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BACKGROUND. Population-based studies of women with epithelial ovarian cancer suggest that black women have worse survival compared to white women. The primary objective of this study was to determine if, at a National Cancer Institute (NCI)-Designated Comprehensive Cancer Center (CCC) serving a diverse racial and socioeconomic population, race is independently associated with differences in survival. METHODS. A retrospective review of women with EOC diagnosed between 2004–2009 undergoing treatment with follow-up at our institution was performed. Records were reviewed for demographics, comorbidities (as defined by the Charlson Comorbidity Index (CCI)), tumor characteristics, treatment, progression-free (PFS), and overall survival (OS). Survival was calculated using the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed with Cox (proportional hazards) model. RESULTS. 367 patients met inclusion criteria. 54 (15%) were black and 308 (84%) were white. Compared to white women, black women had higher BMI, lower rates of optimal surgical cytoreduction, lower rates of intraperitoneal chemotherapy, and higher CCI scores. The median PFS for black and white women were 9.7 and 14.6 months, respectively (p = 0.033). The median overall survival was 21.7 months for black women and 42.6 months for white women (p < 0.001). On multivariate analysis, black race independently correlated with a worse overall survival (HR 1.61, 95% CI 1.06–2.43). CONCLUSION. In this cohort, racial disparities may be due to higher medical comorbidities and lower rates of optimal surgical cytoreduction. After accounting for these differences, race remained an independent predictor of worse overall survival.

Objective To evaluate the potential impact of a standardized preoperative algorithm on outcomes of patients with suspected ovarian cancer. Methods From January 1 to December 31, 2013, patients with suspected ovarian cancer were triaged to primary debulking surgery or neoadjuvant chemotherapy/interval debulking surgery (NACT/IDS) based on a comprehensive review of preoperative clinical data as part of a quality improvement project. Demographics, surgical, and postoperative data were collected. Results A total of 110 patients with newly diagnosed ovarian cancer were identified: 68 (62%) underwent PDS with an 85% optimal debulking rate. The 30-day readmission rate was 14.7% with a 2.9% 60-day mortality rate. Forty-two patients (38%) underwent NACT. Two patients (4.8%) died before receiving NACT. Thirty-five patients have undergone IDS with an 89% optimal debulking rate. The 30-day readmission rate was 8.5% with a 5.7% 60-day mortality rate after IDS. Conclusions Although it is difficult to predict which patients will undergo optimal debulking at the time of PDS, surgical morbidity and mortality can be decreased by using NACT in select patients. The initiation of a quality improvement project has contributed to an improvement in patient outcomes at our institution.

Diabetes mellitus (DM) is a risk factor for endometrial cancer and is associated with poorer outcomes in breast and colon cancers. This association is less clear in epithelial ovarian cancer (EOC). We sought to examine the effect of DM on progression-free (PFS) and overall survival (OS) in women with EOC.A retrospective cohort study of EOC patients diagnosed between 2004 and 2009 at a single institution was performed. Demographic, pathologic and DM diagnosis data were abstracted. Pearson chi-square test and t test were used to compare variables. The Kaplan-Meier method and the log rank test were used to compare PFS and OS between non-diabetic (ND) and DM patients.62 (17%) of 367 patients had a diagnosis of DM. No differences in age, histology, debulking status, or administration of intraperitoneal chemotherapy between ND and DM patients were present, although there were more stage I and IV patients in the ND group (p=0.04). BMI was significantly different between the two groups (ND vs. DM, 27.5 vs. 30.7kg/m(2), p0.001). While there were no differences in survival based on BMI, diabetic patients had a poorer PFS (10.3 vs. 16.3months, p=0.024) and OS (26.1 vs. 42.2months, p=0.005) compared to ND patients. Metformin use among diabetic patients did not appear to affect PFS or OS.EOC patients with DM have poorer survival than patients without diabetes; this association is independent of obesity. Metformin use did not affect outcomes. The pathophysiology of this observation requires more inquiry.

// Zachary C. Dobbin 1,2 , Ashwini A. Katre 1 , Adam D. Steg 1 , Britt K. Erickson 1 , Monjri M. Shah 1 , Ronald D. Alvarez 1 , Michael G. Conner 3 , David Schneider 4 , Dongquan Chen 5 and Charles N. Landen 6 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham 2 NIH Medical Scientist Training Program, University of Alabama at Birmingham 3 Department of Pathology, University of Alabama at Birmingham 4 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham 5 Division of Preventative Medicine, Department of Medicine, University of Alabama at Birmingham 6 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Virginia, Charlottesville, VA Correspondence: Charles N. Landen Jr, email: // Keywords : Ovarian Cancer, Patient-derived xenograft, cancer stem cells, chemoresistance, animal models of cancer Received : August 08, 2014 Accepted : August 18, 2014 Published : August 19, 2014 Abstract A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient’s tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor’s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer

The National Comprehensive Cancer Network (NCCN) has established guidelines for treating epithelial ovarian cancer (EOC) which includes cytoreductive surgery and platinum and taxane-based chemotherapy (CT). The objective of this study was to determine the reasons for failure to deliver NCCN-adherent care at an NCCN cancer center serving a diverse racial and socioeconomic population.Medical records of women with EOC diagnosed between 2004 and 2009 were reviewed for demographic, clinical, tumor, treatment, and survival data. Independent reviewers determined if their treatment met criteria for being NCCN-adherent. Progression-free survival (PFS) and overall survival (OS) were calculated with Kaplan-Meier estimates and compared with the log-rank test.367 patients were identified. 79 (21.5%) did not receive NCCN-adherent care. Non-adherent CT in 75 patients was the most common reason for failure to receive NCCN-adherent care. 39 patients did not complete CT due to treatment toxicities or disease progression. 12 patients received single agent CT only and 4 received no CT due to comorbidities. 2 patients declined CT. 18 patients died in the postoperative period without receiving CT. 8 patients did not undergo cytoreduction due to disease progression or comorbidities. PFS and OS were improved in the NCCN-adherent cohort (PFS: 5.7 vs. 18.3 months, p.005) (OS: 11.4 vs. 49.5 months, p.005).The vast majority of patients at an NCCN cancer center received NCCN-adherent treatment. Reasons for failure to receive NCCN-adherent care were variable, but most did not receive chemotherapy in accordance with guidelines due to comorbidities or disease progression.

The cancer stem cell hypothesis has been put forward as a paradigm to describe varying levels of aggressiveness in heterogeneous tumors. Specifically, many subpopulations have been clearly demonstrated to possess increased tumorigenicity in mice, broad differentiating capacity, and resistance to therapy. However, it is still not clear the extent to which these experimental findings are potentially clinically significant. This review will describe the principles of this emerging hypothesis, ways in which it may be appropriate in ovarian cancer based on the clinical course of the disease, and how we might exploit it to improve outcomes in ovarian cancer patients.

BACKGROUND: Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum and primarily presents with pulmonary symptoms. Immunocompromised individuals are at high risk for contracting disseminated histoplasmosis, which can be fatal if left untreated. CASE: We present a case involving a 50-year-old woman with acquired immunodeficiency syndrome with an ulcerated vulvar lesion concerning for carcinoma. Extensive workup revealed disseminated histoplasmosis without pulmonary manifestations. She was treated with an extended course of an antifungal agent. Her vulvar lesion resolved. CONCLUSION: Vulvar histoplasmosis is a rare etiology of vulvar pathology but one that should be considered in immunocompromised patients.

OBJECTIVE To estimate the use of venous thromboembolism prophylaxis in women undergoing gynecologic surgery and to estimate the patient, physician, and hospital characteristics associated with guideline-based prophylaxis. METHODS A commercial database was used to examine women who underwent major gynecologic surgery from 2000 to 2010. Venous thromboembolism prophylaxis was classified as none, mechanical, pharmacologic, or a combination. Multivariable logistic regression models of factors associated with any prophylaxis and pharmacologic and combination prophylaxis were developed. RESULTS We identified a total of 738,150 women who underwent gynecologic surgery. No prophylaxis was given to 292,034 (39.6%) women, whereas 344,068 (46.6%) received mechanical prophylaxis, 40,268 (5.5%) pharmacologic prophylaxis, and 61,780 (8.4%) combination prophylaxis. Use of prophylaxis increased from 53.5% in 2000 to 67.5% in 2010. Prophylaxis was more commonly used in older women, those with Medicare, women with more comorbidities, white women, patients treated at rural hospitals, teaching facilities, and in patients treated by high-volume surgeons and at high-volume centers (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.23-1.27, P

Despite the diagnostic value of lymphadenectomy for early-stage cervical cancer, its therapeutic role is unknown. We examined the therapeutic potential of extensive lymphadenectomy in women with early-stage cervical cancer.Women with stage IA2-IIA cervical cancer who underwent radical hysterectomy with lymphadenectomy in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patients were stratified according to the number of nodes removed. The effect of the extent of lymphadenectomy on overall and cancer-specific survival was examined using multivariable Cox proportional hazards models. Separate analyses were performed for node positive and node negative patients.Among 5522 women, 893 (16%) had10 nodes, 2030 (37%) had 11-20, 1487 (27%) had 21-30 nodes, and 1112 (20%) had30 nodes removed. Black women, those65 years of age and those diagnosed later in the study, were less likely to have 10 or more nodes removed (P.05 for all). Among women with positive lymph nodes, a more extensive lymphadenectomy had no effect on survival (HR = 0.75; 95% CI, 0.47-1.22). For women with negative lymph nodes, a more extensive lymphadenectomy was associated with improved survival. Compared with node negative patients with less than 10 nodes removed, patients with 21-30 nodes removed were 24% (HR = 0.76; 95% CI, 0.53-1.09) less likely to die, whereas those with30 nodes removed were 37% (HR = 0.64; 95% CI, 0.43-0.96) less likely to die from their tumors.Node negative, early-stage cervical cancer patients who undergo a more extensive lymphadenectomy have an improved survival.

To examine adherence to evidence-based recommendations for preoperative testing and health care costs associated with excessive testing.An institutional review of women who underwent gynecologic surgery between 2005 and 2007 was performed. Data on the type of surgery, age, comorbidities, and perioperative testing was extracted. We noted the preoperative performance of chest X-ray, electrocardiogram, metabolic panel, complete blood count, coagulation studies, liver function tests, and urinalysis. Each test was classified as being guideline-based (appropriate) or non-guideline-based (inappropriate) as described by the National Institute of Clinical Excellence perioperative guidelines.A total of 1,402 patients were identified. Ninety-five percent of patients underwent all of the guideline-recommended preoperative testing. Ninety percent of women underwent at least one nonindicated preoperative test. None of the 749 urinalyses, 407 liver function tests, or 1,046 coagulation studies performed was appropriate. Ninety-nine percent of the 427 chest X-rays ordered were inappropriate. Only 17% of metabolic panels, 36% of electrocardiograms, and 29% of complete blood counts were in accordance with evidence-based guidelines. Inappropriate perioperative tests led to a direct cost of more than $418,000. Of the inappropriate tests ordered, abnormalities were noted frequently but rarely changed management.Adherence to evidence-based recommendations for preoperative testing is poor. Inappropriate preoperative tests represent a major health care expenditure.III.

To examine factors that influence the morbidity and mortality of peripartum hysterectomy and analyze the effect of hospital volume on maternal mortality.We examined women who underwent peripartum hysterectomy at the time of cesarean delivery in a quality and resource utilization database. Procedure-associated intraoperative, perioperative, and postoperative medical complications, length of stay, intensive care unit use, and maternal mortality were analyzed. Hospitals were stratified into tertiles based on procedure volume and complications and compared using adjusted generalized estimating equations. Results are reported as odds ratios.Maternal mortality among the 2,209 women who underwent peripartum hysterectomy was 1.2%. After adjusting for other clinical and demographic factors, perioperative mortality was 71% (odds ratio 0.29, 95% confidence interval 0.10-0.88) lower in women who underwent operation at high-volume hospitals compared with those treated at low-volume facilities. Hospital volume had no effect on the rates of intraoperative injuries, medical complications, length of stay, or transfusion. In contrast, compared with women treated at low-volume centers, patients who underwent operation at high-volume hospitals had a lower incidence of perioperative surgical complications (odds ratio 0.66, 95% confidence interval 0.47-0.93) and a lower rate of intensive care unit usage (odds ratio 0.53, 95% confidence interval 0.34-0.83).Peripartum hysterectomy is associated with substantial morbidity and mortality. Maternal mortality is lower when the procedure is performed in high-volume hospital settings.II.

To perform a population-based analysis to examine the morbidity and mortality of peripartum hysterectomy in comparison with nonobstetric hysterectomy.Data from the Nationwide Inpatient Sample were used to compare peripartum and nonobstetric hysterectomy in women younger than 50 years of age. Intraoperative, perioperative, and postoperative medical complications were examined. The outcomes of peripartum and nonobstetric hysterectomy were compared using chi square. Odds ratios were calculated using multivariable logistic regression models for each individual complication.A total of 4,967 women who underwent peripartum hysterectomy and 578,179 patients who had a nonobstetric hysterectomy were identified. Bladder (9% compared with 1%) and ureteral (0.7% compared with 0.1%) injuries were more common for peripartum hysterectomy (P.001). There were no differences in the rates of intestinal or vascular injuries between peripartum and nonobstetric hysterectomy. Rates of reoperation (4% compared with 0.5%), postoperative hemorrhage (5% compared with 2%), wound complications (10% compared with 3%), and venous thromboembolism (1% compared with 0.7%) were all higher in women who underwent peripartum hysterectomy. In multivariable analysis, the odds ratio for death for peripartum compared to nonobstetric hysterectomy was 14.4 (95% confidence interval 9.84-20.98).Peripartum hysterectomy is accompanied by substantial morbidity and mortality. Compared with nonobstetric hysterectomy, the procedure is associated with increased rates of both intraoperative and postoperative complications. The mortality of peripartum hysterectomy is more than 25 times that of hysterectomy performed outside of pregnancy.II.

Recent evidence has challenged the traditional paradigm in gynecology that women over the age of 45 years who are undergoing hysterectomy should also undergo prophylactic oophorectomy. Oophorectomy in young women is associated with an increased risk in cardiac disease, osteoporosis and all-cause mortality. With the increasing incidence of endometrial cancer in young women, the decision of whether to perform an oophorectomy in premenopausal women undergoing endometrial cancer staging is becoming increasingly common. We present the risks and benefits of oophorectomy, as well as discuss the literature concerning oophorectomy in young women with endometrial cancer.

Purpose Oophorectomy is commonly performed in premenopausal women with endometrial cancer who undergo hysterectomy. The benefits of oophorectomy in this setting are unknown, and the procedure subjects women to the long-term sequelae of estrogen deprivation. We examined the safety of ovarian preservation in young women with endometrial cancer who underwent hysterectomy. Patients and Methods Women ≤ 45 years of age with stage I endometrial cancer recorded from 1988 to 2004 in the Surveillance, Epidemiology, and End Results Database were examined. We developed Cox proportional hazards models and Kaplan-Meier curves to compare women who underwent oophorectomy with those who had ovarian preservation. Results A total of 3,269 women, including 402 patients (12%) who had ovarian preservation, were identified. Younger age (P < .0001), later year of diagnosis (P = .04), residence in the eastern United States (P = .02), and low tumor grade (P < .0001) were associated with ovarian preservation. In a multivariate Cox model, ovarian preservation had no effect on either cancer-specific (hazard ratio [HR] = 0.58; 95% CI, 0.14 to 2.44) or overall (HR = 0.68; 95% CI, 0.34 to 1.35) survival. The findings were unchanged when women who received pelvic radiotherapy were excluded. Conclusion Ovarian preservation in premenopausal women with early-stage endometrial cancer may be safe and not associated with an increase in cancer-related mortality.

BRCA-positive ovarian cancer patients derive benefit PARP inhibitors. Approximately 50% of ovarian cancer tumors have homologous recombination (HR) deficiencies and are therefore "BRCA-like," possibly rendering them sensitive to PARP inhibition. However, no predictive assay exists to identify these patients. We sought to determine if irradiation-induced Rad51 foci formation, a known marker of HR, correlated to PARP inhibitor response in an ovarian cancer model.Ovarian cancer cell lines were exposed to PARP-inhibitor ABT-888 to determine effect on growth. Rad51 protein expression prior to irradiation was determined via Western blot. Cultured cells and patient-derived xenograft tumors (PDX) were irradiated and probed for Rad51 foci. In vivo PDX tumors were treated with ABT-888 and carboplatin; these results were correlated with the ex vivo ionizing radiation assay.Three of seven cell lines were sensitive to ABT-888. Sensitive lines had the lowest Rad51 foci formation rate after irradiation, indicating functional HR deficiency. Approximately 50% of the PDX samples had decreased Rad51 foci formation. Total Rad51 protein levels were consistently low, suggesting that DNA damage induction is required to characterize HR status. The ex vivo IR assay accurately predicted which PDX models were sensitive to PARP inhibition in vitro and in vivo. ABT-888 alone reduced orthotopic tumor growth by 51% in A2780ip2 cell line, predicted to respond by the ex vivo assay. Three PDX models' response also correlated with the assay.The ex vivo IR assay correlates with response to PARP inhibition. Analysis of total Rad51 protein is not a reliable substitute.

Background: Notch family members function as both oncogenes and tumor suppressors. NOTCH2 is down-regulated in colon cancer, and reduced expression is associated with a less differentiated, more aggressive phenotype, and reduced overall survival. NOTCH2 has also been shown to have pro-apoptotic and growth suppressive effects in thyroid carcinoma, and carcinoid tumors. The expression pattern of NOTCH2 in ovarian cancer is unknown. Methods: An immunohistochemical analysis using a polyclonal antibody to the NOTCH2 intracellular domain was performed on a total of 119 ovarian carcinomas, and 7 serous borderline tumors, arranged onto tissue arrays. Normal ovarian and fallopian tube epithelium were used as controls. Specimens were scored as low or high NOTCH2 expression. The score distributions for the subtypes were analyzed with the chi square test. Results: Fifty two of 61 (85.2%) papillary serous, eight of 13 (61.5%) clear cell, and 23 of 30 (76.7%) endometrioid, demonstrated negative or lower NOTCH2 expression than normal fallopian tubal epithelium or ovarian surface epithelium. In contrast, 10 of 15 (66.7%) mucinous carcinomas had a high level of NOTCH2 expression and consistently demonstrated intense polarized staining (P

Purpose: Endoglin (CD105) is a membranous protein overexpressed in tumor-associated endothelial cells, chemoresistant populations of ovarian cancer cells, and potentially stem cells. Our objective was to evaluate the effects and mechanisms of targeting endoglin in ovarian cancer. Experimental Design: Global and membranous endoglin expression was evaluated in multiple ovarian cancer lines. In vitro, the effects of siRNA-mediated endoglin knockdown with and without chemotherapy were evaluated by MTT assay, cell-cycle analysis, alkaline comet assay, γ-H2AX foci formation, and quantitative PCR. In an orthotopic mouse model, endoglin was targeted with chitosan-encapsulated siRNA with and without carboplatin. Results: Endoglin expression was surprisingly predominantly cytoplasmic, with a small population of surface-positive cells. Endoglin inhibition decreased cell viability, increased apoptosis, induced double-stranded DNA damage, and increased cisplatin sensitivity. Targeting endoglin downregulates expression of numerous DNA repair genes, including BARD1, H2AFX, NBN, NTHL1, and SIRT1. BARD1 was also associated with platinum resistance, and was induced by platinum exposure. In vivo, antiendoglin treatment decreased tumor weight in both ES2 and HeyA8MDR models when compared with control (35%–41% reduction, P < 0.05). Endoglin inhibition with carboplatin was associated with even greater inhibitory effect when compared with control (58%–62% reduction, P < 0.001). Conclusions: Endoglin downregulation promotes apoptosis, induces significant DNA damage through modulation of numerous DNA repair genes, and improves platinum sensitivity both in vivo and in vitro. Antiendoglin therapy would allow dual treatment of both tumor angiogenesis and a subset of aggressive tumor cells expressing endoglin and is being actively pursued as therapy in ovarian cancer. Clin Cancer Res; 19(1); 170–82. ©2012 AACR.

Objective: We analyzed use of venous thromboembolism (VTE) prophylaxis in patients undergoing oncologic surgery and examined the influence of surgeon and hospital characteristics on prophylaxis. Background: Cancer patients undergoing surgery are at high-risk for VTE. Despite the risk of VTE, the use of prophylaxis is variable. Little is known about the patient, surgeon, and hospital characteristics that influence the use of prophylaxis. Methods: Patients undergoing oncologic surgery from 2003 to 2007 and recorded in the Perspective database were analyzed. Surgeons and hospitals were stratified into volume-based tertiles for analysis. The effects of surgeon and hospital volume on use of any prophylaxis and pharmacologic prophylaxis were examined using generalized estimating equations adjusted for confounding variables. Results: In the cohort of 252,950 patients, some form of prophylaxis was given to 79% of patients whereas 46% received pharmacologic prophylaxis. The rate of VTE prophylaxis was 82.7% at high-volume hospitals compared with 75.6% at low-volume facilities (P < 0.0001). After adjustment for case mix and surgeon volume, the odds ratio for receipt of prophylaxis at high-versus low-volume hospitals was 1.40 (95% CI, 1.20-163). The odds ratio for prophylaxis for patients treated by high-volume surgeons was 1.35 (95% CI, 1.14-160) after adjusting for case mix and hospital volume. The rate of pharmacologic VTE prophylaxis was 53.1% in high-volume hospitals versus 38.8% in low-volume hospitals (P < 0.0001). Treatment at a high-volume hospital was associated with an odds ratio of 1.42 (95% CI, 1.22-1.66) for pharmacologic prophylaxis whereas the odds ratio for pharmacologic prophylaxis for patients treated by high-volume surgeons was 1.28 (95% CI, 1.08-1.51). Conclusion: VTE prophylaxis is underutilized in patients undergoing oncologic surgery. Patients treated by high-volume surgeons and at high-volume hospitals are more likely to receive appropriate prophylaxis.

25 — Exhibit A doi:10.1016/j.ygyno.2014.04.015 Session III: Integrative Oncology Moderator: Allison Axtell, MD, Kaiser Permanente Medical Group The Charlson Comorbidity Index predicts survival in women with epithelial ovarian cancer independent of surgical debulking status B. Erickson, T. Matin, J. Martin, M. Shah, C. Haygood, D. Pasko, L. Daily, J. Straughn Jr., C. Leath III, University of Alabama at Birmingham Division of Gynecologic Oncology, Birmingham, AL, USA, University of Alabama at Birmingham Department of OB/GYN, Birmingham, AL, USA Objectives: Our objective is to determine if patient comorbidities impact progression free survival (PFS) and overall survival (OS) in patients with epithelial ovarian cancer (EOC). Methods: Eligible subjects for this retrospective cohort study included women diagnosed with EOC between 2004 and 2009 who received primary treatment and follow-up at our institution. After IRB approval, records were reviewed for demographics, tumor characteristics, recurrence, survival, and comorbidity as quantified using the Charlson Co-morbidity Index (CCI). The CCI is a validated predictor of hospital mortality and includes 19 separately weighted medical conditions. For our analysis, patients were separated into 3 0090-8258/$ – see front matter. Gynecologic Oncology 134 (2014) 428–437

BACKGROUND: Surgical management of ovarian cancer consists of hysterectomy with bilateral oophorectomy. In young women, this results in the loss of reproductive function and estrogen deprivation. In the current study, the authors examined the safety of fertility-conserving surgery in premenopausal women with epithelial ovarian cancers. METHODS: Women aged ≤50 years with stage IA or IC epithelial ovarian cancer who were registered in the Surveillance, Epidemiology, and End Results database were examined. Patients who underwent bilateral oophorectomy were compared with those who underwent ovarian conservation. A second analysis examined uterine conservation versus hysterectomy. Multivariate Poisson regression models were developed to describe predictors of fertility preservation. Survival was examined using Cox proportional hazards models and the Kaplan-Meier method. RESULTS: In total, 1186 women, including 754 women (64%) who underwent bilateral oophorectomy and 432 women (36%) who underwent ovarian preservation, were identified. Younger age, later year of diagnosis, and residence in the eastern or western United States were associated with ovarian preservation (P < .05 for all). Women with endometrioid and clear cell histologies and stage IC disease were less likely to have ovarian conservation (P < .05). In a Cox model, ovarian preservation had no effect on survival (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.39-1.20). Young age, later year of diagnosis, residence in the eastern or western United States, single women, mucinous tumors, and patients with stage IA disease were more likely to have uterine preservation (P < .05 for all). In a multivariate model, uterine preservation had no effect on survival (HR, 0.87; 95% CI, 0.62-1.22). CONCLUSIONS: Ovarian and uterine-conserving surgery were safe in young women who had stage IA and IC epithelial ovarian cancer. Cancer 2009. © 2009 American Cancer Society.

Obstetric hemorrhage is often a sudden, life-threatening event. Successful management hinges on both preoperative preparation if hemorrhage is anticipated as well as knowledge of interventions. Uterine-sparing techniques, such as aggressive and early use of uterotonics, balloon tamponade, uterine compression sutures, arterial ligation, and selective arterial embolization, may be used to control hemorrhage. If these techniques are not adequate, the decision must be made to proceed with hysterectomy. The type of hysterectomy (subtotal vs. total) must be individualized to each patient. Hemostatic agents may be particularly useful in patients who have excessive blood loss from raw tissue surfaces.

Solid organ transplantation can prolong the life of individuals with end-stage diseases that affect the kidney, liver, lung, heart, and pancreas. The improved survival of transplant recipients has led to increased attention on quality of life issues, including controlling fertility and having children. Perturbations of the hypothalamic-pituitary-ovarian axis in women with chronic renal failure or severe hepatic dysfunction result in anovulation and reduced fertility. Most often, fertility is restored with successful organ transplantation and good overall health. Although there are case reports of children born subsequent to assisted reproductive technologies (ART) in female transplant recipients, the approach to infertility in this population has not been described. Recognizing the unique medical, ethical, and psycho-social concerns involved in treating infertile female transplant recipients, reproductive endocrinologists must work with a multi-disciplinary team to ensure a successful pregnancy outcome without compromising graft function or maternal health. The primary goal of ART is a singleton pregnancy without complications, such as ovarian hyperstimulation syndrome, that pose greater risks in transplant recipients.

Introduction: A cornerstone of preclinical ovarian cancer research over the last 30 years has been the use of cell lines both in vitro and in vivo. This resource has underperformed in its ability to identify effective novel therapeutics and evaluate the heterogeneity of an ovarian neoplasm. Developing a patient-derived xenograft (PDX) allows for a comprehensive study of the heterogeneous tumor and potentially the identification of cellular populations responsible for chemoresistance and recurrence, but has not been fully characterized for ovarian cancer. We have developed an ovarian PDX model to demonstrate many important similarities and differences between these and primary patient tumors, and begun to explore its utility in identifying mediators of chemoresistance and personalizing therapy. Methods: Tumors removed from patients undergoing primary tumor reductive surgery were implanted into the subcutaneous flanks of SCID mice. Once a tumor developed, it was expanded into additional mice to propagate a PDX line. Tumors were analyzed for heterogeneity by examination of the tumor initiating cell populations, its stromal content with HLA immunohistochemistry, and proliferation with Ki-67. Cohorts of PDX lines were treated with maximum-tolerated dose of combined carboplatin and paclitaxel or vehicle and response was compared between the PDX and the patient. Chemoresistant PDX lines were generated by treatment with MTD carboplatin and paclitaxel until no evidence of disease (NED), observation until recurrence, and retreatment until fully resistant. RNAseq was conducted comparing treated PDX lines to the untreated PDX lines (n=6 pair) to identify important mediators of chemotherapy resistance. Finally, PDX lines were characterized for defects in homologous recombination (HR) repair with an ex vivo assay, correlating HR status with response to PARP inhibition in vivo. Results: Refinement of xenografting procedures yields an 85% success rate in establishing a PDX. PDX tumors maintain the patient's histology, but the stromal component is replaced by murine cells in the first generation. The xenografts retain primary tumor heterogeneity, at least in expression of putative tumor initiating cells (TIC) (ALDH: 17% vs 19%, CD44: 2.4% vs 5%, CD133 10% vs 3%). However, treatment with chemotherapy significantly increases these populations (ALDH1 increased to 36.1% from 16.2% (p=0.002); CD133 increased to 33.8% from 16.2% (p=0.026), suggesting a role in chemotherapy resistance. The treated PDX tumors showed a decrease in Ki67 staining (from 64% to 34%, p=0.001), suggesting dormancy is induced in the surviving population. The PDX tumors show similar response to chemotherapy as patient tumors, in that PDX tumors from patients with a partial response respond more slowly (if at all) than those from patients achieving a complete response (mean change in tumor volume -5.11% vs -63.73%, p=0.029). RNAseq comparing treated and untreated PDX lines indicate only 54 common genes with a significant change in mRNA (p Conclusions: The ovarian PDX model recapitulates patient tumor heterogeneity and mirrors response to chemotherapy. This model may prove superior in predicting response to therapy in patients, and allows a better model to study complex tumor biology that is impacted by tumor heterogeneity, such as survival of small populations with chemotherapy. Citation Format: Zachary C. Dobbin, Ashwini K. Katre, Monjri M. Shah, Britt K. Erickson, Hauping Chen, Ronald D. Alvarez, Michael G. Conner, Dongquan Chen, Charles N. Landen. An ovarian patient-derived xenograft model to identify the chemoresistant population. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A58.

Background: Endoglin (ENG, CD105) is a protein markedly overexpressed in tumor-associated endothelial cells, and a target for anti-angiogenic therapy. Recently we have noted it to be overexpressed in chemoresistant ovarian cancer cells as well. Our objective was to evaluate the effects and mechanisms of targeting endoglin specifically in ovarian cancer cells. Methods: Endoglin expression was assessed in multiple ovarian cancer lines by Western blot, immunohistochemistry, and flow cytometry. Anti-endoglin siRNAs were used to downregulate expression in ES2 and HeyA8MDR. In vitro, the effects of endoglin-knockdown individually and with chemotherapy were evaluated by MTT assay, cell-cycle analysis, alkaline comet assay, γ-H2AX foci formation and qPCR array for mediators of DNA damage and repair. In an orthotopic murine model, mice inoculated with ES2 or HeyA8MDR cell lines were administered chitosan-encapsulated anti-ENG siRNA or control siRNA with and without carboplatin. PCNA, γH2AX, and 53BP1 IHC and the TUNEL assay were performed to examine biologic effects of endoglin knockdown. Results: Endoglin is expressed to varying degrees by multiple ovarian cancer cell lines. Expression was on the cell surface, consistent with its recognized role as a cofactor with TGF-beta receptor, in only 5% of cells, with most other cells having cytoplasmic expression. In ES2 and HeyA8MDR cell lines, endoglin inhibition decreased cell viability, increased apoptosis, induced double-stranded DNA damage, and increased cisplatin sensitivity. Endoglin downregulation led to a decrease in expression of several DNA repair genes, including NBN, NTHL1, BARD1, H2AFX and SIRT1, and an increase in expression of DDIT3 and PPP1R15A. BARD1-specific downregulation, in turn, led to a significant decrease in BRCA1 expression, likely through ubiqutinylation. In vivo, anti-endoglin treatment decreased tumor weight in both ES2 and HeyA8MDR models when compared to control (35-41% reduction, p Citation Format: Angela J. Ziebarth, Somaria Nowsheen, Adam D. Steg, Monjri M. Shah, Ashwini A. Katre, Zachary C. Dobbin, Anil K. Sood, Michael G. Conner, Eddy S. Yang, Charles N. Landen. Endoglin (CD105) is a target for ovarian cancer cell-specific therapy through induction of DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5475. doi:10.1158/1538-7445.AM2013-5475 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Objective We examined predictors of massive blood loss for women with placenta accreta who had undergone hysterectomy. Study Design A retrospective review of women who underwent peripartum hysterectomy for pathologically confirmed placenta accreta was performed. Characteristics that are associated with massive blood loss (≥5000 mL) and large-volume transfusion (≥10 units packed red cells) were examined. Results A total of 77 patients were identified. The median blood loss was 3000 mL, with a median of 5 units of red cells transfused. There was no association among maternal age, gravidity, number of previous deliveries, number of previous cesarean deliveries, degree of placental invasion, or antenatal bleeding and massive blood loss or large-volume transfusion ( P > .05). Among women with a known diagnosis of placenta accreta, 41.7% had an estimated blood loss of ≥5000 mL, compared with 12.0% of those who did not receive the diagnosis antenatally with ultrasound scanning ( P = .01). Conclusion There are few reliable predictors of massive blood loss in women with placenta accreta.

5036 Background: Current xenograft and transgenic models of ovarian cancer are mainly homogeneous and poorly predict response to therapy. Use of patient tumors may represent a better model for tumor biology and offer potential to test personalized medicine approaches, but poor take rates and questions of recapitulation of patient tumors have limited this approach. We have developed a protocol for improved feasibility of such a model and examined its similarity to the patient tumor. Methods: Under IRB and IACUC approval, 23 metastatic ovarian cancer samples were collected at the time of tumor reductive surgery. Samples were implanted either subcutaneously (SQ), intraperitoneally (IP), in the mammary fat pad (MFP), or in the subrenal capsule (SRC) and monitored for tumor growth. Cohorts from 8 xenolines were treated with combined carboplatin and paclitaxel or vehicle, and response to therapy compared between xenografts and patients. Expression of tumor-initiating cell (TIC) markers ALDH1, CD133, and CD44 was assessed by immunohistochemistry in tumors from patients and treated and untreated xenografts. Results: At least one SQ implanted tumor developed in 91.3% of xenografts, significantly higher than in the MFP (63.6%), IP (23.5%), or SRC (8%). Xenografts were similar in expression of putative TIC’s compared to patient tumors. The patients and the xenografts also have similar responses to chemotherapy in that xenografts from patients with a partial response responded more slowly than those from patients achieving a complete response (45 vs 21 days, p=.004). Treated xenografts were more densely composed of TICs. ALDH1 increased to 36.1% from 16.2% (p=0.002) and CD133 increased to 33.8% from 16.2% (p=0.026). Conclusions: Xenoline development can be achieved at a high rate when tumors collected from metastatic sites are implanted SQ. These xenografts are similar to patient tumors with regard to chemotherapy response and TIC expression.. This model may be a more accurate model for in vivo pre-clinical studies as compared to current models. Also, as treated xenografts become chemoresistant, this model is well positioned to evaluate targeted therapies aimed at the most aggressive populations in a heterogeneous tumor.

Objective We examined the effect of radiation on survival for early-stage uterine carcinosarcomas and leiomyosarcomas. Study Design The surveillance, epidemiology, and end results database was used to identify patients with stage I/II carcinosarcomas and leiomyosarcomas. Logistic regression and Cox models were developed to determine radiation use and survival. Results Among 1819 women with carcinosarcomas and 1088 women with leiomyosarcomas, radiation was administered to 667 of the patients (37%) with carcinosarcomas and to 235 of the patients (22%) with leiomyosarcomas. In a multivariate model, adjuvant radiation reduced the risk of death by 21% in women with carcinosarcomas (hazard ratio, 0.79; 95% CI, 0.7-0.9). Radiation reduced mortality rates in patients with carcinosarcomas who had not undergone node dissection but had only a marginal effect on survival in node-negative women. Adjuvant radiation had no effect on survival for early-stage leiomyosarcomas (hazard ratio, 1.1; 95% CI, 0.9-1.4). Conclusion Adjuvant radiotherapy improves survival for select patients with early-stage carcinosarcomas but is of limited value for leiomyosarcomas.