Citations

SummaryIntroductionTo better inform the field of obesity medicine, we set out to describe the current use of pharmacotherapy meant to improve patient weight status among a group of clinicians connected through the Paediatric Obesity Weight Evaluation Registry (POWER), as well as reasons behind clinicians' use or non‐use of the medications.MethodsPaediatric weight management (PWM) programs participating in POWER were asked to complete a program profile survey in 2014 (n = 30) and 2017 (n = 33); questions about pharmacotherapy use were included. Descriptive statistics were used to identify: (a) the proportion of PWM programs offering obesity pharmacotherapy; (b) the medications most commonly prescribed; and (c) reasons among non‐prescribers for not offering pharmacotherapy.ResultsThe 2014 and 2017 surveys were completed by 29 PWM programs (97%) and 30 PWM programs (91%), respectively. Twenty‐one programs completed both surveys. In 2014, 10 (34%) programs reported offering pharmacologic agents specifically for weight control, whereas in 2017, 16 (53%) reported offering pharmacotherapy for a primary indication of weight loss. Metformin was reported as the most commonly used agent in 2014, and topiramate in 2017. Largest reported increases in use over time were for topiramate and phentermine.DiscussionOur survey results demonstrate that a majority of this group of PWM programs offered pharmacotherapy to promote weight loss in patients with complications or associated medical conditions. There was a trend indicating increasing use over time, despite the significant gap regarding pharmacotherapy use in the literature.ConclusionsThese data suggest the need for (a) additional robust paediatric drug trials to further develop the evidence base guiding use or non‐use of pharmacotherapy in paediatric weight management, and (b) increased understanding of both facilitators and barriers to prescribing anti‐obesity pharmacotherapy for youth with obesity.

Abstract VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

AbstractTalaromycosis is a fungal infection endemic in Southeast Asia. We report a case of a renal transplant recipient who developed infection after a trip to South China. She presented with constitutional symptoms and was found to have an FDG‐avid lung mass. Histopathology demonstrated small yeast cells and culture grew Talaromyces marneffei. The patient was treated with 2 weeks of liposomal amphotericin B followed by itraconazole. The dose of tacrolimus was significantly reduced because of the interaction with itraconazole. Mycophenolate mofetil was discontinued. After 12 months of treatment, the mass had completely resolved. Talaromycosis has mainly been reported in patients with AIDS and is uncommon among solid organ transplant recipients. The immune response against T. marneffei infection is mediated predominantly by T cells and macrophages. The diagnosis may not be suspected outside of endemic areas. We propose a therapeutic approach in transplant patients by extrapolating the evidence from the HIV literature and following practices applied to other endemic mycoses.

AbstractBackgroundTranscatheter aortic valve replacement (TAVR) is a reliable method of treating patients with severe aortic stenosis, but is associated with postprocedure conduction defects.ObjectiveThe purpose of this study was to compare clinical outcomes in patients who developed advanced conduction defects post‐TAVR to those who did not.MethodsWe conducted a retrospective chart review of 243 patients who underwent balloon‐expandable TAVR with the Edwards Sapien valve to determine the incidence of advanced conduction defects in our cohort. We compared clinical outcomes including overall mortality, improvement in symptomatology, and improvement in left ventricular ejection fraction.ResultsAmong the 243 patients included in the study, 9.1% (22/243) required permanent pacemaker (PPM); 19.8% (48/243) developed left bundle branch block (LBBB), and 71.2% (173/243) did not develop any permanent advanced conduction defects. Overall 1‐year mortality was similar across all three groups. There was significant improvement in New York Heart Association functional capacity of all groups post‐TAVR, but this was much less in the PPM group (45.5% vs 68.8%, P = .04). Postprocedure from TAVR, patients with LBBB or PM were less likely to have improvement in their ejection fraction (net loss of −0.7% for LBBB and −5.7% for PPM compared to a net gain of 2.3% for no‐LBBB/PM (P = .02).ConclusionPatients who develop LBBB or require PM post‐TAVR with Edwards Sapien valves are less likely to improve New York Heart Association functional capacity and more likely to have no improvement or deterioration of their pre‐TAVR left ventricular ejection fraction.

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P<.0001). The OS benefit with BRI was greater for the subgroup with high volume disease (HV) (HR=0.51; 95% CI, 0.38-0.68; P<.0001). The cohort with AA+BRI had a significantly shorter ttSRE (HR=1.27; 95% CI; 1.0-1.60; P=.0439) and, notably, the risk of first SRE was more than doubled for the subgroup with LV (HR=2.29; 95% CI, 1.57-3.35; P<.0001). On MVA, BRI vs. no BRI, prior local therapy (PLT) vs. no PLT, LV vs. HV, baseline VAS pain ≤3 vs. >5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]

174 Background: Docetaxel (D) and cabazitaxel (C) are standard chemotherapies for mCRPC. A reliable biomarker predictive of resistance to D or C is yet to be identified. We aimed to assess the association between genetic amplification of the multidrug resistance transporter ABCB1 (ABCB1 amp) and primary resistance (RES) to D or C for mCRPC, using cfDNA. Methods: A cohort (A) of 136 patients (pts) with at least 1 plasma sample drawn and stored within 1 year prior to starting D for mCRPC (2002-2014) and a cohort (B) of 42 pts with at least 1 plasma sample from within 1 year prior to starting C for mCRPC (2010-2016) were identified from the Dana-Farber Cancer Institute IRB approved database. Whole genome sequencing (WGS) at 0.1x coverage, termed ultra-low pass WGS (ULP-WGS), was performed on cfDNA extracted from the selected samples (1000μL/subject) and sequencing data were analyzed using a tool called ichorCNA to identify cases with sufficient tumor DNA content (>7%) for accurate detection of copy number alterations (CNAs) including ABCB1 amp. Primary objective was the association between ABCB1 amp and RES to D or C. RES was defined as lack of response (no PSA50 decline or radiologic response per RECIST criteria 1.1, within 4 months from treatment start). Odds ratio (OR) was used to compare odds of RES to D or C for pts with ABCB1 amp and P-values were calculated by Fisher’s exact test. Results: Of the selected 178 pts, 66 had tumor fraction >7%: 45 pts in cohort A and 21 in cohort B. No significant association was noted between ABCB1 amp and RES to D (P=0.7123; OR=1.600) or C (P=1.000; OR=1.0606). RES was observed in 26 pts (57.8%) of cohort A and 18 (85.7%) of cohort B. ABCB1 amp was found in 9 pts (20%; 95% CI, 9.6-34.6) in group A and 6 of them (66%) had RES to D. ABCB1 amp rate among D-resistant men was 23.1% (95% CI, 9.0-43.7). In group B, 2 pts (9.5%; 95% CI, 1.2-30.4) had ABCB1 amp and both of them had RES to C. ABCB1 rate among C-resistant pts was 11.1% (95% CI, 1.4-34.7). Conclusions: In this study, ABCB1 amp using cfDNA did not show statistically significant correlation with RES to D or C for pts with mCRPC. Future studies including ABCB1 amp in a suite of putative biomarkers and larger sample size may aid drawing definitive conclusions.

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]

Abstract Funding Acknowledgements None Background Cardiac Power Index (CPI) is an integrative hemodynamic measure of cardiac pumping capability and is the product of the simultaneously measured mean arterial pressure (MAP) and cardiac output (CO). In patients with aortic stenosis (AS), MAP is not reflective of mean systolic left ventricular (LV) pressure due to the transvalvular gradient. Non-invasive assessment of mean systolic LV pressure is challenging in severe aortic stenosis. CPI assessed using systemic MAP was previously shown to predict survival post transcatheter aortic valve replacement (TAVR). Purpose We evaluated the utility of a gradient adjusted CPI in predicting survival post TAVR compared to CPI alone Methods A retrospective study was performed including patients undergoing TAVR with 1 year follow-up. Baseline demographics, clinical, and echocardiographic data were abstracted from a cohort of 1,011 patients. CPI was calculated, (CO x MAP)/ (451 x BSA) Watts/m2. Gradient adjusted CPI was calculated using an augmented MAP i) adding aortic valve mean gradient(AVMG) to systolic blood pressure (CPI1); ii) adding aortic valve maximal instantaneous gradient to systolic blood pressure (CPI2) and iii) adding AVMG to MAP (CPI3). Patient survival score was calculated using a step up technique to identify the cut off value for CPI and gradient adjusted CPI to identify, where the maximum difference in mortality occurred. Multivariate cox-regression analysis was performed to adjust for baseline covariates. Receiver operator curves(ROC) for CPI and gradient adjusted CPI were calculated to predict survival post TAVR. Results The mortality rate at 1 yr was 16%. Mean age and AVMG of survivors was 81 +/- 9 yrs and 43 +/-14 mmHg vs 80 +/-9 yrs and 42 +/- 13 mmHg in the deceased group. Proportion of female patients was similar in both groups (p = 0.7). Patients in the deceased group at baseline had a higher prevalence of chronic lung disease, atrial fibrillation, heart failure within 2-weeks of procedure, higher STS-PROM score, lower serum albumin level, higher prevalence of moderate to severe tricuspid regurgitation, higher right ventricular systolic pressure and higher prevalence of dialysis. Both CPI and gradient adjusted CPI were independently associated with survival at 1 year. The area under ROC for CP, CP1, CP2 and CP3 were 0.67 (95% confidence interval [CI] 0.62 - 0.72), 0.65 (95% CI 0.60 – 0.70), 0.66 (95% CI 0.61 – 0.71) and 0.63 (95% CI 0.58 – 0.68) respectively. Conclusion Gradient adjusted CPI did not improve accuracy of predicting post TAVR survival at 1 year compared to CPI alone. Abstract P339 Figure. Area under ROC