OKN-007 is an Effective Anticancer Therapeutic Agent Targeting Inflammatory and Immune Metabolism Pathways in Endometrial Cancer.

Advanced-stage endometrial cancer patients typically receive a combination of platinum and paclitaxel chemotherapy. However, limited treatment options are available for those with recurrent disease, and there is a need to identify alternative treatment options for the advanced setting. Our goal was to evaluate the pre-clinical efficacy and mechanism of action of Oklahoma Nitrone 007 (OKN-007) alone and in combination with carboplatin and paclitaxel in endometrial cancer. The effect of OKN-007 on the metabolic viability of endometrial cancer cells in both two- and three-dimensional (2D and 3D) cultures, as well as on clonogenic growth, in vitro was assessed. We also evaluated OKN-007 in vivo using an intraperitoneal xenograft model and targeted gene expression profiling to determine the molecular mechanism and gene expression programs altered by OKN-007. Our results showed that endometrial cancer cells were generally sensitive to OKN-007 in both 2D and 3D cultures. OKN-007 displayed a reduction in 3D spheroid and clonogenic growth. Subsequent targeted gene expression profiling revealed that OKN-007 significantly downregulated the immunosuppressive and immunometabolic enzyme indolamine 2,3-dioxygenase 1 (IDO1) (-11.27-fold change) and modulated upstream inflammatory pathways that regulate IDO1 expression (interferon- (IFN-), Jak-STAT, TGF-ß, and NF-kB), downstream IDO1 effector pathways (mTOR and aryl hydrocarbon receptor (AhR)) and altered T-cell co-signaling pathways. OKN-007 treatment reduced IDO1, SULF2, and TGF-ß protein expression in vivo, and inhibited TGF-ß, NF-kB, and AhR- receptor-mediated nuclear signaling in vitro. These findings indicate that OKN-007 surmounts pro-inflammatory, immunosuppressive, and pro-tumorigenic pathways and is a promising approach for the effective treat endometrial cancer. Significance Statement Women with advanced and recurrent endometrial cancer have limited therapeutic options. OKN-007, which has minimal toxicity and is currently being evaluated in early-phase clinical trials for the treatment of cancer, is a potential new strategy for the treatment of endometrial cancer.

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute-Comprehensive Cancer Center.

Germline mutations (eg, BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.

Does supraphysiologic estradiol level during IVF have any effect on oocyte/embryo quality? A sibling embryo cohort analysis of fresh and subsequent frozen embryo transfer.

BACKGROUND: The aim of this paper was to determine the effect of supraphysiologic serum estradiol (E2) level on oocyte and embryo development during IVF cycles. METHODS: This is a retrospective data analysis of all autologous IVF cycles where fresh embryo transfer was performed followed by subsequent frozen embryo transfer (FET) using cryopreserved sibling embryos. Primary outcome was live birth rate (LBR). Secondary outcomes were oocyte and embryo characteristics. RESULTS: Patients with high E2 (defined as serum peak E2>50th percentile [3727 pg/mL]) recorded prior to HCG trigger had significantly higher number of matured oocytes, zygotes exhibiting two pronuclei, cleavage stage embryos, blastocysts, and vitrified embryos. Following FET, LBR was higher among patients with high than normal E2 (55% vs. 37%, odds ratio [OR] 2.02; 95% confidence interval [CI] 1.05-3.88, P=0.03). Paired analysis revealed that the likelihood of achieving live birth was higher with FET compared to fresh transfer both among high E2 (54.7% vs. 26.7%; OR 3.3; 95% CI: 1.67-6.58, P<0.001) and normal E2 (37.3% vs. 18.7%; OR 2.6; 95% CI 1.23-5.47, P=0.01) patients. CONCLUSIONS: Supraphysiologic serum E2 level prior to HCG trigger does not appear to have negative impact on oocyte and embryo quality.

Determining the fertility benefit of controlled ovarian hyperstimulation with intrauterine insemination after operative laparoscopy in patients with endometriosis.

STUDY OBJECTIVE: To determine the fertility benefit of controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI) in surgically treated endometriosis. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Cleveland Clinic Foundation, tertiary care center. PATIENTS: Ninety-six women of reproductive age who underwent operative laparoscopy to treat endometriosis-related infertility (endometriosis stage I/II n = 67; stage III/IV n = 29) from 2001 to 2011 at the Cleveland Clinic Foundation. INTERVENTIONS: COH via letrozole, clomiphene, or gonadotropins, with or without IUI. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier estimations of cumulative pregnancy rates were compared by stage between COH/IUI and spontaneous cycles. Patients with stage I/II endometriosis attempted spontaneous pregnancy for 669 months and 216 COH + IUI cycles, and patients with stage III/IV endometriosis attempted spontaneous pregnancy for 379 months and 74 COH + IUI cycles. Crude pregnancy rates were 45.7% in stage I/II and 40.5% in stage III/IV. Twelve-month cumulative pregnancy rates in stage I/II were 45% for spontaneous attempts and 42% for COH + IUI, and in stage III/IV were 20% for spontaneous attempts and 10% for COH + IUI (not significant). Cumulative pregnancy rates for COH/IUI in stage I/II were significantly higher than in stage III/IV. Monthly fecundity rates were 3.81% for stage I/II spontaneous, 4.59% for COH/IUI, 3.05% for stage III/IV spontaneous, and 1.68% for COH/IUI (not significant). CONCLUSIONS: COH + IUI did not improve pregnancy rates in any stage of endometriosis. In stage III/IV we recommend postoperative in vitro fertilization.