Citations

5073 Background: Recent molecular exploration of high-grade epithelial ovarian cancer (OC) has revealed potential targets for novel therapy based on altered DNA repair function, deregulated pathways and recurrent amplifications (Cancer Genome Atlas Research Network. 2011. Nature 474). Improved pre-clinical models allowing analysis of specific molecular subsets of ovarian cancer are urgently required to test novel treatment strategies. Methods: We have generated a novel xenograft model of human high-grade serous OC (HG-SOC). Histologic, functional and molecular analysis of the novel xenograft cohort (at baseline and following xenotransplantation) allows stratification of individual HG-SOC for testing with appropriate targeted therapy. We perform functional analysis of in vitro Homologous Recombination (HR) DNA repair and drug response capabilities on fresh human HG-SOC immediately following surgical resection. Molecular classification (similar to Tothill [Clin Canc Res. 2008;14]); analysis of NHEJ pathway (Proc Natl Acad Sci. 2011;108) and other DNA repair genes (Proc Natl Acad Sci USA 2011;108) is performed. In vivo drug response is studied in murine xenografts. Results: Sixteen chemotherapy-naive potentially HG-SOC samples and associated clinical data have been collected. Functional evidence of DNA repair (HR) capability and response to DNA damaging agents will be presented, including IHC for markers of DNA damage (gH2AX), DNA repair (RAD51AP1) and apoptosis (capsase 3 cleavage). Molecular classification, DNA repair gene and DNA repair pathway analyses are underway. Twelve HG-SOC have been transplanted and 6 of the first 8 have successfully xenografted, with serial transplantation and phenotyping of xenograft derivatives underway. In vivo drug response will be presented. Conclusions: This xenograft model will enable us to address hypotheses generated by recent molecular analyses of human HG-SOC (Cancer Genome Atlas Research Network. 2011. Nature 474; Clin Canc Res. 2008;14). Clinical, functional and molecular annotation will allow pre-clinical drug testing based on the plausible hypothesis approach.

208 Background: Treatment of high risk prostate cancer (HRPCa) with external beam radiotherapy (EBRT) plus brachytherapy (BT) boost (EBRT+BT) has been prospectively associated with lower rates of BCR, albeit potentially with increased toxicity, and retrospectively linked to decreased distant metastasis (DM) and PCa-specific mortality (PCSM) compared to EBRT alone. However, it is unclear whether patients who develop BCR following either approach have similar downstream oncologic outcomes. Methods: We identified 706 out of 3820 men with HRPCa treated at 13 institutions from 1998-2015 with EBRT (n=468/2134) or EBRT+BT (n=238/1686) who developed BCR. We compared rates of DM, PCSM, and all-cause mortality (ACM) after BCR between treatment groups using Fine-Gray competing risk regression. Models were adjusted for age, Gleason grade group, initial PSA (iPSA), clinical T stage, time-dependent use of systemic salvage, and interval to BCR using inverse probability of treatment weighting. Results: Median follow-up was 9.9 years from RT and 4.8 years from BCR. Groups were similar in age, iPSA, presence of ≥2 HR features, and median interval to BCR (3.3 years). Most men received neoadjuvant/concurrent androgen deprivation therapy (ADT), 92.5% and 91.0% for EBRT and EBRT+BT, respectively, though for a longer duration with EBRT (median 14.7 vs. 9.0 months, p=0.0012). Local and systemic salvage rates were 2.3% and 36.3% after EBRT, and 2.6% and 43.6% after EBRT+BT, respectively. Initial EBRT+BT was associated with significantly lower rates of DM after BCR (HR 0.48, 95% CI 0.36-0.64, p<0.001). Rates of PCSM and ACM did not significantly differ (HR 0.93, 95% CI 0.67-1.30, p=0.93, and HR 0.8, 95% CI 0.6-1.1, p=0.11, respectively). Conclusions: In this large retrospective series of radiorecurrent HRPCa, initial treatment with EBRT+BT was associated with significantly lower rates of DM after BCR compared with EBRT, despite shorter ADT use and a similar median interval to BCR. Local salvage was widely underutilized in both groups. In the absence of salvage for local failure after EBRT, upfront treatment intensification with BT may reduce DM, though not PCSM or ACM, even after development of BCR.

Background: Patients with immune thrombocytopenia (ITP) may require treatment to raise the platelet count before surgery. Intravenous immune globulin (IVIG) is commonly used for this purpose, but eltrombopag, an oral thrombopoietin receptor agonist, may be a good alternative. We compared perioperative eltrombopag or IVIG for the achievement of platelet count targets for major or minor surgery. Methods: We conducted a randomized, non-inferiority trial at 8 centers in Canada.ITP patients with a platelet count &lt;100 x109/L or &lt;50 x109/L before elective major or minor surgery, respectively, were assigned to receive daily oral eltrombopag starting 3 weeks preoperatively or IVIG 1 week preoperatively. Eltrombopag was discontinued 1 week after surgical hemostasis, and a repeat dose of IVIG was permitted up to 1 week after surgical hemostasis. The primary endpoint was the achievement of platelet count targets (90 x109/L for major surgery, or 45 x109/L for minor surgery) immediately before surgery and for 7 days after surgical hemostasis without rescue treatment. Intention-to-treat and per-protocol analyses were done using a one-sided test for the difference in rates of achieving perioperative platelet count targets with a non-inferiority margin of 10% at a significance level of 0.05. Patients were followed for 4 weeks postoperatively. Secondary outcomes were thrombosis, adverse events and treatment satisfaction as measured using a validated patient questionnaire. Results: From 2013 to 2019, 38 patients were assigned to received eltrombopag and 36 patients were assigned to receive IVIG before major (n= 31) or minor (n= 43) surgery. Five patients did not complete the study. By intention to treat, 30/38 (78.9%) patients on eltrombopag achieved perioperative platelet count targets compared with 22/36 (61.1%) on IVIG (absolute risk difference, 17.8%; one-sided lower limit of the 95% confidence interval, 0.4%; p=0.005 for non-inferiority). Results were similar in the per protocol analysis (absolute risk difference: 15.8%; one-sided lower limit of the 95% CI, -2.1%; p=0.009). Eltrombopag was superior to IVIG in the intention-to-treat analysis (p=0.047) but not in the per-protocol analysis (p =0.074). One patient developed pulmonary embolism 14 days after minor surgery (skin biopsy) and 7 days after stopping eltrombopag when the platelet count was 135 x109/L. Of 18 patients who underwent splenectomy on study, marked post-splenectomy thrombocytosis (platelets &gt;1,000 x109/L) occurred in 2 (11.1%) patients, both of whom were on eltrombopag. Global treatment satisfaction scores were higher for eltrombopag. Conclusion: Eltrombopag is non-inferior and may be superior to IVIG for achieving target platelet counts perioperatively for patients with ITP. Post-operative thromboprophylaxis should be considered with eltrombopag. Funding Source:This was an investigator-initiated trial funded by Novartis. Disclosures Arnold: Novartis: Honoraria, Research Funding; Rigel: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Principia: Consultancy. Heddle:Novartis: Research Funding. Hsia:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Jansen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sholzberg:Novartis: Honoraria; Amgen: Honoraria, Research Funding. Lin:Pfizer: Consultancy; Novartis: Research Funding; Octapharma: Research Funding; Amgen: Consultancy. Larratt:Novartis: Honoraria. Amini:Amgen NL: Research Funding; Novartis NL: Research Funding. Schipperus:Novartis: Research Funding. Lim:Pfizer Canada: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Honoraria. OffLabel Disclosure: Eltrombopag is not licenced for perioperative treatment in patients with ITP.

PURPOSE: Gender disparity persists in academic medicine. Female faculty are underrepresented in leadership positions and have lower research output. We studied gender differences in faculty rank and departmental leadership and contributing factors among academic hematologists and oncologists in the United States. METHODS: For clinical faculty at 146 hematology or oncology fellowship programs listed in the Fellowship and Residency Electronic Interactive Database, we collected data on demographics, academic rank, and research output using the Doximity and Scopus databases. We compared unadjusted characteristics of men and women by using 2-sided t tests and χ2 tests where appropriate. To predict probability of full professorship or leadership position among men versus women, we performed multivariable logistic regression analysis adjusted for clinical experience in years, number of publications, h-index, clinical trial investigator status, National Institutes of Health funding, and workplace ranking (top 20 v not). RESULTS: Two thousand one hundred sixty academic hematologists and oncologists were included. Women composed 21.9% (n = 142) of full professors, 35.7% (n = 169) of associate professors, and 45.4% (n = 415) of assistant professors. Thirty percent (n = 70) of departmental leaders were women. Female faculty, compared with male faculty, had a lower mean h-index (12.1 v 20.9, respectively; P < .001) and fewer years of professional experience since fellowship (10 v 16 years, respectively; P < .001). After adjusting for duration of clinical experience, academic productivity, and workplace ranking, the odds of obtaining professorship (odds ratio [OR], 1.05; 95% CI, 0.71 to 1.57; P = .85) or divisional leadership (OR, 0.57; 95% CI, 0.20 to 1.58; P = .28) for female physicians were not different compared with male physicians. CONCLUSION: Gender disparity exists in senior ranks of academic hematology and oncology; however, gender is not a significant predictor in achieving professorship or department leadership position.

612 Background: The aim of this study was to examine the impact of diabetes mellitus (DM) on survival in neuroendocrine tumor and the impact of neuroendocrine tumor on glycemic control in DM. Methods: Patients with newly diagnosed neuroendocrine tumor with and without DM were matched 1:1 according to age, gender, and year of cancer diagnosis (2005-2017). The file was linked to the electronic medical record to obtain information on DM and neuroendocrine tumor therapies and laboratory results. There were 59 matched pairs (total 118 patients) included in the analysis. We compared characteristics between cases and controls and assessed survival with the Kaplan-Meier method and Cox proportional hazards model. Mixed models compared hemoglobin A1c and glucose levels over time. Results: Median age of patients at diagnosis was 67 (40-86); 41% had stage IV disease. Women constituted 49% of the study population; 22% had pancreatic neuroendocrine tumor and 45% had another GI primary neuroendocrine tumor. No differences in race/ethnicity, marital status, alcohol or tobacco use were detected between cancer patients with and without DM. Mean BMI was significantly different between DM and non-DM patients (31.0 [7.90] versus 26.4 [5.27]); p = 0.011. Among those with DM, mean HbA1c during the year following cancer diagnosis was 7.3%. Mean glucose was significantly different between DM (159.1 [43.5] versus non-DM pts 117 [31.5]); p < 0.001. Median follow-up time was 32.8 (2.4-165.4) months in alive patients. Three year survival was estimated at 72% (95% CI: 60-86%) for DM patients versus 80% (95% CI: 70-92%) in non-DM patients by Kaplan Meier method (p = 0.82 log rank test). Hazard ratio (stratification for matched pairs) = 1.33 (95% CI: 0.56 – 3.16; p = 0.51). Conclusions: DM did not adversely impact survival in patients with neuroendocrine tumor. Neuroendocrine tumor and its treatment did not affect glycemic control. This should be reassuring to oncologists and endocrinologists who treat patients with neuroendocrine tumors and diabetes.

Problem definition: Organ-transplanted patients typically receive high amounts of immunosuppressive drugs (e.g., tacrolimus) as a mechanism to reduce their risk of organ rejection. However, because of the diabetogenic effect of these drugs, this practice exposes them to a greater risk of new-onset diabetes after transplantation (NODAT), and hence, becoming insulin dependent. We study and develop effective medication management strategies to address the common conundrum of balancing the risk of organ rejection versus that of NODAT. Academic/practical relevance: Our research contributes to the healthcare operations management literature by developing a robust stochastic decision-making framework that allows for incorporating (1) false-positive and false-negative errors of medical tests, (2) inevitable estimation errors when data sets are used, (3) variability among physician’ attitudes toward ambiguous outcomes, and (4) dynamic and patient risk-profile-dependent progression of health conditions. Methodology: We apply an ambiguous partially observable Markov decision process (APOMDP) approach where dynamic optimization with respect to a “cloud” of possible models allows us to make decisions that are robust to potential misspecifications of risks. Results: We first provide various structural results that facilitate characterizing the optimal medication policies. Utilizing a clinical data set, we then compare the performance of the optimal medication policies obtained from our APOMDP model with the policies currently used in the medical practice. We observe that, in one year after transplant, our proposed policies can improve the life expectancy of each patient up to 4.58%, while reducing the medical expenditures up to 11.57%. Managerial implications: Balancing the risks of organ rejection and diabetes complications and considering factors such as physicians’ attitudes toward ambiguous outcomes, partial observability of medical tests, and patient-specific risk factors are shown to result in more cost-effective strategies for management of post-transplant medications compared with the current medical practice. Finally, simultaneous management of medications can facilitate the care coordination process between transplantation/nephrology and endocrinology departments of a hospital that are typically in charge of administering such medications.

Abstract Objectives This article aims to evaluate adult type 1 diabetes mellitus (T1DM) self-management behaviors (SMBs) related to exercise and alcohol on a survey versus a smartphone app to compare self-reported and self-tracked SMBs, and examine inter- and intrapatient variability. Methods Adults with T1DM on insulin pump therapy were surveyed about their alcohol, meal, and exercise SMBs. For 4 weeks, participants self-tracked their alcohol, meal, and exercise events, and their SMBs corresponding with these events via an investigator-developed app. Descriptive statistics and generalized linear mixed-effect models were used to analyze the data Results Thirty-five participants self-tracked over 5,000 interactions using the app. Variability in how participants perceived the effects of exercise and alcohol on their blood glucose was observed. The congruity between SMBs self-reported on the survey and those self-tracked with the app was measured as mean (SD). The lowest congruity was for alcohol and exercise with 61.9% (22.7) and 66.4% (20.2), respectively. Congruity was higher for meals with 80.9% (21.0). There was significant daily intra- and interpatient variability in SMBs related to preprandial bolusing: recommended bolus, p < 0.05; own bolus choice, p < 0.01; and recommended basal adjustment, p < 0.01. Conclusion This study highlights the variability in intra- and interpatient SMBs obtained through the use of a survey and app. The outcomes of this study indicate that clinicians could use both one-time and every-day assessment tools to assess SMBs related to meals. For alcohol and exercise, further research is needed to understand the best assessment method for SMBs. Given this degree of patient variability, there is a need for an educational intervention that goes beyond the traditional “one-size-fits-all” approach of diabetes management to target individualized treatment barriers.

Myeloid sarcomas (MS) are a rare manifestation of myeloid malignancies and can often be misdiagnosed, leading to a delay in treatment. The objective of this clinical case is to highlight the challenges of the clinical presentation and to emphasize the importance of this manifestation ensuring timely diagnosis and therapy. Here, we present a 43-year-old man who was diagnosed with acute myeloblastic leukemia (AML) after being evaluated for unintentional weight loss, subcutaneous nodules, thrombocytopenia, and anemia. The patient underwent chemotherapy with complete remission and presented 4 months later with dysphagia and cranial nerve palsies. Appropriate imaging and biopsy led to a diagnosis of myeloid sarcoma, and a decision was made to begin reinduction chemotherapy for AML achieving a second complete remission although his neurological deficits did not improve. Our case illustrates the protean presentation of myeloid sarcomas; clinicians should have a high suspicion for MS and remain vigilant when unexplained signs and symptoms arise in the background of a myeloid malignancy although challenges still remain when presentation is de novo. Advancements in understanding the pathophysiology of MS have been performed but remain not completely understood. High clinical suspicion, appropriate imaging, biopsy techniques, and expertise are paramount for timely diagnosis and treatment.