 1) having an adolescent daughter between 9 and19 years-old and 2) demonstrating a willingness to discuss HPV-related topics. Thirty semi-structured interviews were conducted to generate qualitative data analyzed using Grounded Theory methodology. RESULTS: Three thematic constructs emerged from the interviews. Mothers' motivations to vaccinate centered on disease prevention and trust in the medical system but were influenced by notions of sexual liberalism and promiscuity. Second, participants desired, but often had trouble finding, adequate information about vaccine safety and turned to the internet. Third, joint decision making in the family about vaccination led to open family discussions about sex and sexuality. CONCLUSION: Chile's school-based opt-out HPV vaccination program engenders a unique landscape of maternal decision-making, risk-benefit analysis, information-seeking, and at-home discussion. More studies are needed around the variable role of fathers in the decision-making process.

COVID-19 in pregnancy: creating an outpatient surveillance model in a public hospital system.

Objectives We describe a standardized, scalable outpatient surveillance model for pregnant women with COVID-19 with several objectives: (1) to identify and track known, presumed, and suspected COVID-positive pregnant patients both during their acute illness and after recovery, (2) to regularly assess patient symptoms and escalate care for those with worsening disease while reducing unnecessary hospital exposure for others, (3) to educate affected patients on warning symptoms, hygiene, and quarantine recommendations, and (4) to cohort patient care, isolating stable infected patients at home and later within the same physical clinic area upon their return to prenatal care. Methods Pregnant women in an urban public hospital system with presumed or confirmed COVID-19 were added to a list in our electronic medical record as they came to the attention of providers. They received a series of phone calls based on their illness severity and were periodically assessed until deemed stable. Results A total of 83 patients were followed between March 19 and May 31, 2020. Seven (8%) were asymptomatic, 62 (75%) had mild disease, 11 (13%) had severe disease, and three (4%) had critical illness. Conclusions We encourage others to develop and utilize outpatient surveillance systems to facilitate appropriate care and to optimize maternal and fetal well-being.

Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer.

Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/ß-catenin signaling and its downstream pathway, epithelial-to-mesenchymal transition (EMT), play a key role in ovarian cancer metastasis and chemoresistance. To study the clinical implications of FILIP1L in regulating the WNT/ß-catenin pathway, the expression of FILIP1L, ß-catenin, SNAIL and SLUG was analyzed by immunohistochemistry on tissue microarrays of 369 ovarian samples ranging from normal to metastatic. In addition, the results were validated in mouse model and in vitro cell culture. In the present study, we demonstrated that FILIP1L expression was inversely correlated with poor prognosis, stage and chemoresistance in ovarian cancer. Notably, low FILIP1L expression was independent negative prognostic factor with respect to overall and disease-free survival. FILIP1L inhibited peritoneal metastases in orthotopic mouse model. FILIP1L knockdown induced chemoresistance in ovarian cancer cells and this phenotype was rescued by simultaneous knockdown of FILIP1L and SLUG, an EMT activator. We also demonstrated that FILIP1L regulates ß-catenin degradation. FILIP1L co-localizes with phospho-ß-catenin and increases phospho-ß-catenin at the centrosomes, destined for proteosomal degradation. Finally, we showed that FILIP1L regulates EMT. Overall, these findings suggest that FILIP1L promotes ß-catenin degradation and suppresses EMT, thereby inhibiting metastases and chemoresistance. Our study provides the first clinical relevance of FILIP1L in human cancer, and suggests that FILIP1L may be a novel prognostic marker for chemotherapy in ovarian cancer patients. Further, the modulation of FILIP1L expression may have the potential to be a target for cancer therapy.