Search

To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer.This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety.Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52-71%) in the overall population and 76% (95% CI 61-87) in the homologous recombination deficient (HRd), 47% (95% CI 31-64%) in the HR proficient (HRp), and 56% (95% CI 31-79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9-32.5 months), median PFS was 19.6 months (95% CI 16.5-25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9-NE), 14.2 months (95% CI 8.6-16.8), and 12.1 months (95% CI 8.0-NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff).Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

Objectives: Niraparib improves progression-free survival (PFS) in newly diagnosed, recurrent, and heavily pretreated ovarian cancer (OC) in patients (pts) after platinum-based chemotherapy in all biomarker-defined subgroups. Bevacizumab-induced hypoxia can drive genomic instability by altering DNA damage repair pathways, including homologous recombination (HR), and it is hypothesized to sensitize tumors to poly(ADP-ribose) polymerase inhibition. OVARIO (NCT03326193) is a single-arm, open-label study evaluating niraparib + bevacizumab treatment in advanced OC after response to first-line (1L) platinum-based chemotherapy + bevacizumab. Methods: All pts with newly diagnosed high-grade serous or endometrioid stage IIIB-IV OC who had a complete response (CR), partial response, or no evidence of disease (NED) after 1L platinum-based chemotherapy + bevacizumab were eligible. Pts receiving neoadjuvant chemotherapy (NACT) or primary debulking surgery were eligible. All pts underwent tissue testing for HR deficiency (HRd) or proficiency (HRp) at enrollment. Bevacizumab dosage was 15 mg/kg q3w up to 22 cycles, including time on 1L chemotherapy. Niraparib, 300 or 200 mg qd, based on baseline body weight and platelet count, was started within 12 weeks of completing 1L treatment and continued for 3 years or until progressive disease or unacceptable toxicity. The primary endpoint was PFS rate at 18 months from treatment initiation of niraparib + bevacizumab maintenance. Results: The study completed enrollment at 105 pts. Most pts were stage III (79%), had serous histology (95%), received NACT (63%), and had CR/NED at the completion of 1L (63%). Overall, 47% of pts were HRd, including HRd-BRCA mutated and HRd-BRCA wild-type. The niraparib starting dose was 200 mg in 78% of pts. At 6 and 12 months, PFS rates were 90% and 75%, respectively. At 12 months, the most common grade ≥3 related treatment-emergent adverse events were thrombocytopenia, anemia, and hypertension (49% of pts had pre-existing hypertension). Further safety data and PFS rates at 18 months will be presented at the meeting. Conclusions: Safety of the niraparib + bevacizumab combination was consistent with the known side effects of each drug as monotherapy, and the preliminary data suggest that the combination is efficacious. ClinicalTrials.gov number: NCT03326193

Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Recently, the existence of ovarian cancer stem cells has been reported. Sox2, Nanog and Oct4 are key markers of “stemness”. The objective of this study was to determine whether Sox2, Nanog, and Oct4 are associated with EOC and poor outcome. The expression of these markers was assessed by immunofluorescence staining and real-time RT-PCR in human EOC cell lines MDAH-2774 and SKOV-3, while the cancer genome atlas (TCGA) dataset was analyzed for associations with survival. Sox2, Nanog and Oct4 (POU5F1) were all detected by immunofluorescence staining and these results were confirmed by real-time RT-PCR. The TCGA dataset revealed a 26%, 9%, and 6% amplification of Sox2, Nanog and POU5F1, respectively. Additionally, K-M survival analyses showed a significant median overall survival difference (41 versus 48.3 months, P = .01) for Sox2 amplification, but not for Nanog (44.1 versus 36.2 months, P > .05) and POU5F1 (43.5 versus 45.0 months, P > .05). Our results suggest that Sox2 gene amplification significantly influences overall survival.

Over the past several years, there has been increasing recognition that pathogenesis of adhesion development includes significant contributions of hypoxia induced at the site of surgery, the resulting oxidative stress, and the subsequent free radical production. Mitochondrial dysfunction generated by surgically induced tissue hypoxia and inflammation can lead to the production of reactive oxygen and nitrogen species as well as antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase which when optimal have the potential to abrogate mitochondrial dysfunction and oxidative stress, preventing the cascade of events leading to the development of adhesions in injured peritoneum. There is a significant cross talk between the several processes leading to whether or not adhesions would eventually develop. Several of these processes present avenues for the development of measures that can help in abrogating adhesion formation or reformation after intraabdominal surgery.

Chemoresistance remains a major challenge in the treatment of ovarian cancer. As part of a survival mechanism, tumor cells have been shown to release proangiogenic factors, such as vascular endothelial growth factor (VEGF), through a mechanism that involves the upregulation of hypoxia-induced factor (HIF)-1α. The objective of this study was to compare the expression of VEGF and its receptors (R1 and R2) as well as HIF-1α in chemoresistant epithelial ovarian cancer (EOC) cells to their chemosensitive counterparts and determine their impact on angiogenesis. Two human EOC cell lines, MDAH-2774 and SKOV-3, and their cisplatin- or taxotere-resistant counterparts were used. Total RNA and protein were subjected to real-time reverse transcriptase–polymerase chain reaction, immunoprecipitation/Western blot and enzyme-linked immunosorbent assay to evaluate the expression of VEGF, VEGF receptors (R1 and R2), and HIF-1α. Angiogenesis was assessed with an in vitro angiogenesis assay. Data were analyzed using independent Student t tests and chi-square. Both taxotere- and cisplatin-resistant MDAH-2774 and SKOV-3 EOC cell lines manifested a significant decrease in VEGF, VEGF receptors, HIF-1α messenger RNA, and protein levels as compared to their chemosensitive counterparts. There was a significant decrease in the number and thickness of polygon blood vessel formation in chemoresistant EOC cells compared to chemosensitive counterparts. Cisplatin- and taxotere-resistant EOC cells are characterized by lower VEGF, VEGF receptors, and HIF-1α, and decreased angiogenesis. These findings may indicate a decrease in drug delivery at the tumor site, hence allowing the persistence of chemoresistant EOC cells.

Objective: The study sought to identify whether a relationship exists between serum myeloperoxidase (MPO) and free iron with stages of ovarian cancer. Methods: Serum and tissue samples were collected from women with stages I through IV ovarian cancer, benign gynecologic conditions, inflammation, and healthy controls. Myeloperoxidase ELISA and VITROS Fe Slide assays were used to measure serum and tissue MPO and free iron levels, respectively. Data were analyzed with a one-way ANOVA with post-hoc comparisons ( p< 0.05 considered significant). Results: There was a significant increase in the level of free iron in serum and tissues obtained from stages II-IV as compared to early-stage (stage I) ovarian cancer. There was an overlap between early-stage and inflammation serum MPO levels, however serum free iron levels were significantly higher in early-stage. There was no significant change in serum free iron levels between non-cancer groups. In contrast, there was a significant increase in serum free iron levels in early-stage as compared to non-cancer groups. Conclusions: Collectively, these findings clearly indicate a role for the combination of serum MPO and free iron as biomarkers for early detection and prognosis of ovarian cancer.

Chemoradiation is an alternative to radical vulvectomy with en bloc node dissection for advanced vulvar cancer. We report a case of complete clinical and pathologic response with chemotherapy alone in a patient with advanced vulvar cancer.A middle-aged woman known to have had human immunodeficiency virus (HIV) for 10 years was newly diagnosed with advanced-stage squamous carcinoma of the vulva. She was treated with a total of nine cycles of platinum-based combination chemotherapy, with complete clinical and pathologic response. She remains in complete clinical remission without evidence of recurrent disease by noninvasive testing in the absence of any further therapy 24 months after her last chemotherapy treatment.Platinum-based combination chemotherapy may be used successfully for patients with advanced-stage squamous carcinoma of the vulva.

Objective To report a case of small bowel obstruction (SBO) subsequent to Essure microinsert sterilization. Design Case report. Setting University teaching hospital. Patient(s) A 38-year-old woman, gravida 1, para 1, with a history of pelvic pain, vaginal spotting, nausea, vomiting, and constipation 1 month after Essure hysteroscopic sterilization. Intervention(s) Radiologic investigation, including a computed tomography scan of the abdomen and pelvis, followed by operative laparoscopy. Main Outcome Measure(s) Alleviation of the SBO. Result(s) Radiologic investigation suggested a distal SBO, with the left Essure microinsert noted in the left lower pelvis. These findings, including an inflamed appendix, were confirmed at operative laparoscopy. Lysis of adhesions, removal of the Essure microinsert, appendectomy, and left salpingectomy were performed. Conclusion(s) This case is reported to increase awareness that SBO is a potential complication of Essure microinsert placement.

To investigate the role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer (EOC).Two parent EOC cell lines (MDAH-2774 and SKOV-3) and their chemoresistant counterparts (cisplatin, 50 µmol/L) were used. Total RNA was extracted and subjected to real-time reverse transcriptase polymerase chain reaction to evaluate the expression of glutathione reductase (GSR) and inducible nitric oxide synthase (iNOS), as well as nitrate/nitrite levels. Analysis of variance was used for main effects and Tukey for post hoc analysis at P.05 for statistical significance.Both cisplatin resistant cell lines displayed a significant decrease in GSR messenger RNA (mRNA) levels and activity (P.01). As compared to sensitive controls, nitrate/nitrite levels were significantly higher in SKOV-3 cisplatin resistant cells while iNOS mRNA levels were significantly higher in MDAH-2774 cisplatin resistant cells (P.05).Our data suggest that the development of cisplatin resistance tilts the balance toward a pro-oxidant state in EOC.

Squamous cell carcinoma of the vulva is a rare disease with good prognosis if diagnosed early. The standard primary therapy is surgery. Neoadjuvant radiation or chemotherapy has been used to achieve resectability of the tumor and to decrease the radicality of the surgery. Chemotherapy with platinum compounds, paclitaxel and targeted therapy (erlotinib) has shown activity. International collaborative trials are needed to identify the best therapeutic strategy for patients with squamous cell cancer of the vulva who are not candidates for primary surgery or concomitant chemoradiation. We review the various treatment options available to patients with advanced or recurrent squamous cell cancer of the vulva.

Background: We have previously demonstrated that cisplatin resistant epithelial ovarian cancer (EOC) cells manifest a severe prooxidant state, which may be responsible for the maintenance of the resistant oncogenic phenotype. Objective: The objective of this study was to determine whether superoxide dismutase (SOD), a key antioxidant, could delay the development of cisplatin resistance in EOC cells. Methods: Human EOC cell lines, SKOV-3 and MDAH-2774 were utilized for this study. Cells were divided into three groups; untreated, cisplatin treated controls, and combined treated cisplatin plus SOD (20 U/ml). Control cells were cultured in the presence of a stepwise increase in cisplatin (0.25 μM increments every 72 hours up to a final dose of 1 μM). Combined treated cells were cultured in the same fashion as controls except for the addition of 20 U/ml SOD every 72 hours. Cells were considered resistant to cisplatin when a significantly similar or greater fold change of live cells was observed despite an increase in the concentration of cisplatin as compared to the untreated cells. The number of live and dead cells was determined every 72 hours, utilizing the Trypan blue dye exclusion method. Statistical analysis: Z-scores were used for statistical analysis at p-value 0.05 two-tailed; 2.81 untreated cells vs. cisplatin-treated controls 1.53 in SKOV-3, p>0.05 two-tailed). Similarly, combined treatment cells demonstrated cisplatin resistance at a concentration of 1 μM (1.00 untreated cells vs. 24.75 SOD+cisplatin-treated controls for MDAH-2774, p>0.05 two-tailed; 2.81 untreated cells vs. 1.00 SOD+cisplatin-treated controls 1.00 for SKOV-3, p>0.05 two-tailed). However, with increasing concentrations of SOD (40 and then 60 U/ml) there was a significant decrease in the fold change of live cells (23.75 cisplatin-treated controls versus 1.00 SOD+cisplatin-treated (p0.05); 1.45 cisplatin-treated controls versus 1.00 SOD+cisplatin-treated (p>0.05), 1.00 SOD+cisplatin-treated versus 0.97 cisplatin-treated controls (p>0.05), at 40 and 60 U/ml respectively in SKOV-3). Conclusion: Our results indicate a potential role for SOD in protecting against the acquisition of chemoresistance in ovarian cancer cells and may serve as a potential therapeutic intervention in combination with chemotherapy treatment. Citation Format: Jimmy Belotte, Osama Nusrat, Nicole F. Fletcher, Mohammed G. Saed, Bailey Neubauer, Husam M. Abu-Soud. Superoxide dismutase significantly reversed the development of cisplatin resistance in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B01.

Objective: To investigate the role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer (EOC). Methods: Two parent EOC cell lines (MDAH-2774 and SKOV-3) and their chemoresistant counterparts were used. Total RNA was extracted and subjected to real-time RT-PCR to evaluate the expression of inducible nitric oxide synthase (iNOS) and glutathione reductase (GSR) in all cells. Nitrate/nitrite levels and GSR activity were also measured using colorimetric and ELISA assays respectively. Cell proliferation was assessed using Ki-67 immunostaining in all cells. Unpaired t-tests were used for statistical analysis at p-value Results: Both EOC cisplatin sensitive cells manifested significant increase in the expression and activity of GSR as compared to their resistant counterparts (p Conclusion: Our data suggests that the development of cisplatin resistance heighten the prooxidant state in EOC leading to a further increase in cell proliferation. Citation Format: Jimmy Belotte, Nicole Fletcher, Awoniyi Awonuga, Mitchell Alexis, Husam Abu-soud, Michael Diamond, Mohammed Saed, Ghassan Saed. The role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer. [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 B49.

We investigated the association of a SNP in catalase (CAT) and in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22-phox subunit with an increased risk of development of ovarian and breast cancers. Both enzymes play major roles in the regulation of the redox balance. In the general population, the minor allele frequency (MAF) for CAT SNP C-262T (rs1001179) is 12.4% and 30.3%for NADPH oxidase SNP C242T (rs4673). The risk of breast cancer has been associated with decreased activity of CAT, which was attributed to this specific SNP. Similarly, an increase in NADPH oxidase activity has been associated with specific SNP in the CYBA gene, encoding the p22-phox subunit of NAPDH oxidase, substituting allele C with T at position 242 located on chromosome 16q24. Patients (n=190) were recruited from the Karmanos Cancer Institute, Detroit, MI for genetic counseling based on personal and family histories. Stored blood samples were subjected to DNA extraction (QIAamp DNA mini kit) followed by TaqMan® SNP Genotyping Assay Sets for rs1001179 or rs4673 run on the QuantStudio™ 12K Flex Real-Time PCR System. Data were analyzed using SPSS for Mac V.21, utilizing Chi-squared and regression analysis with p The genotype frequency for the CAT SNP was: CC= 60.3%; CT= 37.0% and TT= 2.7%. Data was not reported in 1 of the cases, estimated at 1% of the cohort. The mutant allele was present at a frequency of 39.7% as compared to 12.4% in the general population and was statistically significant (Chi-Square=51, p Our findings suggest that both the CAT C-262T SNP and NADPH oxidase C242T SNP could be used in risk stratification for patients affected by either breast or ovarian cancers. Citation Format: Jimmy Belotte, Nicole M. Fletcher, Nancy K. Levin, Michael S. Simon, Husam M. Abu-Soud, Michael P. Diamond, Michael A. Tainsky, Ghassan M. Saed. Catalase and NADPH oxidase single nucleotide polymorphisms are associated with increased risk and serve as potential targets for breast and ovarian cancers. [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 LB-356. doi:10.1158/1538-7445.AM2013-LB-356 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.