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Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models., Methods: Human ovarian cancer cells were treated with WNT974 in vitro . RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and β-TCR repertoire analysis were used to determine the immune response., Results: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8 + T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4 + and CD8 + T cells. Treatment also decreased the expression of inhibitory receptors on CD8 + T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire., Conclusions: These findings suggest that inhibiting the Wnt/β-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel., Competing Interests: Conflict of interest statement: JJL is a consultant to and receives clinical trial research support from Novartis. The remaining authors declare no potential conflicts of interest., (© The Author(s), 2020.)

Ovarian cancer is the deadliest gynecologic malignancy, and relapse after initial treatment is frequently fatal. Although ovarian cancer typically has an immunosuppressive tumor microenvironment, a strong intratumoral T cell presence is associated with an improved response to chemotherapy and better overall prognosis. Given the success of checkpoint inhibitors in the treatment of other malignancies, there has been an attempt to replicate these results in ovarian cancer clinical trials. Preclincal studies in ovarian cancer have also been conducted over the past decade, and most of the focus has been on the use of programmed cell death protein 1 (PD-1). Several other checkpoint inhibitors have also been investigated in various combinations with chemotherapy, oncolytic vaccines, co-stimulatory molecules, poly ADP ribose polymerase (PARP) inhibitors, and other checkpoint inhibitors. Unfortunately, these successes have yet to translate to the clinical realm. Whether this is because the drug class is truly ineffective in ovarian cancer, or simply because the research is lacking is unclear. Either way, it is evident that preclinical data on the use of checkpoint inhibitors is woefully deficient in ovarian cancer and more research is urgently needed to inform the translation of immune checkpoint blockade into successful clinical use. In this review, we discuss the results from preclinical studies using checkpoint inhibitors to treat ovarian cancer, with a focus on strategies that show potential for clinical use.

A recent survey of fellowship program directors (PD) within gynecologic oncology (GO) noted concerns regarding the abilities of incoming fellows. The objective of this study was to evaluate the perceptions of current and former fellows in gynecologic oncology of their readiness for fellowship training. A previously used survey was modified and distributed in 2016 to current and former fellows in GO. The survey explored domains of independent practice, psychomotor ability, clinical evaluation and scholarship. A standard Likert scale was employed and domains/responses were tailored to the subspecialty. A total of 150 current and recently former fellows responded to the survey, for a response rate of 38.7%. Nearly 70% of respondents reported being able to independently perform a hysterectomy when starting fellowship, and nearly 50% felt they could perform lysis of adhesions either without assistance. Although nearly 95% reported having had the opportunity to develop a plan of action for patients on labor and delivery, only 40.7% felt able to independently manage postoperative complications without assistance. Common themes that emerged in the open-ended responses pertained to self-perception of inadequate surgical skills and knowledge specific to gynecologic oncology. Although the majority of current and former fellows in gynecologic oncology report feeling prepared for fellowship, themes noted in the open-ended responses suggest a lack of confidence in surgical skills and clinical knowledge.

The objective of this study was to investigate the relationship of insulin-like growth factor 2 (IGF2) expression and survival in women with uterine carcinosarcoma (UCS). Insulin-like growth factor 2 protein expression was determined by immunohistochemical staining of tumor tissues from 103 patients with UCS. The H-score (product of staining intensity and percentage positive cells) was quantified for the epithelial cytoplasmic (EC), epithelial nuclear (EN), and malignant stromal compartments. Multivariable Cox proportional hazard regression models were used to examine the relationship of IGF2 levels with progression-free survival (PFS) and overall survival (OS). Adjusting for stage, race, and adjuvant therapy, PFS and OS were reduced in patients with high IGF2 (H-score ≥ median) in the EC and EN compartments. Black race was independently associated with reduced PFS and OS in patients with early-stage disease, and IGF2 levels in the EC were higher in black than in white patients (P = 0.02, Wilcoxon test). In a race-stratified multivariable analysis, high IGF2 in the epithelial compartments more than doubled the risk of death in black women; HR = 2.43 (95% CI: 1.18-5.01, P = 0.02) for high IGF2 in the EC; and HR = 2.34 (95% CI: 1.25-4.39, P = 0.008) for high IGF2 in the EN. In conclusion, high tumor IGF2 expression is an independent risk factor for reduced PFS and OS in UCS. Black women have elevated tumor IGF2 compared with white women, and decreased survival associated with high IGF2. These findings identify IGF2 as a candidate biomarker for survival linked to racial disparity in women with UCS., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Residency training in obstetrics and gynecology is being challenged by increasingly stringent regulations and decreased operative experience. We sought to determine the perception of preparedness of incoming gynecologic oncology fellows for advanced surgical training in gynecologic oncology. An online survey was sent to gynecologic oncologists involved in fellowship training in the United States. They were asked to evaluate their most recent incoming clinical fellows in the domains of professionalism, level of independence/graduated responsibility, psychomotor ability, clinical evaluation and management, and academia and scholarship using a standard Likert-style scale. The response rate among attending physicians was 40% (n = 105/260) and 61% (n = 28/46) for program directors. Of those who participated, 49% reported that their incoming fellows could not independently perform a hysterectomy, 59% reported that they could not independently perform 30 min of a major procedure, 40% reported that they could not control bleeding, 40% reported that they could not recognize anatomy and tissue planes, and 58% reported that they could not dissect tissue planes. Fellows lacked an understanding of pathophysiology, treatment recommendations, and the ability to identify and treat critically ill patients. In the academic domain, respondents agreed that fellows were deficient in the areas of protocol design (54%), statistical analysis (54%), and manuscript writing (65%). These results suggest that general Ob/Gyn residency is ineffective in preparing fellows for advanced training in gynecologic oncology and should prompt a revision of the goals and objectives of resident education to correct these deficiencies.

Oxidative damage to DNA constitutes a major threat to the faithful replication of DNA in all organisms and it is therefore important to understand the various mechanisms that are responsible for repair of such damage and the consequences of unrepaired damage. In these experiments, we make use of a reporter system in Saccharomyces cerevisiae that can measure the specific increase of each type of base pair mutation by measuring reversion to a Trp+ phenotype. We demonstrate that increased oxidative damage due to the absence of the superoxide dismutase gene, SOD1, increases all types of base pair mutations and that mismatch repair (MMR) reduces some, but not all, types of mutations. By analyzing various strains that can revert only via a specific CG→AT transversion in backgrounds deficient in Ogg1 (encoding an 8-oxoG glycosylase), we can study mutagenesis due to a known 8-oxoG base. We show as expected that MMR helps prevent mutagenesis due to this damaged base and that Pol η is important for its accurate replication. In addition we find that its accurate replication is facilitated by template switching, as loss of either RAD5 or MMS2 leads to a significant decrease in accurate replication. We observe that these ogg1 strains accumulate revertants during prolonged incubation on plates, in a process most likely due to retromutagenesis.