OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab.

OBJECTIVE: To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. METHODS: 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. RESULTS: 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). CONCLUSION: Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

Comparing niraparib versus platinum-taxane doublet chemotherapy as neoadjuvant treatment in patients with newly diagnosed homologous recombination-deficient stage III/IV ovarian cancer: study protocol for cohort C of the open-label, phase 2, randomized controlled multicenter OPAL trial.

BACKGROUND: Maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib's efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination-deficient tumors. METHODS: OPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator's discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator's discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination-deficient. The primary endpoint is the pre-interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1. DISCUSSION: OPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination-deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT03574779. Registered on February 28, 2022.

Specific point mutations in key redox enzymes are associated with chemoresistance in epithelial ovarian cancer.

Oxidative stress plays an important role in the pathophysiology of ovarian cancer. Resistance to chemotherapy presents a significant challenge for ovarian cancer treatment. Specific single nucleotide polymorphisms (SNPs) in key redox enzymes have been associated with ovarian cancer survival and progression. The objective of this study was to determine whether chemotherapy induces point mutations in key redox enzymes that lead to the acquisition of chemoresistance in epithelial ovarian cancer (EOC). Human EOC cell lines and their chemoresistant counterpart were utilized for this study. Specific SNPs in key redox enzymes were analyzed by TaqMan SNP Genotyping. Activities and levels of key redox enzymes were determined by real-time RT-PCR, ELISA and a greiss assay. Point mutations in key redox enzymes were introduced into sensitive EOC cells via the CRISPR/Cas9 system. Cell viability and IC50 for cisplatin were determined by the MTT Cell Proliferation Assay. Data was analyzed with SPSS using Student's two-tailed t-tests and One-way ANOVA followed by Dunnett's or Tukey's post hoc tests, p<0.05. Here, we demonstrate that chemoresistant EOC cells are characterized by a further enhancement in oxidative stress as compared to sensitive counterparts. Additionally, chemoresistant EOC cells manifested specific point mutations, which are associated with altered enzymatic activity, in key redox enzymes that are not detected in sensitive counterparts. Supplementation of an antioxidant was able to successfully sensitize EOC cells to chemotherapeutics. Causality was established by the induction of these point mutations in sensitive EOC cells, which resulted in a significant increase in the level of chemoresistance. These findings indicate that chemotherapy induces specific point mutations in key redox enzymes that contribute to the acquisition of chemoresistance in EOC cells, highlighting a potential novel mechanism. Identification of targets for chemoresistance with either biomarker and/or screening potential will have a significant impact for the treatment of this disease.

The Role of Angiogenesis in the Persistence of Chemoresistance in Epithelial Ovarian Cancer.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Sox2 gene amplification significantly impacts overall survival in serous epithelial ovarian cancer.

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.

A Single Nucleotide Polymorphism in Catalase Is Strongly Associated with Ovarian Cancer Survival.

Ovarian cancer is the deadliest of all gynecologic cancers. Recent evidence demonstrates an association between enzymatic activity altering single nucleotide polymorphisms (SNP) with human cancer susceptibility. We sought to evaluate the association of SNPs in key oxidant and antioxidant enzymes with increased risk and survival in epithelial ovarian cancer. Individuals (n = 143) recruited were divided into controls, (n = 94): healthy volunteers, (n = 18), high-risk BRCA1/2 negative (n = 53), high-risk BRCA1/2 positive (n = 23) and ovarian cancer cases (n = 49). DNA was subjected to TaqMan SNP genotype analysis for selected oxidant and antioxidant enzymes. Of the seven selected SNP studied, no association with ovarian cancer risk (Pearson Chi-square) was found. However, a catalase SNP was identified as a predictor of ovarian cancer survival by the Cox regression model. The presence of this SNP was associated with a higher likelihood of death (hazard ratio (HR) of 3.68 (95% confidence interval (CI): 1.149-11.836)) for ovarian cancer patients. Kaplan-Meier survival analysis demonstrated a significant median overall survival difference (108 versus 60 months, p<0.05) for those without the catalase SNP as compared to those with the SNP. Additionally, age at diagnosis greater than the median was found to be a significant predictor of death (HR of 2.78 (95% CI: 1.022-7.578)). This study indicates a strong association with the catalase SNP and survival of ovarian cancer patients, and thus may serve as a prognosticator.

Advances in the Pathogenesis of Adhesion Development: The Role of Oxidative Stress.

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.

Successful laparoscopic management of ruptured tubal pregnancy with an ipsilateral ectopic pelvic kidney.

Objective. To report a case of successful laparoscopic management of a left ruptured tubal pregnancy in the setting of an ipsilateral ectopic pelvic kidney. Method. Case report was prepared at Wayne State University/Detroit Medical Center. The patient is a young woman gravida 2 para 0 in her twenties who presented with severe abdominal pain and vaginal bleeding. She had a plateaued beta HCG and ultrasonographic findings suggestive of ectopic left tubal pregnancy along with an ectopic ipsilateral pelvic kidney. The IRB approval is not needed, as this is a case report. The informed consent could not be obtained, as the patient was not reachable. Result. Multiple intraperitoneal adhesions, left ruptured ampullary ectopic pregnancy and left retroperitoneal pelvic mass consistent with ipsilateral ectopic pelvic kidney. Conclusion. Laparoscopic management of tubal pregnancy can be safely performed in the setting of an ipsilateral ectopic pelvic kidney.

The role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer.

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 (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. RESULTS: 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). CONCLUSION: Our data suggest that the development of cisplatin resistance tilts the balance toward a pro-oxidant state in EOC.

Chemotherapy of vulvar cancer: a review.

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.

Platinum-based combination chemotherapy for the treatment of advanced-stage squamous cell carcinoma of the vulva.

BACKGROUND: 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. CASE: 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. CONCLUSION: Platinum-based combination chemotherapy may be used successfully for patients with advanced-stage squamous carcinoma of the vulva.

Small bowel obstruction subsequent to Essure microinsert sterilization: a case report.

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.

Myeloperoxidase and free iron levels: potential biomarkers for early detection and prognosis of ovarian cancer.

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.