Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer.

Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10-15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT2 PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.

Cancer Stem Cell Assay for the Treatment of Platinum-Resistant Recurrent Ovarian Cancer.

BACKGROUND: Disease recurrence and progression of ovarian cancer is a common event, which is accompanied by the development of platinum-resistant or refractory disease. The presence of chemo-resistant Cancer Stem Cells (CSCs) contribute to tumor propagation, maintenance, and treatment resistance of this difficult to treat disease. We have developed ChemoID, a cytotoxic synergy assay against CSCs that identifies the most effective chemotherapy treatment from a panel of FDA-approved chemotherapies using fresh cancer biopsies. PATIENTS AND METHODS: Ascites or interventional radiology biopsies were collected under physician order from 78 consecutive patients affected by 3rd relapsed ovarian cancer. Test results from the assay were used when possible to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, if needed. A chart analysis and review of CT and PET scans were performed to determine patients' outcomes for tumor response, Progression-Free Survival (PFS), and Overall Survival (OS). RESULTS: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in their median PFS and OS when compared to historical median PFS and OS and/or when compared to patients who could not receive high cell kill chemotherapies (PFS low cell kill 3.5 months vs. high cell kill 12.0 months; OS low cell kill 6.0 months vs. high cell kill 15.0 months). CONCLUSION: This data indicates that the drug cytotoxicity assay aimed at targeting CSCs may be a useful tool for optimizing treatment selection when first-line therapy fails, and when there are multiple clinically-acceptable and -equivalent treatments available.

Simulated management of inferior vena cava injury during robotic paraaortic lymphadenectomy utilizing the porcine model.

Injury of the inferior vena cava is an infrequent but serious complication of paraaortic lymphadenectomy. Training in the management of this injury might be enhanced through animate simulation. Our objective was to assess a simulated animal model for training in intraoperative management of inferior vena cava injury in the context of robotic paraaortic lymphadenectomy. We used a female domestic pig to create an injury of the inferior vena cava, which was then managed two ways with robotically assisted surgery. Edited videos of the two models were assessed by 32 senior learners and 23 attending faculty. The assessments included key competencies and domains of fidelity. A scale of poor, fair, or good was utilized. The injury and management simulated those seen in humans, both anatomically and surgically, although deficiencies were noted. Specifically, a reduced rapidity of bleeding and a related greater ease of control contributed to lower ratings for some aspects of fidelity. Fidelity and addressing the key competency of suture repair also received some lower ratings, particularly from vascular surgeons and their trainees. The porcine model for simulation of inferior vena cava injury during robotically assisted paraaortic lymphadenectomy may be useful for training purposes.

Expression of poly-ADP-ribose polymerase (PARP) in endometrial adenocarcinoma: Prognostic potential.

BACKGROUND: In the United States endometrial carcinoma is the most common female gynecologic malignancy. An average of more than 60,000 new cases of endometrial carcinomas have been diagnosed yearly over the past 5 years, with a higher incidence occurring in the central Appalachian states of Ohio and West Virginia. In the U.S., the national average of newly diagnosed endometrial carcinomas is 26.8 in every 100,000 women, while in the states of Ohio and West Virginia the average is 30.5 and 31.1 in every 100,000 women, respectively. This notable increase in the incidence of endometrial carcinomas may be due a variety of elevated risk factors including but not limited to: tobacco use, obesity, and genetic predisposition of the predominant demographic. The American Cancer Society estimates that approximately 55,000 new cases of endometrial carcinoma will be diagnosed in 2020 yet, this disease is widely considered understudied and under-represented in mainstream cancer research circles. METHODS: The aim of this study was to quantitate the co-expression of two DNA repair proteins poly-ADP-ribose polymerase 1 and 2 (Parp-1 and Parp-2) by enzyme- linked immuno-sorbent assay (ELISA) in 60 endometrioid endometrial tumor samples and compare their expression to matched non-malignant endometrial tissue from the same corresponding donors from central Appalachia. RESULTS: We found that Parp-1 was significantly overexpressed in endometrial carcinoma relative to corresponding normal tissue. This overexpression implicates Parp inhibition therapy as a possible treatment for the disease. Our results also found a protective effect of native Parp-2 expression in non-malignant endometrial tissue with each 1 ng/mL increase in PARP-2 concentration in normal tissue was associated with a 10 % reduction in the hazard of tumor progression (HR = 0.90; p = 0.039) and a 21 % reduction in the hazard of death (HR = 0.79; p = 0.044). CONCLUSIONS: This study demonstrated the over-expression of the druggable target Parp-1 in endometrial adenocarcinoma and observed a strong negative correlation of native Parp-2 expression and disease progression via the quantification of the Parp proteins using enzyme- linked immuno-sorbent assay (ELISA) assays.

Clinical relevance of cancer stem cell chemotherapeutic assay for recurrent ovarian cancer.

INTRODUCTION: Disease recurrence and progression of ovarian cancer is common with the development of platinum-resistant or refractory disease. This is due in large part to the presence of chemo-resistant cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. We developed a CSCs drug cytotoxicity assay (ChemoID) to identify the most effective chemotherapy treatment from a panel of FDA approved chemotherapies. METHODS: Ascites and pleural fluid samples were collected under physician order from 45 consecutive patients affected by 3rd-5th relapsed ovarian cancer. Test results from the assay were used to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, as needed. A retrospective chart review of CT and PET scans was used to determine patients' outcomes for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). RESULTS: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in the median PFS corresponding to 5.4 months (3rd relapse), 3.6 months (4th relapse), and 3.9 months (5th relapse) when compared to historical data. Additionally, we observed that ovarian cancer patients identified as non-responders by the CSC drug response assay had 30 times the hazard of death compared to those women that were identified as responders with respective median survivals of 6 months vs. 13 months. We also found that ChemoID treated patients on average had an incremental cost-effectiveness ratio (ICER) between -$18,421 and $7,241 per life-year saved (LYS). CONCLUSIONS: This study demonstrated improved PFS and OS for recurrent ovarian cancer patients treated with assay-guided chemotherapies while decreasing the cost of treatment.

Primary Retroperitoneal Melanoma Presented in a Rare Extracutaneous Site for Malignant Melanoma.

Malignant melanoma, as the name implies, is a malignant tumor of melanocytes, found in the skin, eyes, meningeal lining and the mucosal epithelium of the aero-digestive and genitourinary tracts. Malignant melanoma is typically skin malignancy, which rarely presents at extracutaneous site. Here we present a rare case of primary retroperitoneal melanoma and review the findings in comparison with other cases described in literature.

Sensitivity of ovarian cancer cells to acetaminophen reveals biological pathways that affect patient survival.

Experimental and epidemiological data support the potential activity of acetaminophen against ovarian cancer (OVCA). In this study, we sought to confirm the activity of acetaminophen in OVCA cell lines and to investigate the molecular basis of response. A total of 16 OVCA cell lines underwent pretreatment (baseline) genome-wide expression measurements and were then treated with and analyzed for acetaminophen sensitivity. Pearson's correlation analysis was performed to identify genes that were associated with OVCA acetaminophen response. The identified genes were subjected to pathway analysis, and the expression of each represented pathway was summarized using principal component analysis. OVCA acetaminophen response pathways were analyzed in 4 external clinico-genomic datasets from 820 women for associations with overall survival from OVCA. Acetaminophen exhibited antiproliferative activity against all tested OVCA cell lines, with half maximal inhibitory concentration values ranging from 63.2 to 403 µM. Pearson's correlation followed by biological pathway analysis identified 13 pathways to be associated with acetaminophen sensitivity (P<0.01). Associations were observed between patient survival from OVCA and expression of the following pathways: Development/angiotensin signaling via ß-arrestin (P=0.04), protein folding and maturation/angiotensin system maturation (P=0.02), signal transduction/c-Jun N-terminal kinase (JNK) pathway (P=0.03) and androstenedione and testosterone biosynthesis and metabolism (P=0.02). We confirmed that acetaminophen was active against OVCA cells in vitro. Furthermore, we identified 4 molecular signaling pathways associated with acetaminophen response that may also affect overall survival in women with OVCA, including the JNK pathway, which has been previously implicated in the mechanism of action of acetaminophen and is predictive of decreased survival in women with OVCA.