Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors.

Background: There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer.

Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response.

In various cancer models, dietary interventions have been shown to inhibit tumor growth, improve anticancer drug efficacy, and enhance immunity, but no such evidence exists for epithelial ovarian cancer (EOC), the most lethal gynecologic cancer. The anticancer immune responses induced by 16-h intermittent fasting (IF) were studied in mice with EOC. IF consistently reduced metabolic growth factors and cytokines that stimulate tumor growth, creating a tumor-hostile environment.

A patient perspective on applying intermittent fasting in gynecologic cancer.

Objective: Researchers sought patient feedback on a proposed randomized controlled trial (RCT) in which gynecological cancer patients would modify their diets with intermittent fasting to gain insight into patients' perspectives, receptivity, and potential obstacles. A convenience sample of 47 patients who met the inclusion criteria of the proposed RCT provided their feedback on the feasibility and protocols of the RCT using a multi-method approach consisting of focus groups (n = 8 patients) and surveys (n = 36 patients).

Results: Patients were generally receptive to the concept of intermittent fasting, and many expressed an interest in attempting it themselves.

Intermittent Fasting induced ketogenesis inhibits mouse epithelial ovarian tumors by promoting anti-tumor T cell response.

Epithelial Ovarian Cancer (EOC) is the most lethal gynecologic cancer with limited genetic alterations identified that can be therapeutically targeted. In tumor bearing mice, short-term fasting, fasting mimicking diet and calorie restriction enhance the activity of antineoplastic treatment by modulating systemic metabolism and boosting anti-tumor immunity. We tested the outcome of sixteen-hour intermittent fasting (IF) on mouse EOC progression with focus on fasting driven antitumor immune responses.

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo.

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines.

Ovarian cancer modulates the immunosuppressive function of CD11bGr1 myeloid cells via glutamine metabolism.

Objective: Immature CD11b  Gr1 myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11bGr1 myeloid cells.

Methods: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model.

Autophagic adaptation to oxidative stress alters peritoneal residential macrophage survival and ovarian cancer metastasis.

Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression.

The impact of a wireless audio system on communication in robotic-assisted laparoscopic surgery: A prospective controlled trial.

Background: Robotic surgery presents a challenge to effective teamwork and communication in the operating theatre (OR). Our objective was to evaluate the effect of using a wireless audio headset device on communication, efficiency and patient outcome in robotic surgery.

Methods And Findings: A prospective controlled trial of team members participating in gynecologic and urologic robotic procedures between January and March 2015.

A Matched Analysis on the Prognostic Impact of Race on Survival Endpoints of Women with Early-Stage Endometrial Cancer.

Objective: To compare survival endpoints between African American (AA) and non-AA (NAA) women with endometrial carcinoma (EC) stage I-II using a robust matching analysis.

Methods And Materials: Patients were matched by stage, grade, adjuvant management (surveillance, vaginal brachytherapy or pelvic radiation treatment), age, and year of hysterectomy. Recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were calculated.

The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis.

Objective: As the optimal adjuvant management of stage IA serous or clear cell endometrial cancer is controversial, a multi-institutional review was conducted with the objective of evaluating the appropriateness of various strategies including observation.

Methods: Retrospective chart reviews for 414 consecutive patients who underwent hysterectomy for FIGO stage IA endometrial cancer with serous, clear cell or mixed histology between 2004 and 2015 were conducted in 6 North American centers. Time-to-event outcomes were analyzed by Kaplan-Meier estimates, log-rank test, univariable and multivariable cox proportional hazard regression models.

Does Age-Adjusted Charlson Comorbidity Score Impact Survival Endpoints in Women with Federation of Gynecology and Obstetrics-Stage III Endometrial Cancer?

Objectives: We sought to evaluate the impact of age-adjusted Charlson comorbidity index (AACCI) score on survival endpoints for women with advanced stage endometrial carcinoma (EC).

Methods And Materials: We identified 238 women with stage III EC. AACCI score was calculated and 3 groups were created accordingly; group 1 with a score of 0-2, group 2 with score 3-4, and group 3 with score ≥5.

Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity.

Naïve T cells are poorly studied in cancer patients. We report that naïve T cells are prone to undergo apoptosis due to a selective loss of FAK family-interacting protein of 200 kDa (FIP200) in ovarian cancer patients and tumor-bearing mice. This results in poor antitumor immunity via autophagy deficiency, mitochondria overactivation, and high reactive oxygen species production in T cells.

Clear Cell Carcinoma of the Endometrium: Evaluation of Prognostic Parameters in a Multi-institutional Cohort of 165 Cases.

Objectives: Clear cell carcinoma (CCC) comprises a rare yet an aggressive subtype, accounting for less than 5% of all uterine carcinomas. Several clinicopathologic features have been predictive of poor prognosis; however, data remain controversial. The aim of this study was to evaluate the clinicopathologic features of a multi-institutional cohort of endometrial CCC in order to identify which, if any, have prognostic significance.

Bioenergetic Adaptations in Chemoresistant Ovarian Cancer Cells.

Earlier investigations have revealed that tumor cells undergo metabolic reprogramming and mainly derive their cellular energy from aerobic glycolysis rather than oxidative phosphorylation even in the presence of oxygen. However, recent studies have shown that certain cancer cells display increased oxidative phosphorylation or high metabolically active phenotype. Cellular bioenergetic profiling of 13 established and 12 patient derived ovarian cancer cell lines revealed significant bioenergetics diversity.

Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.

Objective: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor.

External pelvic and vaginal irradiation vs. vaginal irradiation alone as postoperative therapy in women with early stage uterine serous carcinoma: Results of a National Cancer Database analysis.

Purpose: Adjuvant treatment in early stage uterine serous carcinoma (USC) usually consists of chemotherapy with vaginal brachytherapy (VB), pelvic external beam radiation therapy (EBRT), or combination. We compared survival outcomes across these various radiation treatment modalities using the National Cancer Database.

Methods And Materials: The National Cancer Database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I-II USC diagnosed from 2003 to 2013 treated definitively with hysterectomy, adjuvant chemotherapy, and radiation therapy.

Involvement and comfort of gynecologic oncologists in the treatment of pediatric, adolescent, and young adult patients with gynecologic malignancies.

Objective: To investigate the provision of care for pediatric and adolescent patients by gynecologic oncologists.

Methods: The present prospective cross-sectional study enrolled attending physicians and fellows specializing in gynecologic oncology from the USA during December 2012 and January 2013. A 33-question survey collecting demographic data and details of participant opinions on existing practices was distributed to potential respondents.

Predictive Capacity of 3 Comorbidity Indices in Estimating Survival Endpoints in Women With Early-Stage Endometrial Carcinoma.

Objective: The negative impact of comorbidity on survival in women with endometrial carcinoma (EC) is well-known. Few validated comorbidity indices are available for clinical use, such as the Charlson Comorbidity Index (CCI), the Age-Adjusted CCI (AACCI), and the Adult Comorbidity Evaluation-27 (ACE-27). The aim of the study is to determine which index best correlates with survival endpoints in women with EC.

Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.

Objectives: BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells.

Cancer and the world's poor: What's a gynecologic cancer specialist to do?

Women in low- and middle-income countries (LMICs) face a drastically increased burden of cervical cancer and the same burden of other gynecologic cancers as do women in high-income countries, yet there are few resources or specialists to meet their needs. 85% of deaths from cervical cancer occur in LMICs. As the population of these regions age, and as death from infectious diseases decrease, this burden will increase further without strong intervention.

Predictors of Survival After Recurrence in Women With Early-Stage Endometrial Carcinoma.

Objective: Factors predictive of survival after recurrent early-stage endometrial carcinoma have not been thoroughly investigated. The purpose of this study was to explore factors that impact disease-specific survival (DSS) and overall survival (OS) after recurrence in women with early-stage endometrial carcinoma.

Materials And Methods: After institutional review board approval, we identified 104 women with 2009 International Federation of Gynecology and Obstetrics stage I to II uterine endometrioid carcinoma who developed disease recurrence between January 1990 and December 2014.

Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.

Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy.

Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency.