Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer.

ONC206, a dopamine receptor D2 (DRD2) antagonist and imipridone, is a chemically modified derivative of ONC201. Recently, ONC206 and other imipridones were identified as activators of the mitochondrial protease ClpP, inducing downstream pathways that allow them to selectively target cancer cells. Clinical trials showed that ONC201, the first in class imipridone, was well tolerated and exhibited tumor regression in some solid tumors. Our goal was to evaluate the effect of ONC206 on cell proliferation and tumor growth in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer (KpB model). ONC206 was more potent than ONC201 in inhibiting cell proliferation, as evidenced by a 10-fold decrease in IC50 for the SKOV3 and OVCAR5 cell lines. This was accompanied by the results that ONC206 significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, and inhibited adhesion and invasion in vitro. Treatment of obese and non-obese KpB mice with ONC206 elevated Bip and ClpP expression and reduced KI67, BCL-XL and DRD2 expression in the ovarian tumors. Our findings demonstrate that ONC206 has anti-tumorigenic effects in ovarian cancer as previously demonstrated by ONC201 but appears to be as well tolerated and more potent. Thus, ONC206 deserves further evaluation in clinical trials.

ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer.

BACKGROUND:Minimally invasive surgical (MIS) staging is the standard treatment approach for clinical stage I endometrial cancer. Historical rates of inoperability in endometrial cancer are approximately 10%. Given surgical and medical advancements against increasing population obesity, we aimed to describe a contemporary incidence of medical inoperability in clinical stage I endometrial cancer. PATIENTS AND METHODS:Patients diagnosed with clinical stage I endometrial cancer of any histology from April 2014 to December 2018 were included in this retrospective cohort study. The primary outcome, medical inoperability, was defined as (1) patients deemed inoperable by a gynecologic oncologist at initial consultation, (2) patients deemed inoperable during preoperative clearance, or (3) an aborted hysterectomy. Fisher's exact or χ2, and Student's t-test or Wilcoxon rank sum test were used, as appropriate, for data analysis. Multivariable logistic regression was also employed. RESULTS:Overall, 767 patients were included, of which 4.6% (35/767) were determined to be inoperable. The inoperable group had a higher body mass index (52.7 vs. 33.9, p < 0.001), and increased rates of diabetes (62.8%, 22/35 vs. 27.1%, 199/732, p < 0.001), coronary artery disease (31.4%, 11/35 vs. 7.1%, 52/732, p < 0.001), and hypertension (94.3%, 33/35 vs. 70.2%, 514/732, p < 0.001). Of those with attempted surgical staging, hysterectomy was aborted intraoperatively in 0.68% (5/737). The overall complication rate was 11.6% (86/737). CONCLUSIONS:With maximal surgical effort and MIS, hysterectomy is possible in > 95% of patients with newly diagnosed endometrial cancer treated at a high-volume center. Complication rates were comparable to other trials evaluating the safety of MIS staging for endometrial cancer.

Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1(fl/fl)p53(fl/fl) mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1(fl/fl)/p53(fl/fl) mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Importance Endometrial cancer is the most common gynecologic malignancy, with an estimated 54,000 new cases and 10,000 deaths in the United States in 2015. The obesity epidemic directly contributes to the escalating prevalence of chronic diseases, including obesity-related cancers. Patient body weight and nutritional status markedly impact perioperative oncologic care, chemotherapy administration, recurrence risk, and survivorship goals. Objective The objective of this review is to explore the association between obesity and the development, treatment, and survival outcomes of gynecologic cancers. Evidence Acquisition A systematic literature review was performed utilizing PubMed and ClinicalTrials.gov. Conclusions and Relevance Caring for obese women with gynecologic cancers presents unique challenges. A coordinated multidisciplinary and system effort is required to address the prevention and treatment of obesity, as the sequela of this disease is a clear risk factor for the development of gynecologic malignancy and other comorbidities. Health care providers must be ready to address this worldwide health problem. Target Audience Obstetricians, gynecologists, family physicians, midwives, nurse practitioners, and dietitians Learning Objectives After completion of this activity, the learner should be better able to describe the pathophysiologic correlation between obesity and common gynecologic malignancies; identify limitations in cancer care due to obesity and associated comorbidities; and counsel patients regarding management strategies for treatment of obesity.

•Paraneoplastic cerebellar degeneration in recurrence of fallopian tube cancer.•Describes the initial symptoms of paraneoplastic cerebellar degeneration.•Identify a diagnosis that can lead to rapid irreversible deterioration.•Describe management and outcomes of paraneoplastic cerebellar degeneration.

Background Adjuvant therapy in early-stage endometrial cancer has not shown a clear overall survival benefit, and hence, patient selection remains crucial. Objective To determine whether women with high-intermediate risk, early-stage endometrial cancer with lymphovascular space invasion particularly benefit from adjuvant treatment in improving oncologic outcomes. Methods A multi-center retrospective study was conducted in women with stage IA, IB, and II endometrial cancer with lymphovascular space invasion who met criteria for high-intermediate risk by Gynecologic Oncology Group (GOG) 99. Patients were stratified by the type of adjuvant treatment received. Clinical and pathologic features were abstracted. Progression-free and overall survival were evaluated using multivariable analysis. Results 405 patients were included with the median age of 67 years (range 27-92, IQR 59-73). 75.0% of the patients had full staging with lymphadenectomy, and 8.6% had sentinel lymph node biopsy (total 83.6%). After surgery, 24.9% of the patients underwent observation and 75.1% received adjuvant therapy, which included external beam radiation therapy (15.1%), vaginal brachytherapy (45.4%), and combined brachytherapy + chemotherapy (19.1%). Overall, adjuvant treatment resulted in improved oncologic outcomes for both 5-year progression-free survival (77.2% vs 69.6%, HR 0.55, p=0.01) and overall survival (81.5% vs 60.2%, HR 0.42, p<0.001). After adjusting for stage, grade 2/3, and age, improved progression-free survival and overall survival were observed for the following adjuvant subgroups compared with observation: external beam radiation (overall survival HR 0.47, p=0.047, progression-free survival not significant), vaginal brachytherapy (overall survival HR 0.35, p<0.001; progression-free survival HR 0.42, p=0.003), and brachytherapy + chemotherapy (overall survival HR 0.30 p=0.002; progression-free survival HR 0.35, p=0.006). Compared with vaginal brachytherapy alone, external beam radiation or the addition of chemotherapy did not further improve progression-free survival (p=0.80, p=0.65, respectively) or overall survival (p=0.47, p=0.74, respectively). Conclusion Adjuvant therapy improves both progression-free survival and overall survival in women with early-stage endometrial cancer meeting high-intermediate risk criteria with lymphovascular space invasion. External beam radiation or adding chemotherapy did not confer additional survival advantage compared with vaginal brachytherapy alone.

ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33µM vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201.

OBJECTIVE:We aim to describe the false negative (FN) and false positive (FP) rates of preoperative cross-sectional imaging (PCI) prior to radical surgery for cervical cancer.METHODS:A retrospective cohort study of patients who underwent radical hysterectomy for early-stage cervical cancer from January 2010 until December 2017 at a single tertiary care center was performed. Patients were included if they underwent preoperative PCI and radical surgery. Patient demographics and clinicopathologic information were recorded from medical record review. Descriptive statistics were used.RESULTS:Overall, 106 patients met inclusion criteria. Eighty-four percent (89/106) of patients had no suspicion for metastatic disease on PCI, while 16% (17/106) had suspicion for metastatic disease. Of the 89 without suspicion for metastatic disease on PCI, 16% (14/89) had a false negative study with metastatic disease identified on final surgical pathology. False negative rates by modality were 16% (11/70) for PET/CT and 6% (2/33) for diagnostic CT. Of the 17 cases with suspicion for metastatic disease on imaging, 53% (9/17) were false positive studies with no metastatic disease identified histologically. False positive rates by modality were 7% (5/70) for PET/CT and 12% (4/33) for diagnostic CT.CONCLUSION:PCI is a tool to help identify patients who are optimal candidates for radical surgery. In this sample, the false negative rate was 16%, and false positive rate was 53% for PCI among women who underwent primary radical surgery. Further study is needed to explore preoperative testing that may more accurately identify optimal surgical candidates.

Paclitaxel is one of the most effective and widely used agents in treating a variety of cancers, including endometrial cancer. Because of its poor solubility in water, the current intravenous pharmaceutical paclitaxel is formulated in Cremophor EL and dehydrated in ethanol in equal volumes. Cremophor EL is capable of causing complement activation, which can trigger an immediate hypersensitivity reaction. SPR064 is a pro-drug of paclitaxel which has a much higher solubility as compared to the parent drug; hence, SPR064 can be conveniently formulated in non-cremapor based medium, reducing the risk of cremaphor-related hypersensitivity reactions. The pharmacokinetics and solubility of SPR064 were evaluated in rats. The anti-tumorigenic potential of SPR064 was compared to paclitaxel in endometrial cancer cell lines and a genetically engineered mouse model (Lkbfl/flp53fl/fl ) of endometrial cancer. Overall, SPR064 exhibited improved solubility and better exposure to drug in rats when compared to paclitaxel. SPR064 and paclitaxel inhibited cell proliferation, induced apoptosis, enhanced cellular stress and caused cell cycle G1 arrest in endometrial cancer cell lines, with similar potency. Both SPR064 and paclitaxel reduced tumor weight in the Lkbfl/flp53fl/fl mouse model under obese and lean conditions compared to their respective controls. Immunohistochemical staining demonstrated that SPR064 and paclitaxel significantly reduced the expression of Ki-67 and BCL-xL in the endometrial tumors of both obese and lean mice. In summary, SPR064 has anti-tumorigenic effects that are equivalent to paclitaxel in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Thus, SPR064 may be a promising therapy for endometrial cancer without the significant risk of hypersensitivity reactions seen with paclitaxel.

Objectives. Severe skeletal muscle loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased treatment toxicity. Our goal was to evaluate if sarcopenia was associated with worse survival outcomes and chemotoxicity in EOC patients undergoing primary platinum and taxane-based chemotherapy. Methods. EOC patients diagnosed between 06/2000 and 02/2017 who received treatment with platinum and taxane-based chemotherapy were included. CT abdominal images closest to the time of diagnosis were retrospectively evaluated for skeletal muscle area at the 3rd lumbar vertebrae. Measurements were obtained with use of TomoVision radiological software (SliceOmatic-version 5.0, Quebec, Canada). Sarcopenia was defined as Skeletal Muscle Index (SMI) 5 41. Data analysis included Kaplan-Meier plots to assess survival, and unpaired t-tests were used to compare the means by groups. Results. 201 EOC patients were evaluated. Sixty-four percent (128/201) met criteria for sarcopenia (SMI 5 41) at time of diagnosis. The mean overall survival did not differ between patients with SMI > 41 and SMI 5. 41 (36.5 vs 40.8 months, p = 0.4, respectively). No difference in frequency of dose reduction, dose delay, hospital admissions, changes in regimen, blood transfusion, or toxicity was noted. There was no difference in distribution of toxicity grade. Conclusion. Sarcopenia was not associated with worse survival outcomes or chemotoxcity in EOC patients receiving first-line platinum and taxane-based chemotherapy in this cohort Future prospective studies should focus on interventions to prevent or reverse sarcopenia and possibly increase ovarian cancer survival, performance status, and quality of life. (C) 2020 Elsevier Inc. All rights reserved.

PURPOSE To compare the disease-free survival (DFS) between open and minimally invasive radical hysterectomies (RH) performed in academic medical institutions METHODS Retrospective multi-institutional review of patients undergoing RH for stage IA1 (with lymphovascular invasion), IA2, and IB1 squamous, adenocarcinoma, or adenosquamous carcinoma between January 1, 2010 and December 31, 2017. RESULTS Of 815 patients, open RH was performed in 255 cases (29.1%) and minimally invasive RH in 560 cases (70.9%). There were 19 (7.5%) recurrences in the open RH and 51 (9.1%) recurrences in the minimally invasive group ( P = .43). Risk-adjusted analysis revealed that minimally invasive RH was independently associated with an increased hazard of recurrence (aHR, 1.88; 95% CI, 1.04 to 3.25). Other factors independently associated with an increased hazard of recurrence included tumor size, grade, and adjuvant radiation. Conization before surgery was associated with lower recurrence risk (aHR, 0.4; 95% CI, 0.23 to 0.71). There was no difference in OS in the unadjusted analysis (HR, 1.14; 95% CI, 0.61 to 2.11) or after risk adjustment (aHR, 1.01; 95% CI, 0.5 to 2.2). Of 264 patients with tumors ≤ 2 cm on final pathology (excluding those with no residual tumor on final pathology), 2/82 (2.4%) recurred in the open RH group and 16/182 (8.8%) in the minimally invasive RH group ( P = .058). In propensity score matching analysis, 7/159 (4.4%) recurrences were noted in the open RH group and 18/156 (11.5%) in the minimally invasive RH group ( P = .019). Survival analysis revealed an increased risk of recurrence in the minimally invasive group in propensity-matched cohort (HR, 2.83; 95% CI, 1.1 to 7.18) CONCLUSION In this retrospective series, patients undergoing minimally invasive radical hysterectomy, including those with tumor size ≤ 2 cm on final pathology, had inferior DFS but not overall survival in the entire cohort.

Omega-3 polyunsaturated fatty acids (PUFAs), such as those found in fish oil, are thought to have anti-tumorigenic effects and may help to treat and prevent cancer, including ovarian cancer. Thus, we aimed to evaluate the potential of docosahexaenoic acid (DHA), an omega-3 PUFA, as a therapeutic agent in ovarian cancer cell lines and a transgenic mouse model of ovarian cancer. DHA significantly inhibited cellular proliferation, induced cell cycle arrest and caused apoptosis in Hey and IGROV-1 cells. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed DHA-induced caspase 3 activity and prevented DHA-reduced cell proliferation. DHA also induced cellular reactive oxygen species (ROS) and inhibited adhesion and invasion in IGROV-1 and Hey cells. Furthermore, treatment with DHA demonstrated anti-tumorigenic and anti-invasive activity in a K18-gT121+/-; p53fl/fl; Brca1fl/fl mouse model of ovarian cancer including downregulation of Ki67 and VEGF expression. The data provide a preclinical rationale for applying DHA for dietary intervention and therapeutic adjunct in patients with ovarian cancer.

Objective Effective postpartum contraception can improve interpregnancy intervals. Opportunities exist for counseling and education during prenatal care. Few studies have assessed the use of multimedia as a tool to improve long-acting reversible contraception (LARC) use postpartum. The objective of this study was to evaluate whether LARC-focused video counseling during prenatal care increases uptake of postpartum LARC and overall contraception use. Methods In this randomized controlled trial, women receiving their prenatal care at a university-based resident clinic were randomized to receive LARC FIRST video contraceptive counseling along with routine prenatal care or routine prenatal care alone. All of the participants received information regarding access to free LARC methods in the postpartum period. The primary outcome was LARC uptake by 12 weeks postpartum. Secondary outcomes included overall contraception use at 12 weeks postpartum, postpartum visit attendance, and acceptability of video counseling. Results LARC use at 12 weeks postpartum rose from an estimated 6% preintervention to 39.4% (13/33) in the video group compared with 29.4% (10/34) of the control group. The difference between groups was not statistically significant. Although overall contraceptive use (72.7% vs 54.8%) and postpartum visit attendance (91% vs. 76.5%) were higher in the video group relative to the control group, these differences were not statistically significant. Participants overwhelmingly liked the video (95.2%, 41/42) and believed viewing it was a good use of their appointment time (92%, 38/42). Conclusions LARC use increased 32% across the entire study cohort; however, video-based contraceptive counseling did not increase LARC uptake at 12 weeks postpartum compared with routine prenatal care alone. Patients viewing the video reported high levels of acceptability and improved contraceptive knowledge. Video counseling may be a useful adjunct in many clinical settings.

Malignant Brenner tumor (MBTs) is a rare histological subtype of epithelial ovarian cancer, accounting for < 0.05% of all ovarian neoplasms. As such, current evidence on the treatment of MBTs is predominantly limited to case studies and small case series. To add to existing literature, we performed a retrospective review of 10 cases of MBT diagnosed and treated at a single institution between 1999 and 2018. For the 10 cases included in our cohort, the median age was 64 and the median tumor stage was IIa/IIb. All patients underwent either a primary or interval debulking surgery and achieved an R0 resection per classifications set by the Union for International Cancer Control (UICC). Lymph node dissections were performed on 6 patients and found no evidence of positive nodal disease. 7 patients received platinum-based adjuvant chemotherapy and experienced a median progression-free survival (PFS) of 37 months. Recurrent disease was varied in terms of locoregional versus distant spread, and these patients had largely suboptimal responses to salvage chemotherapy with doxorubicin, gemcitabine, and eribulin. Sites of metastatic disease included the liver, lungs, bone, and brain. While there is no consensus for the optimal treatment of this rare disease, MBTs seem to respond well to adjuvant platinum-taxane treatment after complete surgical resection, consistent with the current management approach of other epithelial ovarian cancers. Recurrent disease is considerably more difficult to manage, and clinicians may consider a wider avenue of treatment options to include hormonal, biologic, and radiation therapies.

This article was migrated. The article was marked as recommended. Objectives: Our objective is to describe a process for development and implementation of a web-based curriculum addressing gynecologic perioperative complications. Methods: Residents, Fellows, and Faculty completed a needs assessment survey addressing satisfaction with baseline perioperative complications curriculum. Residents completed a knowledge pretest. Residents received weekly emails with links to developed topic-specific materials over 4 weeks. Residents completed a post-implementation survey to assess satisfaction and to retest knowledge. Results: 75% (21/28) of Residents and 47% (40/86) Fellows/Faculty completed the needs assessment. 95% (20/21) of Residents and 90% (36/40) Fellows/Faculty reported dissatisfaction with baseline perioperative complications curriculum. Ureteral injury, bowel injury, vaginal cuff dehiscence, and bladder injury were prioritized topics, while assigned readings, interactive web-based case modules, and intraoperative instruction were prioritized modalities for curriculum development. Resident pretest mean score was 72% (40-90%, SD = 15). Weekly curriculum emails were successfully distributed all Resident learners. Eighteen percent of Residents completed the post-implementation survey, with 100% reporting satisfaction with the web-based case modules. Post-test knowledge mean score was 84% (60-100%, SD = 15). Conclusion: Low satisfaction rate with baseline curriculum was reported. Materials were developed and distributed weekly to all Residents, who successfully and consistently accessed the developed web-based curriculum.

Purpose of investigation: The authors sought to investigate the significance of radiographically bulky nodes (BN) on progression free survival (PFS) and overall survival (OS) in patients with locally advanced cervical cancer (CC) in an era of cisplatin chemoradiation. Methods and Materials: The authors performed a retrospective, IRB-approved review of women with Stage IB1 to IVA CC undergoing primary chemoradiation with cisplatin from February 2000 to February 2015. BN were defined as > 1.5 centimeters on pretreatment imaging. Results: Of the 127 patients identified, 29 (22.8%) had radiographically BN. Median PFS was 16.6 months for patients with BN compared to 57.4 months for those without (p = 0.001). Median OS for patients with BN was not statistically different from for those without. BN had no impact on site of recurrence (p = 0.99). Both stage (p = 0.01) and BN (p = 0.01) were independently prognostic for PFS; only stage (p = 0.002) was prognostic for OS. Conclusions: For locally advance CC, BN disease shortened PFS but did not affect OS.

Abstract Objectives: Obesity and diabetes are associated with increased risk and worse outcomes in endometrial cancer (EC). Anti-diabetic biguanide drugs such as metformin/phenformin may have anti-tumorigenic effects by behaving as AMPK activators. Metformin requires organic cation transporters (OCTs) for entry into cells whereas phenformin is not as reliant on OCTs for cell entry. NT1195 (NovaTarg) is a novel biguanide designed to have greater affinity for the OCT1/3, PMAT and MATE1 transporters. Thus, we compared head-to-head the pharmacokinetic properties and anti-tumorigenic potential of metformin vs phenformin vs NT1195 in a genetically engineered mouse model of endometrioid EC (LKB1fl/flp53fl/fl). Methods: Pharmacokinetic parameters, including half-life, AUC, bioavailability and uterine concentration were measured in female control mice after oral dosing of metformin, phenformin and NT1195 (5 mg/kg oral for all drugs). AdCre was injected at 6 wks of age to induce invasive EC in LKB1fl/flp53fl/fl mice. Following tumor onset, mice were treated with placebo vs metformin vs phenformin vs NT1195 for 4 wks (50 mg/kg, oral for all drugs). Results: NT1195 (> 24 hrs) had a longer half-life when compared to metformin (3.7 hrs) and phenformin (7.2 hrs). Drug bioavailability was heightened in the NT1195-treated mice when compared to metformin and phenformin (149 vs 83.5 vs 8.31%, respectively). The AUC (h*kg*ng/ml/mg) for NT1195 was significantly higher at 1143 than that of metformin (26) and phenformin (184). Drug accumulation in uterine tissue at 24 hrs post dose demonstrated markedly increased presence of NT1195 (45.4 ng/g), compared to metformin and phenformin, which yielded levels below the limits of quantification. NT1195 had increased anti-tumorigenic efficacy in LKB1fl/flp53fl/fl mice, inhibiting tumor growth by 88% compared to 78% for metformin and 80% for phenformin (p<0.01). Conclusions: When compared to metformin/phenformin, NT1196 had superior bioavailability, a longer half-life and greater uterine tissue penetration, culminating in improved efficacy in an EC mouse model. Thus, NT1195 may be a promising novel biguanide therapy in EC, particularly in women who want to avoid hysterectomy and preserve fertility or are poor surgical candidates. Citation Format: Katherine Tucker, Allison Staley, Yali Fan, Xiaoling Zhao, Yajie Yin, Ziwei Fang, Wenchuan Sun, Kenneth Batchelor, Nick Livingston, Chunziao Zhou, Victoria Bae-Jump. NT1195, a novel biguanide, exhibits superior uterine penetration and anti-tumorigenic efficacy as compared to metformin/phenformin in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 361.