A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Phosphodiesterase 10A (PDE10A) as a novel target to suppress ß-catenin and RAS signaling in epithelial ovarian cancer.

A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced ß-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Perivascular epithelioid cell tumor (PEComa) of the uterus: Challenges of pregnancy in determining prognosis and optimal treatment.

Background: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that exhibits immunohistochemical evidence of smooth muscle and melanocytic differentiation.Case: We report a case of uterine PEComa in a 21 year-old primigravida, presenting at time of c-section as a small subserosal lesion that expressed soft tan-brown tissue fragments. Microscopically the cells were epithelioid, staining positive for TFE3 and HMB45. Significant cytologic atypia and mitotic activity were concerning for malignancy. The patient was treated post-partum with total robotic hysterectomy and right salpingo-oopherectomy, and is currently without evidence of disease. Conclusion: This case of PEComa diagnosed during pregnancy highlights the importance of intra-operative biopsy and the difficulty of predicting malignant potential of PEComa in the setting of a gravid uterus with a dynamic smooth muscle architecture.

A novel proteomic-based screening method for ovarian cancer using cervicovaginal fluids: A window into the abdomen.

OBJECTIVE: Our objective is to develop a site-specific proteomic-based screening test for ovarian cancer(OC) using the mucus of the cervix and vagina and evaluate a potential means for home testing. METHODS: Cervicovaginal fluid samples were obtained from ovarian cancer and normal control patients for LC-mass spectrometry(MS) proteomic evaluation. Statistical modeling determined the protein panel with the highest penetrance across ovarian cancer samples. A subcohort of patients consented to provide self-collected vaginal samples at home with questionnaire on feasibility. Cohen's kappa methodology was utilized to determine agreement between physician-collected and patient-collected samples. RESULTS: A total of 83 consecutive patient samples were collected prospectively (33 ovarian cancer & 50 controls). Thirty patients consented for self-collection. Using LC-MS, 30 peptides demonstrated independent statistical significance for detecting ovarian cancer. Using statistical modeling, the protein panel that determined the best predictor for detecting OC formed a "fingerprint" consisting of 5 proteins: serine proteinase inhibitor A1; periplakin; profilin1; apolipoprotein A1; and thymosin beta4-like protein. These peptides demonstrated a significant increase probability of detecting ovarian cancer with the ROC curve having an AUC of 0.86 (p = 0.00001). Physician-collected and patient-collected specimens demonstrated moderate agreement with kappa average of 0.6 with upper bound of 0.75. CONCLUSIONS: Using novel site-specific collection methods, we identified an OC "fingerprint" with adequate sensitivity and specificity to warrant further evaluation in a larger cohort. Agreement of physician-collected and patient-collected samples were encouraging and could improve access to screening with a home self-collection if this screening test is validated in future studies.

Not immune to inequity: minority under-representation in immunotherapy trials for breast and gynecologic cancers.

OBJECTIVE: To describe the participation of minority women in clinical trials using immunologic agents for breast and gynecologic cancers. METHODS: A retrospective review of completed clinical trials involving immunotherapy for breast and gynecologic cancers was performed. Completed trials were examined for data on race, tumor type, and start year. Minority enrollment was stratified by tumor site. Based on Center for Disease Control and Prevention age-adjusted incidence for race, expected and observed ratios of racial participation were calculated and compared using Χ2 testing, p≤0.05. RESULTS: A total of 53 completed immunotherapy clinical trials involving 8820 patients were reviewed. Breast cancer trials were most common (n=24) and involved the most patients (n=6248, 71%). Racial breakdown was provided in 41 studies (77%) for a total of 7201 patients. Race reporting was lowest in uterine (n=4, 67%) and cervical cancer trials (n=6, 67%), and highest in ovarian cancer trials (n=12, 86%). White patients comprised 70% (n=5022) of all the patients included. Only 5% of patients involved were black (n=339), and 83% of these patients (n=282) were enrolled in breast cancer trials. Observed enrollment of black women was 32-fold lower for ovarian, 19-fold lower for cervical, 15-fold lower for uterine, and 11-fold lower for breast cancer than expected. While all trials reported race between 2013 and 2015, no consistent trend was seen towards increasing race reporting or in enrollment of black patients over time. CONCLUSION: Racial disparities exist in clinical trials evaluating immunologic agents for breast and gynecologic cancers. Recruitment of black women is particularly low. In order to address inequity in outcomes for these cancers, it is crucial that significant attention be directed towards minority representation in immuno-oncologic clinical trials.

Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response.

Programmed death ligand-1 (PD-L1) inhibitors are currently under investigation as a potential treatment option for ovarian cancer. Although this therapy has shown promise, its efficacy is highly variable among patients. Evidence suggests that genomic instability influences the expression of PD-L1, but little is known about this relationship in ovarian cancer. To examine the relationship between PD-L1 expression and genomic instability, we measured DNA damage using Repair Assisted Damage Detection (RADD). We then correlated the presence of persistent DNA damage in the ovarian tumor with protein expression of PD-L1 using immunohistochemistry. Ovarian tumors showed a high prevalence of oxidative DNA damage. As the level of oxidative DNA damage increased, we saw a significant correlation with PD-L1 expression. The highest correlation between DNA damage and PD-L1 expression was observed for mucinous ovarian tumors (r = 0.82), but a strong correlation was also observed for high grade serous and endometrioid tumors (r = 0.67 and 0.69, respectively). These findings link genomic instability to PD-L1 protein expression in ovarian cancer and suggest that persistent DNA damage can be used as a potential biomarker for patient selection for immunotherapy treatment.

Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer.

BACKGROUND: Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements. METHODS: Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion. RESULTS: As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab. CONCLUSIONS: Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially. LAY SUMMARY: Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy. Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer. Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy.

Minority participation in phase 1 gynecologic oncology clinical trials: Three decades of inequity.

OBJECTIVES: It is important to develop effective therapies in minorities to ensure equity in cancer care. Underrepresentation of minorities in early phase trials may cause therapies that are effective only in majority populations. We evaluated minority participation in gynecologic oncology phase 1 clinical trials. METHODS: In peer-reviewed published articles of gynecologic oncology phase 1 clinical trials from years 1985 to 2018, we manually abstracted racial distribution of enrolled participants, cancer type, and year published. We calculated expected and observed ratios of racial participation on the basis of age-adjusted cancer incidence for race from the United States Centers for Disease Control and Prevention. RESULTS: We identified 357 articles of phase 1 trials (total, 9492 participants), including 213 articles on ovarian cancer (60%). Racial distribution of participants was available in 84 articles (23%) that included 2483 participants (26%): 1950 white (79%), 140 black (5%), and 393 other participants (16%). Other nonwhite races exceeded black enrollment in 46 of 84 trials (55%) that listed race. Enrollment of black participants was less than expected from disease incidence for ovarian (incidence-to-enrollment ratio, 18.5; P < .001), endometrial (3.6; P < .001), and cervical cancer (6.8; P < .001). No phase 1 study met expected enrollment for black participants. Frequency of black participants decreased 1.8-fold from 1995 to 1999 (8 of 70 participants [11%]) to 2015-2018 (55 of 892 participants [6%]; P < .025). CONCLUSIONS: Major racial underrepresentation exists in gynecologic oncology phase 1 clinical trials. Enrollment of more black participants is needed to achieve racial equity.

DNA damage measurements within tissue samples with Repair Assisted Damage Detection (RADD).

Exposures to genotoxic carcinogens and reactive species result in strand breaks and a spectrum of covalent modifications to DNA that can induce mutations and contribute to the initiation and progression of cancer. Measurements of DNA damage within tissue or tumor samples can serve as a biomarker for exposures or assess changes in DNA repair capacity relevant in cancer development and treatment. Numerous methods to characterize DNA damage exist. However, these methods are primarily applicable to isolated DNA or cultured cells, often require a substantial amount of material, and may be limited to the detection and quantification of only a handful of DNA adducts. Here, we used the Repair Assisted Damage Detection (RADD) assay to detect and excise DNA adducts using a cocktail of DNA repair enzymes, then the damage site within the genome are tagged for detection using a modified nucleotide. We previously demonstrated the RADD assay can detect lesions within isolated DNA and fixed cells, and now RADD can be used to detect DNA adducts and DNA strand breaks in formalin-fixed paraffin-embedded (FFPE) tissue samples. We verified the ability of the RADD assay to detect DNA damage in tissue by exogenously inducing DNA damage with X-rays and restriction enzymes. We also showed that RADD can be multiplexed with antibodies to detect cell cycle markers or other proteins of interest. Finally, we showed that RADD can detect DNA damage within clinically relevant ovarian tumor samples. RADD is a flexible and easy-to-use assay that allows relative damage levels to be determined within FFPE samples and allows the heterogeneity of DNA adducts and strand breaks within clinically relevant samples to be measured.

MicroRNAs in gynecological cancers: Small molecules with big implications.

Gynecological cancers (GCs) are often diagnosed at advanced stages, limiting the efficacy of available therapeutic options. Thus, there remains an urgent and unmet need for innovative research for the efficient clinical management of GC patients. Research over past several years has revealed the enormous promise of miRNAs. These small non-coding RNAs can aid in the diagnosis, prognosis and therapy of all major GCs, viz., ovarian cancers, cervical cancers and endometrial cancers. Mechanistic details of the miRNAs-mediated regulation of multiple biological functions are under constant investigation, and a number of miRNAs are now believed to influence growth, proliferation, invasion, metastasis, chemoresistance and the relapse of different GCs. Modulation of tumor microenvironment by miRNAs can possibly explain some of their reported biological effects. miRNA signatures have been proposed as biomarkers for the early detection of GCs, even the various subtypes of individual GCs. miRNA signatures are also being pursued as predictors of response to therapies. This review catalogs the knowledge gained from collective studies, so as to assess the progress made so far. It is time to ponder over the knowledge gained, so that more meaningful pre-clinical and translational studies can be designed to better realize the potential that miRNAs have to offer.

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

BACKGROUND: Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression. METHODS: A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM-1 evaluation, which was performed via enzyme-linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM-1 expression. RESULTS: A retrospective review identified 54 advanced-stage EOC patients. Patients expressing mesothelium VCAM-1 had shortened overall survival (44 vs 79 months, P = 0.035) and progression-free survival (18 vs 67 months, P = 0.010); the median time to platinum resistance was 36 months for VCAM-1-expressing patients and not yet determined for the VCAM-1-negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM-1 expression, and sVCAM-1 did not vary between groups. CONCLUSIONS: Mesothelium VCAM-1 expression is negatively associated with progression-free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM-1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM-1 would substitute for mesothelium expression. Cancer 2017;123:977-84. © 2016 American Cancer Society.

Unraveling the etiology of ovarian cancer racial disparity in the deep south: Is it nature or nurture?

BACKGROUND: Our objective was to evaluate racial treatment and survival disparities in black women with ovarian cancer in the Deep South and to determine how environmental factors / socioeconomic status (SES) influence survival. METHODS: A retrospective study of ovarian cancer patients from 2007 to 2014 was performed. Socioeconomic status (SES) was obtained though U.S. Census block data and compared using Yost scores. Comparisons were performed using standard statistical approaches. RESULTS: A total of 393 patients were evaluated, 325 (83%) white and 68 (17%) black. Demographic information and surgical approach were similar in each racial group. However, compared to whites, black patients had lower rates of optimal debulking [89% vs. 71%, respectively (p=0.001)] and intraperitoneal chemotherapy (19% vs. 11%, p=0.01). Black women had lower SES parameters including education, income, and poverty. As a result, more black patients had the lowest SES (SES-1) when compared to white patients (17% vs. 41%, p<0.001). When controlling for these factors by cox regression analysis, a survival disadvantage was seen in black women for both progression free survival (16 vs. 27months, p=0.003) and overall survival (42 vs. 88months, p<0.001). CONCLUSIONS: Despite controlling for clinical and environmental factors, a survival disadvantage was still observed in black patients with ovarian cancer in the Deep South. Black women had lower optimal debulking rates and more platinum resistant disease. These data suggest other factors like tumor biology may play a role in racial survival differences, however, more research is needed to determine this causation.

A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study.

BACKGROUND: Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. METHODS: In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. FINDINGS: Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0-100), and a negative predictive value of 99·6% (97·9-100). The most common grade 3-4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. INTERPRETATION: Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. FUNDING: Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.

Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer.

Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression. Furthermore, in ovarian cancer cells Rad6 was found to stabilize ß-catenin promoting stem cell-related characteristics, including expression of stem cell markers and anchorage-independent growth. Cancer stem cells can promote chemoresistance, tumor recurrence and metastasis, all of which are limiting factors in treating ovarian cancer. Thus it is significant that Rad6 overexpression led to increased resistance to the chemotherapeutic drug carboplatin and correlated with tumor cell invasion. These findings show the importance of Rad6 in ovarian cancer and emphasize the need for further studies of Rad6 as a potential target for the treatment of ovarian cancer.

Minority participation in Gynecologic Oncology Group (GOG) Studies.

OBJECTIVE: Participation of minority populations in clinical trials is paramount to understanding and overcoming cancer racial disparities. The goal of this project is to evaluate minority participation in published GOG clinical trials. METHODS: GOG publications from 1985 to 2013 were reviewed. Minority enrollment was stratified by tumor site, type of study, and year published. Based on Centers of Disease Control and Prevention (CDC) age-adjusted incidence for race, expected and observed ratios of racial participation were calculated. RESULTS: A total of 445 GOG publications involving 67,568 patients were reviewed. Racial breakdown was provided in 170 studies (38%) for a total of 45,259 patients: 83% White (n=37,617); 8% Black (n=3,686), and 9% Other (n=3,956). The majority of studies were Ovarian (n=202) and Phase 2 (n=290). When evaluating the quartiles of publication year, a steady decline in the proportion of Black patients enrolled was seen. Race was not reported in any publication prior to 1994. Compared to years 1994-2002, a 2.8-fold lower proportion of black enrollment was noted in years 2009-2013 (16% and 5.8%, respectively; p<0.01). Utilizing CDC age-adjusted incidence, observed enrollment of Black patients onto GOG clinical trials was significantly less than expected enrollment. Observed Black enrollment was 15-fold lower than expected for ovarian trials, 10-fold lower for endometrial, 4.5-fold for cervix, and 5.2-fold for sarcoma (each p<0.001). CONCLUSIONS: Based on age-adjusted incidence, observed enrollment of Black patients was lower than expected enrollment onto GOG studies. Despite national emphasis on minority enrollment on clinical trials, fewer Black patients were enrolled over time.

Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation.

Allyl isothiocyanate (AITC), a constituent of many cruciferous vegetables exhibits significant anticancer activities in many cancer models. Our studies provide novel insights into AITC-induced anticancer mechanisms in human A549 and H1299 non-small cell lung cancer (NSCLC) cells. AITC exposure induced replication stress in NSCLC cells as evidenced by γH2AX and FANCD2 foci, ATM/ATR-mediated checkpoint responses and S and G2/M cell cycle arrest. Furthermore, AITC-induced FANCD2 foci displayed co-localization with BrdU foci, indicating stalled or collapsed replication forks in these cells. Although PITC (phenyl isothiocyanate) exhibited concentration-dependent cytotoxic effects, treatment was less effective compared to AITC. Previously, agents that induce cell cycle arrest in S and G2/M phases were shown to sensitize tumor cells to radiation. Similar to these observations, combination therapy involving AITC followed by radiation treatment exhibited increased DDR and cell killing in NSCLC cells compared to single agent treatment. Combination index (CI) analysis revealed synergistic effects at multiple doses of AITC and radiation, resulting in CI values of less than 0.7 at Fa of 0.5 (50% reduction in survival). Collectively, these studies identify an important anticancer mechanism displayed by AITC, and suggest that the combination of AITC and radiation could be an effective therapy for NSCLC.

The trend towards minimally invasive surgery (MIS) for endometrial cancer: an ACS-NSQIP evaluation of surgical outcomes.

OBJECTIVE: Our objective was to evaluate the surgical trend towards increased MIS in the management of endometrial cancer in regard to improvements in patient outcomes. METHODS: Using the American College of Surgeons-National Surgical Quality Improvement Project's database, patients who underwent hysterectomy for endometrial cancer from 2006-2010 were identified and categorized into exploratory laparotomy (XLAP) or MIS. Comparative analyses were performed and stratified by year of surgery to evaluate demographics, surgical outcomes, and 30-day surgical morbidity. RESULTS: A total of 2076 patients (1269 XLAP and 807 MIS) underwent hysterectomy for endometrial cancer between 2006 and 2010. Longer operative times were seen in MIS compared to XLAP (192 vs. 148 min; p<0.001) as well as significant increase in mean hospital stay in the XLAP group of 3.8 days compared to 1.6 days in MIS (p<0.0001). When controlling for preoperative comorbidities, significant increases in postoperative complications were observed in XLAP compared to MIS group (total 396 vs. 91; p<0.0001). MIS increased from 16% in 2006 to 48% in 2010, which correlated to decreases in complications and hospital stays. Each 10% increase in MIS would save $2.8 million and 41 postoperative complications. If used exclusively, MIS would save 6434 hospital days and 416 complications. CONCLUSIONS: Despite increases in operative times, MIS for the treatment of endometrial cancer significantly reduces perioperative complications and hospital stay. Considering the improvements in patient outcomes and the potential savings to the health care system, MIS should be the preferred route for the surgical treatment of this disease when feasible.

ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling.

OBJECTIVE: Aldehyde dehydrogenase (ALDH) expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. METHODS: Isogenic ovarian cancer cell lines for platinum sensitivity (A2780) and platinum resistant (A2780/CP70) as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. RESULTS: ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDHHIGH displayed significantly lower progression free survival than the patients with ALDHLOW cells (9 vs. 3 months, respectively p<0.01). ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ) and replication checkpoint (pS317 Chk1) were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of γ-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. CONCLUSION: This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling.