NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Survival and clinical outcomes of patients with ovarian cancer who were treated on phase 1 clinical trials.

BACKGROUND: Patients with ovarian cancer who are enrolled on phase 1 trials typically have platinum-resistant and heavily pretreated disease, with a poor prognosis. In the current study, the authors assessed prognostic factors and survival in women with recurrent ovarian cancer who were treated on phase 1 clinical trials. METHODS: The authors performed a retrospective analysis of patients treated from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics and treatment and toxicity-related survival data were assessed. Descriptive statistics and Cox proportional hazards models were used to identify risk factors associated with survival time. RESULTS: A total of 132 patients were treated on phase 1 clinical trials. Patients had a median age of 59 years (range, 33-88 years) with a median of 5.5 previous chemotherapy lines (range, 1-13 lines). Of the 132 patients, 53 (40%) were treated on multiple phase 1 trials with a median of 1 (range, 0-5) prior phase 1 trial. The overall response rate was 14.7%. The median overall survival was 11.3 months (95% CI, 9.1-13.4 months). Two patients died on trial due to progression of disease whereas no patients died of treatment-related toxicity. Independent risk factors found to be predictive of shorter survival were an elevated cancer antigen 125 (CA 125) level (hazard ratio [HR], 2.8; 95% CI, 1.6-5.2) and albumin <3.5 g/dL (HR, 2.5; 95% CI, 1.65-3.79). A body mass index >25 kg/m2 was predictive of longer survival (HR, 0.65; 95% CI, 0.44-0.96). CONCLUSIONS: In the current single-institution series, patients with heavily pretreated ovarian cancer who were treated on phase 1 clinical trials experienced a median overall survival of 11.3 months. When available, phase 1 clinical trials represent a reasonable treatment option for patients with heavily pretreated ovarian cancer with a preserved performance status.

Vulvar sarcoma outcomes by histologic subtype: a Surveillance, Epidemiology, and End Results (SEER) database review.

OBJECTIVE: Vulvar cancers account for 5% of all gynecologic malignancies; only 1%-3% of those vulvar cancers are primary vulvar sarcomas. Given the rarity of vulvar sarcomas, outcome data specific to histopathologic subtypes are sparse. The aim of this study was to identify clinical and pathologic factors of primary vulvar sarcomas that are associated with survival and may inform treatment decisions. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was searched for women diagnosed with vulvar sarcoma between 1973 and 2018. We identified 315 patients and reviewed their demographic, clinicopathologic, surgical, and survival information. Statistical analyses included χ2 and t-tests, Kaplan-Meier survival, and Cox regression analyses. RESULTS: The most common histopathologies of vulvar sarcomas were dermatofibrosarcomas (85/315, 27%) and leiomyosarcomas (72/315, 22.9%). Rhabdomyosarcomas (18/315, 5.7%), liposarcomas (16/315, 5.1%), and malignant fibrous histiocytomas (16/315, 5.1%) were less frequent. The majority of patients underwent surgery (292/315, 92.7%), which included lymph node dissections in 21.6% (63/292). Survival and lymph node involvement varied significantly with histologic subtype. The 5-year disease-specific survival for dermatofibrosarcomas, liposarcomas, and fibrosarcomas was 100% and only 60.3% and 62.5% for malignant fibrous histiocytomas and rhabdomyosarcomas, respectively. None of the patients with (dermato)fibrosarcomas, liposarcomas, or leiomyosarcomas had positive lymph nodes, in contrast to rhabdomyosarcomas and malignant fibrous histiocytomas with 77.8% and 40% positive lymph nodes, respectively. The 5-year disease-specific survival for women with positive lymph nodes was 0%. CONCLUSIONS: Vulvar sarcomas are heterogeneous with survival highly dependent on the histopathologic subtype. While surgical excision is the mainstay of treatment for all vulvar sarcomas, staging lymphadenectomy should be deferred for (dermato)fibrosarcomas, liposarcomas, and leiomyosarcomas as there were no cases of lymph nodes metastases.

Activation of Wnt signaling promotes olaparib resistant ovarian cancer.

Epithelial ovarian cancer (EOC) has one of the highest death to incidence ratios among all cancers. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype due to the lack of therapeutic options following debulking surgery and platinum/taxane-based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)-ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair-deficient (HRD) HGSOCs, recent studies have observed a significant benefit in non-HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance. Therefore, there is an urgent clinical need to understand PARPi resistance and to introduce novel combinatorial therapies to manage PARPi resistance and extend HGSOC disease-free intervals. In a panel of HGSOC cell lines, we established matched olaparib sensitive and resistant cells. Transcriptome analysis of the matched olaparib-sensitive vs -resistant cells revealed activation of the Wnt signaling pathway and consequently increased TCF transcriptional activity in PARPi-resistant cells. Forced activation of canonical Wnt signaling in several PARPi-sensitive cells via WNT3A reduced olaparib and rucaparib sensitivity. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA-approved compound, pyrvinium pamoate, which has been shown to promote downregulation of ß-catenin. In both an HGSOC cell line and a patient-derived xenograft model, we observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARP and Wnt inhibitors.

Adiponectin receptor agonist AdipoRon induces apoptotic cell death and suppresses proliferation in human ovarian cancer cells.

We tested the hypothesis that stimulation of adiponectin receptors with the synthetic agonist AdipoRon suppresses proliferation and induces apoptotic death in human high grade serous ovarian tumor cell lines and in ex vivo primary tumors, mediated by activation of 5' AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR). We determined the effect of AdipoRon on high grade serous ovarian tumor cells lines (OVCAR3, OVCAR4, A2780) and ex vivo primary tumor tissue. Western blotting analysis was performed to examine changes in activation of AMPK and mTOR signaling and flow cytometry was utilized to examine changes in cell cycle progression. Immunofluorescence of cleaved caspase-3 positive cells and flow cytometry of annexin V positive cells were used to determine changes in apoptotic response. The CyQUANT proliferation assay was used to assess cell proliferation. AdipoRon treatment increased AMPK phosphorylation (OVCAR3 P = 0.01; A2780 P = 0.02) but did not significantly alter mTOR activity. AdipoRon induced G1 cell cycle arrest in OVCAR3 (+ 12.1%, P = 0.03) and A2780 (+ 12.0%, P = 0.002) cells. OVCAR3 and OVCAR4 cells treated with AdipoRon underwent apoptosis based on cleaved caspase-3 and annexin V staining. AdipoRon treatment resulted in a dose dependent decrease in cell number versus vehicle treatment in OVCAR3 (-61.2%, P < 0.001), OVCAR4 (-79%, P < 0.001), and A2780 (-56.9%, P < 0.001). Ex vivo culture of primary tumors treated with AdipoRon resulted in an increase in apoptosis measured with cleaved caspase-3 immunohistochemistry. AdipoRon induces activation of AMPK and exhibits an anti-tumor effect in ovarian cancer cell lines and primary tumor via a mTOR-independent pathway.

Molecular markers in recurrent stage I, grade 1 endometrioid endometrial cancers.

OBJECTIVES: Stage I, grade 1 endometrial cancers have low recurrence rates and often do not receive adjuvant therapy. We compared recurrent cases to matched non-recurrent controls to evaluate for molecular markers associated with higher risk of recurrence. METHODS: A case-control study including all cases of recurrent stage I, grade 1 endometrioid endometrial cancer at one institution in a ten-year period. Cases were matched to controls by age, BMI, weight and stage. Molecular testing and immunohistochemistry were performed on archival tumor specimens: microsatellite instability (MSI-H), mismatch repair status, POLE mutational status, and next-generation sequencing. RESULTS: 15 stage I, grade 1 endometrial cancer cases with recurrent disease and available tumor specimens were identified. CTNNB1 and MSI-H were present at significantly higher rates in cases than controls (CTNNB1 60% vs. 28%, OR 3.9, 95%CI 1.1-14.7, p = 0.04 and MSI-H 53% vs. 21%, OR 4.4, 95%CI 1.1-17.0, p = 0.03). POLE mutations were found in 0% of cases vs. 7% of controls (p = 0.54). Among specimens demonstrating microsatellite stability (MSS), 100% of cases vs. 26% of controls had CTNNB1 mutations (p < 0.001). CTNNB1 wild type tumors were MSI-H in 100% of cases vs. 19% of controls (p < 0.001). CONCLUSIONS: Compared to controls, CTNNB1 mutation is present at significantly higher rates in recurrent stage I, grade 1 endometrial cancers and is found most commonly in MSS tumors. MSI-H is also present at significantly higher rates in recurrent cases. These markers may be useful for prognostic risk stratification and adjuvant therapy decision-making in this otherwise low-risk population.

A phase II randomized, double-blind trial of a polyvalent Vaccine-KLH conjugate (NSC 748933 IND# 14384) + OPT-821 versus OPT-821 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer who are in second or third complete remission: An NRG Oncology/GOG study.

OBJECTIVE: Early-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity. METHODS: From 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity. RESULTS: Of 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71-1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively. CONCLUSIONS: Vaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches. TRIAL REGISTRATION: NCT00857545.

NCCN Guidelines Insights: Ovarian Cancer, Version 1.2019.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Identification of a novel diagnostic gene expression signature to discriminate uterine leiomyoma from leiomyosarcoma.

Leiomyosarcomas are rare, aggressive tumors, which exhibit a poor prognosis regardless of stage. Pre-operative diagnosis can be difficult as leiomyosarcoma can mimic features of the more common, benign uterine leiomyoma. The goal of this study was to identify specific molecular markers to discriminate between uterine leiomyosarcomas and leiomyomas to facilitate timely, accurate diagnosis and treatment. Gene expression profiles of three leiomyosarcomas, leiomyomas, and normal myometrial tissue samples were analyzed using the Affymetrix Human Gene 1.0 ST Array. GC-robust multiarray average calculation and ANOVA statistical testing were used to identify differentially expressed genes. Sixty genes, with functional roles in tumor progression or suppression, exhibited divergent expression profiles in leiomyosarcomas and leiomyomas, compared to normal myometrium. Differential RNA and protein levels of seven genes, with the most discriminatory expression patterns, were confirmed by RTPCR and immunohistochemistry in an additional 10 leiomyosarcoma and 20 leiomyoma independent samples. CHI3L1, MELK, PRC1, TOP2A, and TPX2 were overexpressed in leiomyosarcomas, while HPGD and TES were overexpressed in leiomyomas. Distinguishing leiomyosarcomas from leiomyomas represents a diagnostic challenge, particularly in the context of minimally invasive surgery. The unique gene expression signatures identified in this study may accurately differentiate between these tumor types at the earliest stage and provides potential prognostic factors and novel therapeutic targets for the treatment of leiomyosarcoma.

Minority Race Predicts Treatment by Non-gynecologic Oncologists in Women with Gynecologic Cancer.

BACKGROUND: Outcomes of women with gynecologic cancer are superior when treated by gynecologic oncologists. The National Surgical Quality Improvement Program (NSQIP) began identifying gynecologic surgeon subspecialty in 2014. We sought to identify characteristics and outcomes of women treated by general gynecologists in comparison with women treated by gynecologic oncologists. PATIENTS AND METHODS: Patients undergoing hysterectomy for gynecologic malignancy in 2014 and 2015 were abstracted from the NSQIP database. Patient characteristics, morbidities, surgeon specialty, and operative outcomes were captured. RESULTS: 7271 hysterectomies were performed for malignant disease, and 669 were performed by generalists. In comparison with generalists, gynecologic oncologists operated on patients who were older (P < 0.001), more likely to be White [odds ratio (OR) 2.1, P < 0.001], had disseminated cancer (OR 3.1, P < 0.001), had ascites (OR 2.6, P < 0.001), and were classified as American Society of Anesthesiologists (ASA) class ≥ 3 (OR 1.7, P < 0.001). Gynecologic oncologists were also more likely to have hospital readmissions (OR 1.7, P = 0.004) and perform lymph node dissections for endometrial cancer (OR 2.2, P < 0.001). On multivariable analysis, older age [adjusted OR (aOR) 1.0, P = 0.021], White race (aOR 2.0, P < 0.001), presence of disseminated cancer (aOR 2.5, P < 0.001), presence of ascites (aOR 1.8, P = 0.036), and ASA class ≥ 3 (aOR 1.6, P < 0.001) remained independent predictive factors for having a gynecologic oncology surgeon. CONCLUSIONS: The majority of gynecologic cancer cases are performed by gynecologic oncologists. Generalists are more likely to operate on minority patients and patients with fewer comorbidities. Further efforts to ensure access to specialized cancer care for all patients are needed.

Statistical performance of image cytometry for DNA, lipids, cytokeratin, & CD45 in a model system for circulation tumor cell detection.

Detection of circulating tumor cells (CTCs) in a blood sample is limited by the sensitivity and specificity of the biomarker panel used to identify CTCs over other blood cells. In this work, we present Bayesian theory that shows how test sensitivity and specificity set the rarity of cell that a test can detect. We perform our calculation of sensitivity and specificity on our image cytometry biomarker panel by testing on pure disease positive (D+ ) populations (MCF7 cells) and pure disease negative populations (D- ) (leukocytes). In this system, we performed multi-channel confocal fluorescence microscopy to image biomarkers of DNA, lipids, CD45, and Cytokeratin. Using custom software, we segmented our confocal images into regions of interest consisting of individual cells and computed the image metrics of total signal, second spatial moment, spatial frequency second moment, and the product of the spatial-spatial frequency moments. We present our analysis of these 16 features. The best performing of the 16 features produced an average separation of three standard deviations between D+ and D- and an average detectable rarity of ∼1 in 200. We performed multivariable regression and feature selection to combine multiple features for increased performance and showed an average separation of seven standard deviations between the D+ and D- populations making our average detectable rarity of ∼1 in 480. Histograms and receiver operating characteristics (ROC) curves for these features and regressions are presented. We conclude that simple regression analysis holds promise to further improve the separation of rare cells in cytometry applications. © 2017 International Society for Advancement of Cytometry.

A method for extracting and characterizing RNA from urine: For downstream PCR and RNAseq analysis.

Readily accessible samples such as urine or blood are seemingly ideal for differentiating and stratifying patients; however, it has proven a daunting task to identify reliable biomarkers in such samples. Noncoding RNA holds great promise as a source of biomarkers distinguishing physiologic wellbeing or illness. Current methods to isolate and characterize RNA molecules in urine are limited. In this proof of concept study, we present a method to extract and identify small noncoding RNAs in urine. Initially, quantitative reverse transcription PCR was applied to confirm the presence of microRNAs in total RNA extracted from urine. Once the presence of micro RNA in urine was confirmed, we developed a method to scale up RNA extraction to provide adequate amounts of RNA for next generation sequence analysis. The method described in this study is applicable to detecting a broad range of small noncoding RNAs in urine; thus, they have wide applicability for health and disease analyses.

PARP inhibitors: Clinical utility and possibilities of overcoming resistance.

PARP inhibitors represent a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers have deficiencies in the homologous recombination (HR) DNA repair pathway, namely BRCA1/2 mutations. Given the limited therapeutic options for recurrent ovarian cancer patients there has been a significant effort to develop novel therapies to exploit DNA repair deficiencies. In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with HR deficiencies. PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors also show significant clinical benefit in patients without HR deficiencies. There are currently three FDA-approved PARP inhibitors for recurrent ovarian cancer and an additional two PARP inhibitors being evaluated in late stage clinical trials. Given the expanding clinical use of PARP inhibitors and the high likelihood of acquired resistance, there is a significant need for clinical strategies to manage PARP inhibitor resistant disease. This review will examine PARP inhibitors in the context of: indications and toxicities, novel biomarkers to predict response, targeted-therapy resistance, and potential approaches to manage resistant disease.

Sexual and Marital Dysfunction in Women With Gynecologic Cancer.

OBJECTIVE: Sexual dysfunction can be a long-term issue for women with gynecologic cancer. This study assesses the extent of sexual and marital dysfunction women face following treatment of a gynecologic cancer. METHODS: A cross-sectional study of women with gynecologic cancer was conducted using a 181-item survey. Sexual dysfunction was measured by change in the Female Sexual Function Index score; marital dysfunction was measured by change in Intimate Bond Measure from prediagnosis to posttreatment. Paired t tests and Fisher exact test were used to compare women with dysfunction to those without dysfunction. RESULTS: Three hundred twenty women were enrolled (mean age, 56.0 [SD, 12.0] years). Among all women, sexual function declined from a score of 21.3 (SD, 10.4) prior to 15.3 (SD, 10.2) (P < 0.001), and sexual activity decreased from 6.1 (SD, 6.8) to 2.6 (SD, 4.9) times per month following treatment (P < 0.001). Among the 208 women who were sexually active at the time of study, sexual dysfunction after treatment was associated with younger age (50.9 [SD, 11.7] years to 57.3 [SD, 12.3] years), ovarian (40.7% vs 30.7%) or cervical (21.0% vs 10.2%) cancer diagnosis, chemotherapy treatment (72.8% vs 50.4%), and being in a relationship (97.3% vs 82.7%). Among women in relationships, 27% experienced marital dysfunction. CONCLUSIONS: Women who are younger, have an ovarian or cervical cancer diagnosis, receive chemotherapy, or are in a committed relationship are at particularly high risk of sexual dysfunction. These women should be provided information about the risks associated with their cancer treatment.

Factors Impacting Use of Robotic Surgery for Treatment of Endometrial Cancer in the United States.

OBJECTIVE: This study was designed to examine the impact of patient socioeconomic, clinical, and hospital characteristics on the utilization of robotics in the surgical staging of endometrial cancer. METHODS: Patients surgically treated for endometrial cancer at facilities that offered robotic and open approaches were identified from the National Inpatient Sample Database from 2008 to 2012. The groups were compared for socioeconomic, clinical, and hospital differences. Medical comorbidity scores were calculated using the Charlson comorbidity index. T tests and χ (2) were used to compare groups. Multivariable analyses were used to determine factors that were independently associated with a robotic approach. RESULTS: A total of 18,284 patients were included (robotic, n = 7169; laparotomy, n = 11,115). Significant differences were noted in all patient clinical and socioeconomic characteristics and all hospital characteristics. Multivariable analyses identified factors that independently predicted patients undergoing robotic surgery. These patients were older [adjusted odds ratio (aOR) 1.008; 95 % confidence interval (CI) 1.004-1.011], white (aOR 1.38; 95 % CI 1.27-1.50), and privately insured (aOR 1.16; 95 % CI 1.07-1.26). Clinically, these women were more likely to be obese (aOR 1.20; 95 % CI 1.11-1.30) and to be undergoing an elective case (aOR 1.25; 95 % CI 1.11-1.40). Hospitals were more likely to be under private control (aOR 1.55, 95 % CI 1.39-1.71) but less likely to be located in the south (aOR 0.87; 0.81-0.93), quantified as large or medium (aOR 0.57; 95 %CI 0.50-0.67), or teaching hospitals (aOR 0.68; 95 % CI 0.63-0.74). CONCLUSIONS: Socioeconomic status and hospital characteristics are factors that independently predict robotic utilization in the United States. These racial, socioeconomic, and geographic disparities warrant further study regarding the utilization of this important technology.

Association Between Preoperative Chemotherapy and Postoperative Complications in Patients Undergoing Surgery for Ovarian Cancer.

BACKGROUND: This study sought to determine the association between preoperative chemotherapy and postoperative morbidity and mortality in ovarian cancer patients. METHODS: The American College of Surgeons National Surgical Quality Improvement Program was used to identify women who underwent surgery for ovarian cancer between 2005 and 2012. The women were divided into two groups based on whether they had received chemotherapy within 30 days before surgery or not. Preoperative variables, intraoperative measures, and postoperative morbidity and mortality were compared using χ(2) and Student's t test. Multivariable analyses using logistic regression modeling were used to correct for potential confounding variables. RESULTS: Of 1807 patients, 1612 (89.2%) underwent primary surgery, and 195 (10.8%) received preoperative chemotherapy. The chemotherapy group had a lower preoperative platelet count (317,640 vs 249,740 plt/µL; P < 0.001), hematocrit (36.9 vs 33.1%; P < 0.001), and white blood cell (WBC) count (7970 vs 6060 WBC/µL; P < 0.001). Postoperatively, the chemotherapy group had a higher rate of organ/space infection (2.2 vs 4.6%; P = 0.04; odds ratio [OR], 2.12; 95% confidence interval [CI], 1.01-4.47) and a higher blood transfusion rate (17.1 vs 32.3%; P < 0.001; OR, 2.31; 95% CI, 1.67-3.20). A subanalysis of only those with disseminated cancer showed myelosuppression and an increased blood transfusion rate in the chemotherapy group. In multivariable analyses, preoperative chemotherapy, hematocrit, and ascites were independent predictors of postoperative blood transfusion in the entire cohort, whereas preoperative chemotherapy was the only independent predictor of postoperative blood transfusion in the disseminated cancer group. CONCLUSIONS: Preoperative chemotherapy for the treatment of ovarian cancer is associated with myelosuppression and an increased risk of postoperative blood transfusion.

Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration.

BACKGROUND: Claudin-4 is a transmembrane protein expressed at high levels in the majority of epithelial ovarian tumors, irrespective of subtype, and has been associated with tumor cells that are both chemoresistant and highly mobile. The objective of this study was to determine the functional role that claudin-4 plays in apoptosis resistance and migration as well as the therapeutic utility of targeting claudin-4 activity with a small mimic peptide. METHODS: We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing. RESULTS: Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice. CONCLUSION: Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden.

Disparities in standard of care treatment and associated survival decrement in patients with locally advanced cervical cancer.

PURPOSE: Standard of care (SOC) treatment for locally advanced cervical cancer includes pelvic external beam radiation (EBRT) with chemotherapy and interdigitated brachytherapy. We evaluated national utilization trends and factors associated with receiving SOC therapy. MATERIALS AND METHODS: We utilized the National Cancer Database (NCDB) to identify women with locally advanced cervical cancer treated with definitive radiation or chemoradiation therapy and stratified these patients by treatment received. RESULTS: We identified 15,194 patients. Only 44.3% of patients received SOC treatment and this group had significantly improved OS. High volume centers, academic centers, comprehensive community cancer centers, private insurance, and higher income, were all associated with an increased likelihood of receiving SOC, whereas Black patients were less likely to receive SOC. We found 26.8% of patients received no radiation boost, 23.8% received an EBRT boost only, and 49.5% of patients received EBRT with brachytherapy. Although an EBRT boost was advantageous over no boost at all (HR 0.720, p<0.001), OS was superior in patients who received brachytherapy (HR 0.554, p<0.001). Patients were more likely to receive no radiotherapy boost if they had lower incomes, Medicaid, were treated at low volume centers, or were treated at non-comprehensive community cancer centers. CONCLUSIONS: SOC for locally advanced cervical cancer offers superior outcomes, yet less than half of patients receive SOC and there are disparities in which patients receive SOC treatment. No additional treatment, including sophisticated EBRT techniques including IMRT or SBRT, can make up for the survival decrement from lack of brachytherapy as a component of definitive care.

Progestin treatment decreases CD133+ cancer stem cell populations in endometrial cancer.

OBJECTIVES: Endometrial cancer is a hormonally responsive malignancy. Response to progestins is associated with estrogen receptor (ER) and progesterone receptor (PR) status. CD133 is a marker of endometrial cancer stem cells. We postulated that CD133+ cells express ER and PR and that progestin therapy differentially regulates CD133+ cells. METHODS: The Ishikawa (ER/PR positive) and KLE (ER/PR negative) cell lines were examined for the presence of CD133 populations. Cell lines were treated with 30.4µM medroxyprogesterone 17-acetate (MPA) for 6days. After treatment, cell counts, apoptosis assays and CD133+ populations were examined. In a clinical project, we identified 12 endometrial cancer patients who were treated with progestin drugs at our institution. Using immunohistochemistry, CD133, ER, PR, and androgen receptor (AR) expression was scored and evaluated for change over time on serial biopsies. RESULTS: CD133+ populations were identified in Ishikawa and KLE cell lines. MPA treatment resulted in a significant reduction in the percentage of live cells (Ishikawa, P=0.036; KLE, P=0.0002), significant increase in apoptosis (Ishikawa, P=0.01; KLE, P=0.0006) and significant decrease in CD133+ populations (Ishikawa, P<0.0001; KLE, P=0.0001). ER, PR, AR and CD133 were present in 96.4%, 96.4%, 89.3% and 100% of patient samples respectively. Paralleling the in vitro results, CD133 expression decreased in patients who had histologic response to progestin treatment. CONCLUSION: CD133+ populations decreased after treatment with MPA in an in vitro model and in patients responding to treatment with progestins. Progestin treatment differentially decreases CD133+ cells.