The impact of race, comorbid conditions and obesity on survival endpoints in women with high grade endometrial carcinoma.

OBJECTIVE: To estimate overall survival, disease-specific survival, and progression-free survival among high grade endometrial carcinoma cases and to determine factors impacting survival for non-Hispanic white and non-Hispanic black women. METHODS: We identified high grade endometrial carcinoma cases among non-Hispanic white and non-Hispanic black women from ongoing institutional studies, and determined eligibility through medical record and pathologic review. We estimated effects of demographic and clinical variables on survival outcomes using Kaplan Meier methods and Cox proportional hazards modelling. RESULTS: Non-Hispanic Black women with BMI <25.0 had poorest overall survival compared to non-Hispanic white women with BMI <25.0 (HR 3.03; 95% CI [1.35, 6.81]), followed by non-Hispanic black women with BMI 25.0+ (HR 2.43; 95% CI [1.28, 4.60]). A similar pattern emerged for disease-specific survival. Non-Hispanic black women also had poorer progression-free survival than non-Hispanic white women (HR 1.40; 95% CI [1.01, 1.93]). Other significant factors impacting survival outcomes included receipt of National Cancer Center Network (NCCN) guideline-concordant treatment (GCT), earlier stage at diagnosis, and fewer comorbid conditions. CONCLUSIONS: BMI and race interact and modify the association with high grade endometrial carcinoma survival. Other potentially modifiable factors, such as reducing comorbidities and increasing access to GCT will potentially improve survival after diagnosis of high grade endometrial carcinomas. A better understanding of the molecular drivers of these high grade carcinomas may lead to targeted therapies that reduce morbidity and mortality associated with these aggressive tumors.

The Impact of Adjuvant Management Strategies on Outcomes in Women With Early Stage Uterine Serous Carcinoma.

Objective To determine the impact of different adjuvant strategies on outcomes in women with early-stage uterine serous carcinoma (USC). Methods Our retrospective database for women with endometrial carcinoma was queried for women with 2009 International Federation of Gynecology and Obstetrics (FIGO) stages I-II USC who underwent surgical staging between January 1991 and April 2019 followed by adjuvant management (observation, radiation therapy (RT), chemotherapy (CT), or combined modality treatment (CRT)). Chi-square tests were performed to compare differences in outcome by type of adjuvant management. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were assessed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses (MVA) were performed to identify statistically significant predictors of survival endpoints. Results We identified 171 women who met our inclusion criteria. The median follow-up time was 70.5 months. Seventy-five percent of the study cohort was FIGO stage IA, 13% were stage IB, and 12% were stage II. All women underwent pelvic lymph node dissection with a median number of dissected lymph nodes of 14. Omentectomy was performed in 64% of patients. Adjuvant RT was utilized in 56% of women (65 patients received vaginal brachytherapy alone, 10 patients received pelvic RT, and 21 patients received a combination of both). The most commonly used chemotherapy regimen was carboplatin and paclitaxel with a median number of cycles of six. A total of 44% of the cohort received CRT, 12% received RT alone, 19% received chemo alone, and 25% were observed. Five-year RFS was 73% for those who received CRT, 84% for those who received RT alone, 68% for those who received CT alone, and 55% for those who were observed (p=0.13). Five-year DSS was 81%, 94%, 71%, and 60%, respectively (p=0.02). Five-year OS was 76%, 70%, 60%, and 56%, respectively (p=0.11). On MVA of OS and DSS, a higher percentage of myometrial invasion, the presence of lower uterine segment involvement, positive peritoneal cytology, and receipt of chemotherapy alone/observation were independent predictors of worse outcomes. The sole independent predictor of worse RFS on MVA was the presence of positive peritoneal cytology. Conclusion In this cohort of women with early-stage USC who underwent surgical staging, adjuvant radiation treatment with or without chemotherapy was associated with improved survival endpoints and trended toward improved recurrence rates.

Increased risk of recurrence in early-stage endometrial carcinoma after delays in adjuvant radiation treatment.

OBJECTIVE: The benefits of adjuvant radiation treatment after hysterectomy have been confirmed in select patients with early-stage endometrial carcinoma. The goal of this study was to evaluate the prognostic impact of the time interval between hysterectomy and starting adjuvant radiation treatment in patients with early-stage endometrial carcinoma. METHODS: Our database was searched for women with early-stage endometrioid endometrial cancer who received adjuvant radiation therapy after hysterectomy. The patients were classified into two groups based on the time interval to adjuvant radiation therapy (≤8 weeks or >8 weeks) after hysterectomy. Recurrence-free survival, disease-specific survival, and overall survival were compared between the two groups. RESULTS: Four hundred and sixty patients were identified. Median follow-up was 70.5 months (range 1-360). One hundred and seventy-six patients (38%) were 2009 International Federation of Gynecology and Obstetrics stage IA, 207 (45%) stage IB, and 77 (17%) stage II. Three hundred and fifty-four women (77%) received adjuvant radiation therapy within 8 weeks after hysterectomy. There was no statistically significant difference between the two groups in baseline demographics, disease and treatment characteristics, except for the modality of adjuvant radiation therapy. Patients who received adjuvant radiation therapy within 8 weeks experienced significantly less disease recurrence (9% vs 18%; p=0.01) and particularly less isolated vaginal recurrence (0% vs 6%, p=0.04). Five-year recurrence-free survival was 89% versus 80% (p=0.04), 5-year disease-specific survival was 93% for both groups, and 5-year overall survival was 86% versus 85% for patients who received adjuvant radiation therapy ≤8 and >8 weeks, respectively (p=0.88). CONCLUSION: Our study suggests that delaying adjuvant radiation therapy beyond 8 weeks after hysterectomy is associated with significantly more cancer recurrences for women with early-stage endometrial carcinoma.

Charlson Comorbidity score influence on prostate cancer survival and radiation-related toxicity.

INTRODUCTION: In addition to survival endpoints, we explored the impact of Charlson Comorbidity-Index (CCI) on the acute and late toxicities in men with localized prostate cancer who received dose-escalated definitive radiotherapy (RT). MATERIALS AND METHODS: CCI scores at diagnosis and survival outcomes were identified for men with intermediate/high-risk prostate cancer treated with RT (1/2007-12/2012). Study-cohort was accordingly grouped into no, mild and severe comorbidity (CCI-0, 1 or 2+). CCI-groups were compared for demographics, prognostic-factors; and RT-related toxicities based on RTOG/CTCAE criteria. Kaplan-Meier curves and Uni/multivariate (MVA) analyses were used to examine the influence of CCI-group on overall (OS), disease-specific (DSS) and biochemical-relapse free (BRFS) survival. RESULTS: We included 257 patients with median age 73 years (48-85), 53% African-American and 67% had intermediate-risk. Median prostate RT-dose was 76 Gy; and 47% received androgen-deprivation therapy. CCI-0,1,2+ groups encompassed 76 (30%), 54 (21%) and 127 (49%) patients, respectively and were well-balanced. Ten and 15-years OS were significantly different (76% versus 46% versus 55% for 10-years OS and 53% versus 31% versus 14% for 15-years OS for CCI-0 versus CCI-1[HR:2.25; CI[1.31-3.87]] versus CCI-2+[HR:2.73; CI[1.73-4.31]]; p < 0.001. CCI-0 had better DSS than CCI-2+ (HR:2.23; CI[1.06-4.68]; p = 0.03) and BRFS was similar (p = 0.99). Late G2/3 RT-toxicities were more common in CCI-2+ (47%) than CCI-1 (44%) and CCI-0 (29%), p = 0.032; with non-different acute-toxicities (p = 0.62). On MVA, increased CCI was deterministic for OS (HR:3.65; CI [1.71:7.79]; p < 0.001) and was only marginal for DSS (HR:2.55; CI [0.98-6.6]; p = 0.05) with no impact on BRFS (p > 0.05). CONCLUSIONS: Higher CCI is a significant predictor for late RT-related side-effects and shorter OS in men with localized prostate cancer. Baseline comorbidities should be considered during initial counseling and follow up visits.

Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction.

BACKGROUND: Prostaglandin E2 (PGE2) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We recently reported that PGE2 via its EP3 receptor could reduce cardiac contractility of isolated myocytes and the working heart preparation. We thus hypothesized that there is an imbalance in the EP3/EP4 ratio towards EP3 in the failing heart and that overexpression of EP4 in a mouse model of heart failure would improve cardiac function. METHODS AND RESULTS: Our hypothesis was tested in a mouse model of myocardial infarction (MI) with the use of AAV9-EP4 driven by the myosin heavy chain promoter to overexpress EP4 in the cardiac myocytes. Echocardiography was performed to assess cardiac function. We found that overexpression of EP4 improved shortening fraction (p = 0.0025), ejection fraction (p = 0.0003), and reduced left ventricular dimension at systole (p = 0.0013). Overexpression of EP4 also significantly reduced indices of cardiac hypertrophy and interstitial collagen fraction. Animals treated with AAV9-EP4 also had a significant decrease in TNFα mRNA expression and in the number of macrophages and T cells migrated post MI coupled with a reduction in the expression of iNOS. CONCLUSION: Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production.