Validation of the Safety and Efficacy of Apixaban as Postoperative Thromboembolism Prophylaxis for Patients with Gynecologic Malignancies.

BACKGROUND: Venous thromboembolism is a preventable complication of gynecologic cancer surgery that leads to postoperative morbidity and mortality. This study compared apixaban with enoxaparin to identify whether apixaban had the same safety and efficacy for patients undergoing gynecologic cancer surgery. METHODS: The study identified patients with a gynecologic malignancy who underwent surgery and were prescribed apixaban at discharge between June 2020 and April 2023. International Classification of Diseases 10 codes were used to identify patients who had a thromboembolism within 90 days or a bleeding event within 60 days after surgery. The rates of events for patients prescribed apixaban were compared with those for a historical cohort of patients who received enoxaparin. Fisher's exact tests were used to compare categorical variables, and t tests were used to compare continuous variables. A logistic regression was performed to compare the odds of thromboembolism between the two groups. RESULTS: Baseline patient characteristics differed in terms of body mass index (BMI), race, route of surgery, and type of cancer. Of the 490 patients in the apixaban cohort, 12 (2.4%) had a thromboembolism compared with 3 (2.1%) of the 138 patients in the enoxaparin group (adjusted odds ratio [aOR], 1.02; 95% confidence interval [CI] 0.30-4.70; p > 0.999). The odds ratio was adjusted for BMI, age, and route of surgery. A bleeding event occurred for 1 (0.2%) of the 490 patients in the apixaban group and for 1 (0.7%) of the 138 patients in the enoxaparin group. CONCLUSIONS: This validation study showed that apixaban is a safe and effective method of postoperative venous thromboembolism prophylaxis. The data provide support to previous data and guideline updates recommending the use of apixaban for postoperative prophylaxis.

Polycomb Repressor Complex 1 (PRC1) in ovarian cancer: A scoping literature review.

High grade serous carcinoma (HGSC) is the most common and the deadliest histologic subtype of epithelial ovarian cancer. HGSC is a therapeutic challenge, as it recurs in 80 % of patients diagnosed, often as chemoresistant disease. The mechanism of this chemoresistance is not fully elucidated, but it is partly attributed to the ability of HGSC to maintain a stem-like phenotype that enables development of resistance to current therapies. Polycomb Repressor Complexes 1 and 2 (PRC1/2) have been implicated in the maintenance of the stem cell compartment through silencing tumor suppressor genes and regulating stem cells. These complexes are comprised of multiple polycomb group (PcG) proteins that play a role in normal development, and when deregulated contribute to the development of cancer [2]. Proteins included in PRC1 include B lymphoma mouse Moloney leukemia virus insertion region (BMI1), RING1, and chromobox (CBX) proteins. We aimed to review each of the protein components of PRC1 and their mechanistic relationships to promoting chemoresistant recurrences and propagation of ovarian cancer. Where possible, we reviewed therapeutic investigations of these proteins. We utilized a scoping literature review through Covidence to identify 42 articles meeting criteria for inclusion. The authors identified four relevant articles and the Yale MeSH Analysis Grid Generator was used to establish additional keywords and heading terms. A medical librarian used these terms and articles to draft an initial search strategy within each of the following databases: MEDLINE, Embase, Cochrane Library, and Web of Science Core Collection, yielding 439 articles based on title and abstract. Abstracts were independently reviewed by the authors, identifying 77 articles for full text review, of which 35 were ultimately excluded, leaving 42 articles for full review. Our review identified the currently known mechanisms of the subunits of PRC1 that contribute to HGSC development, recurrence, and chemoresistance. By compiling a comprehensive review of available scientific knowledge, we support and direct further investigation into PRC1 that can affect meaningful advances in the treatment of HGSC.

Efficacy of Community-Delivered PEERS® for Adolescents: Increases in Social Skills and Decreases in Social Anxiety and Loneliness.

PURPOSE: PEERS® for Adolescents is an evidence-based social skills training program developed for individuals with autism spectrum disorder (ASD), which is now widely implemented by community providers in clinics and schools. However, majority of past efficacy studies on PEERS® were conducted in controlled research settings, with limited information about its effectiveness when delivered in the community. We sought to examine the effects of PEERS® on social functioning and mental health outcomes when delivered in an outpatient autism specialty clinic. METHODS: Clinical data from 45 adolescents with social challenges (age range: 11-18 years old; 31.1% female assigned at birth) were extracted for secondary analyses. Paired t-tests were performed to examine the pre- to post-intervention changes in social and mental health outcomes. Correlations between pre- and post-change scores of outcome measures were examined. RESULTS: Self-reported social skills knowledge, caregiver-reported social skills (measured by the Social Skills Improvement Systems) and the number of get-togethers hosted, increased significantly from pre- to post-intervention. Additionally, caregiver-reported anxiety and self-reported loneliness significantly decreased from pre- to post-intervention. Exploratory analyses showed that increases in caregiver-reported social skills were associated with decreases in self-reported loneliness. CONCLUSIONS: Our findings provide evidence supporting the efficacy of PEERS® for improving social knowledge and skills of adolescents with social challenges when delivered in the community. The current study also showed the potential benefit of PEERS® for improving adolescent mental health.

Targeting Tryptophan Catabolism in Ovarian Cancer to Attenuate Macrophage Infiltration and PD-L1 Expression.

High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME. SIGNIFICANCE: Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum. In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone.