Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer.

The DNA damage response (DDR) results in activation of a series of key target kinases that respond to different DNA damage insults. DDR inhibitors such as PARP inhibitors lead to the accumulation of DNA damage in tumor cells and ultimately apoptosis. However, responses to DDRi monotherapy in the clinic are not durable and resistance ultimately develops. DDRi-DDRi combinations such as PARPi-ATRi, PAPRi-WEE1i and PARPi-AsiDNA can overcome multiple resistance mechanisms to PARP inhibition. In addition, DDRi-DDRi combinations can provide viable treatment options for patients with platinum-resistant disease. In the present chapter we discuss rationale of DDRi-DDRi strategies that capitalize on genomic alterations found in ovarian cancer and other solid tumors and may provide in the near future new treatment options for these patients.

Controversies in the Staging of Patients with Locally Advanced Cervical Cancer.

Approximately 10-25% of patients with locally advanced cervical cancer harbor metastases to the para-aortic lymph nodes. Staging of patients with locally advanced cervical cancer can be performed with imaging techniques, such as PET-CT; however, false negative rates can be as high as 20%, especially for patients with pelvic lymph node metastases. Surgical staging can identify patients with microscopic lymph nodes metastases and aid in accurate treatment planning with the administration of extended-field radiation therapy. Data from retrospective studies investigating the impact of para-aortic lymphadenectomy on the oncological outcomes of patients with locally advanced cervical cancer are mixed, while data from randomized controlled trials do not demonstrate a progression-free survival benefit. In the present review, we explore controversies in the staging of patients with locally advanced cervical cancer and summarize the available literature.

Safety and tolerance of radical hysterectomy for cervical cancer in the elderly.

BACKGROUND: Despite institutional studies that suggest that radical hysterectomy for cervical cancer is well tolerated in the elderly, little population-level data are available on the procedure's outcomes in older women. We performed a population-based analysis to determine the morbidity, mortality, and resource utilization of radical hysterectomy in elderly women with cervical cancer. METHODS: Patients recorded in the Nationwide Inpatient Sample with invasive cervical cancer who underwent abdominal radical hysterectomy between 1998 and 2010 were analyzed. Patients were stratified by age: <50, 50-59, 60-69, and ≥70 years. We examined the association between age and the outcomes of interest using chi square tests and multivariable generalized estimating equations. RESULTS: A total of 8199 women were identified, including 768 (9.4%) women age 60-69 and 462 (5.6%) women ≥70 years of age. All cause morbidity increased from 22.1% in women <50, to 24.7% in those 50-59 years, 31.4% in patients 60-69 years and 34.9% in women >70years of age (P<0.0001). Compared to women<50, those >70 were more likely to have intraoperative complications (4.8% vs. 9.1%, P=0.0003), surgical site complications (10.9% vs. 17.5%, P<0.0001), and medical complications (9.9% vs. 19.5%, P<0.0001). The risk of non-routine discharge (to a nursing facility) was 0.5% in women <50 vs. 12.3% in women ≥70 (P<0.0001). Perioperative mortality women ≥70 years of age was 30 times greater than that of women <50 (P<0.0001). CONCLUSION: Perioperative morbidity and mortality are substantially greater in elderly women who undergo radical hysterectomy for cervical cancer. Non-surgical treatments should be considered in these patients.

Carcinosarcoma of the ovary: natural history, patterns of treatment, and outcome.

OBJECTIVE: Ovarian carcinosarcomas (OCS) are rare tumors composed of both malignant epithelial and mesenchymal elements. We compared the natural history and outcomes of OCS to serous carcinoma of the ovary. METHODS: Patients with OCS and serous carcinomas registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2007 were analyzed. Demographic and clinical characteristics were compared using chi square tests while survival was analyzed using Cox proportional hazards models and the Kaplan-Meier method. RESULTS: A total of 27,737 women, including 1763 (6.4%) with OCS and 25,974 (93.6%) with serous carcinomas, were identified. Patients with carcinosarcomas tended to be older and have unstaged tumors (P<0.0001). After adjusting for other prognostic factors, women with carcinosarcomas were 72% more likely to die from their tumors (HR=1.72; 95% CI, 1.52-1.96). Five-year survival for stage I carcinosarcomas was 65.2% (95% CI, 58.0-71.4%) vs. 80.6% (95% CI, 78.9-82.2%) for serous tumors. Similarly, five-year survival for stage IIIC patients was 18.2% (95% CI, 14.5-22.4%) for carcinosarcomas compared to 33.3% (95% 32.1-34.5%) for serous carcinomas. CONCLUSIONS: Ovarian carcinosarcomas are aggressive tumors with a natural history that is distinct from serous cancers. The survival for both early and late stage carcinosarcoma is inferior to serous tumors.

Validation of automated monitoring of cardiac output for biventricular pacing optimization.

Biventricular pacing (BiVP) can increase cardiac output (CO) during acute failure of the left ventricle (LV) after cardiac surgery. This CO benefit is maximized by adjustment of atrioventricular (AVD) and interventricular (VVD) pacing delays. Real-time CO calculation could facilitate this optimization. Accordingly, we compared real-time automated analysis (AA) of CO with manual analysis (MA) in an animal model of pressure overload of the right ventricle (RV). In six anesthetized pigs, pacing leads were placed on the right atrium, RV, and LV. Complete heart block was induced with ethanol injection, and RV systolic pressure was doubled with a pulmonary artery snare. Atrioventricular pacing delay was varied over seven common values and VVD over nine, in random sequence. Two LV pacing sites (LVPS) were also tested. Aortic flow velocity, measured by ultrasonic flow probe, was integrated by AA and MA to calculate CO. Interexaminer Reliability Coefficient (IRC) was determined by Analysis of Variance (ANOVA) for two 10-second runs in each animal. Cardiac output-AVD and CO-VVD relations were similar for AA and MA. Interexaminer Reliability Coefficients were 0.997 and 0.994 for MA vs. AA. Automated analysis was available in real-time. Manual analysis was delayed at 2 hours or more. Automated analysis merits development for real-time optimization of intraoperative BiVP.