Citations

Background: Serum levels of vascular cell adhesion molecule-1 (VCAM-1) are reflective of endothelial activation, a pathologic process that is associated with subclinical cardiac dysfunction. While VCAM-1 has been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF), the prospective association of VCAM-1 with clinically overt HF is unclear. Methods: In the Multi-Ethnic Study of Atherosclerosis, we evaluated the association of VCAM-1 at Exam 2 (2002-2004) with incident HF across ejection fraction (EF) categories (HFpEF and HF with reduced EF [HFrEF]) after adjustment for cardiovascular risk factors. Incident HF was adjudicated as first hospitalization for symptomatic HF, requiring specific clinical and/or imaging criteria. Results: Of 2,298 participants (mean age: 63.0 years, female: 53%), those with higher VCAM-1 were more likely white race, had higher blood pressure, and lower renal function. Over a median of 16.0 years, there were 102 HF events (HFpEF = 65; HFrEF = 37) ( Figure ). After covariate adjustment, VCAM-1 was independently associated with incident HF ( Table ). Upon evaluation of HF subtypes, VCAM-1 was associated with incident HFpEF, and risk effect estimates were consistent for incident HFrEF. The association of VCAM-1 with incident HF was consistent across the spectrum of age, sex, and BMI. Conclusion: In a multiethnic cohort, VCAM-1 was independently associated with incident HF over long-term follow up. These findings suggest a potential role for endothelial activation in driving clinical HF. Lifestyle and pharmacologic therapies that decrease endothelial activation may prevent the progression to clinical HF.

Introduction: Hepatocyte Growth Factor (HGF) is a mesenchymal cytokine linked to incident heart failure (HF), with recent data from our group showing a strong and independent association with HF with preserved ejection fraction (HFpEF). Cardiac MRI (cMRI) allows for precise analysis of morphologic changes in left ventricular (LV) structure. Increasing LV mass and concentric remodeling (defined by an increasing mass:volume ratio) are imaging markers of HFpEF risk. Whether HGF is associated with adverse LV remodeling over time is unknown. Hypothesis: Higher HGF will be associated with increasing LV mass, decreasing LV volume and increasing mass:volume ratio over 10 yrs. Methods: We studied 4762 participants of the MESA cohort, free of cardiovascular disease (CVD) and HF at baseline, who completed both HGF measurement and cMRI at baseline. Participants with LV EF<50% were excluded. Of these, 2855 completed a 2 nd cMRI at 10 yrs. We examined the cross-sectional and longitudinal associations of HGF and LV parameters using multivariable-adjusted linear mixed effect models. Results: The mean (SD) for age was 61 (10) yrs. Median (IQR) for HGF level was 888 pg/mL (745-1066); 53% women. At baseline, the 3 rd HGF tertile, compared to the 1 st , was associated with greater mass:volume ratio [relative difference 1.66 (0.43, 2.89)] and lower LV end diastolic volume [-1.87 mL (-3.45, -0.28)], after adjustment for CVD risk factors and NT- proBNP (model 2) [Table] . In longitudinal analysis, the 3 rd HGF tertile was also associated with increasing mass:volume ratio [difference in 10-yr change: 4.79 (2.73, 6.85)] and decreasing LV end diastolic volume [-4.97 (-7.10, -2.85)]. Conclusions: In a community cohort, higher HGF levels were independently associated with a concentric LV remodeling pattern of increasing mass:volume ratio and decreasing LV end diastolic volume over 10 yrs. This association may suggest an intermediate phenotype explaining the association of HGF with HFpEF risk.

Purpose: To survey US Clinical Neurophysiology (CNP) fellowship program directors on the nature of CNP and related training programs, current recruitment cycle, and views for a standardized process. Methods: A 23-question electronic survey was sent to all 93 US Accreditation Council for Graduate Medical Education-accredited CNP fellowship program directors from December 2020 to January 2021. Results: The response rate was 60%. There was great variability in the number of CNP positions and CNP tracks offered. The following tracks were identified: 48% EEG dominant, 26% EMG dominant, 22% split equally between EEG and EMG, and 2% and 1% were neurophysiologic intraoperative monitoring and autonomic dominant, respectively. Of the responding institutions, 43% offered a second year of training options to CNP fellows, mainly in conjunction with Epilepsy fellowship, which was pursued by 25% of CNP fellows. Many programs indicated flexibility in their design between different CNP tracks or between CNP and other related training programs based on the available candidates. The median percentage of CNP fellowship positions filled over the last 5 years was 80%, and there was great variation in the recruitment timeline across institutions. Overall, 86% of program directors favored a universal timeline and 71% favored a formal match for CNP. The respondents were split between an independent CNP match (39%) and joining the initiatives of affiliate societies on a standardized process (61%). Conclusions: There is significant heterogeneity in the makeup of the CNP fellowship programs and the recruitment process. The majority of CNP program directors are in favor of standardization of the recruitment process.

Abstract Funding: Supported by National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868, U10CA180863; and in part by Susan G. Komen for the Cure® Research Program, The Hope Foundation for Cancer Research, Breast Cancer Research Foundation, and Genomic Health, Inc. Acknowledgement: The authors wish to thank Dr. Ana M. Gonzalez-Angulo, MD, for her invaluable contributions to the design and implementation of this study. Background: The clinical utility of the RS to determine CT benefit is well established in pts with HR+, HER2-, axillary lymph node (LN)-negative BC. Retrospective analyses from SWOG S8814 support the potential prognostic and predictive role of RS for CT benefit in postmenopausal pts with LN+ BC. SWOG S1007 is a prospective, randomized trial of endocrine therapy (ET) vs. chemoendocrine therapy (CET) in women with 1-3 +LN and a RS &lt; 25 (NCT01272037). Methods: Eligibility criteria included women &gt; 18 years of age with HR+, HER2- BC and 1-3 +LN and no contraindications to taxane and/or anthracycline based CT. Women with a RS &lt; 25 were randomized to receive ET or CET in 1:1 randomization using 3 stratification factors: (1) RS (0-13 vs.14-25); (2) menopausal status; and (3) axillary nodal dissection vs. sentinel node biopsy. The primary objective was to determine the effect of CT on invasive disease-free survival (IDFS) and whether the effect depended on the RS. The primary analysis was to test for a significant interaction of the treatment arm and continuous RS using a Cox regression model for IDFS, adjusting for treatment, RS, and menopausal status. A total of 832 IDFS events were expected for the final analysis. Secondary objectives included overall survival (OS). The protocol specified that interaction between treatment and the stratification variables was to be tested and, if significant, separate analyses performed by stratum. Annual interim analyses were planned starting at 24% of events. At the third interim analysis with 410 IDFS events, the Data and Safety Monitoring Committee recommended reporting results, with a decision by the NCI’s Cancer Therapy Evaluation Program, the study sponsor. Results: Of the 9,383 women screened from 2/28/11-9/29/17, 5,083 pts (54.2%) were randomized. With a median follow-up of 5.1 years, 447 IDFS events have been observed. For the primary analysis, the interaction test for CT benefit and continuous RS was not statistically significant, p=0.30. In a model with CT, RS, and menopausal status (no interaction term), higher continuous RS was associated with worse IDFS [HR 1.06, 2-sided p&lt;0.001, 95% Confidence Interval (CI) 1.04-1.07], and CT was associated with an improvement in IDFS (HR 0.81, p=0.026, 95% CI 0.67-0.98). In a pre-specified analysis, a significant interaction was identified between CT and menopausal status (p=0.004), necessitating separate analyses by menopausal status. In postmenopausal pts (N=3350, 67%), adjusting for continuous RS, the HR for CET vs. ET was not significant (HR=0.97, p=0.82, 95% CI 0.78-1.22; 5-year IDFS 91.6% vs. 91.9%) indicating no benefit from CT. In premenopausal pts (N=1665, 33%), the HR (0.54) was statistically significant (p=0.0004, 95% CI 0.38-0.76; 5-year IDFS 94.2% vs. 89.0%), indicating CT benefit. In premenopausal pts, ovarian suppression was performed in 15.9% vs. 3.7% (ET vs. CET), and 47.9% vs. 26.4% reported menstruation after 6 months of treatment. Although the number of events is limited, the HR for treatment adjusted by RS for OS in premenopausal pts was 0.47 (p=0.032, 95% CI 0.24-0.94). At this time, there is no differential effect with CT in regard to other stratification factors. Conclusions: There is a significant differential treatment effect of CT benefit based on RS for premenopausal vs. postmenopausal women requiring separate analyses. While only 54% of the protocol specified events are recorded and pts will be followed for 15 years, the current data show that adjuvant therapy can be de-escalated to ET alone in postmenopausal pts with a RS &lt; 25 and 1-3 +LN. However, there is a strong IDFS benefit for CET in premenopausal pts, with an early indication of an OS improvement. Citation Format: Kevin Kalinsky, William E Barlow, Funda Meric-Bernstam, Julie R Gralow, Kathy S Albain, Daniel Hayes, Nancy Lin, Edith A Perez, Lori J Goldstein, Stephen Chia, Subkhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martín, Miguel Gil Gil, Claudia Arce-Salinas, Etienne Brain, In Hae Park, Jean-Yves Pierga, Ana Hernandez Lluch, Manuel Ramos Vasquez, Manuel Ruiz Borrego, Kyung Hae Jung, Jean-Marc Ferrero, Anne Schott, Steve Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Debu Tripathy, Gabriel Hortobagyi, Lajos Pusztai. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) &lt; 25: SWOG S1007 (RxPonder) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-00.

Obesity is a chronic, multifactorial disease associated with a large number of comorbidities. The clinical management of obesity involves a stepwise integrated approach, beginning with behavioral and lifestyle modification, followed by antiobesity medications, endobariatric procedures, and bariatric surgery. Weight gain and subsequent obesity are common side effects of medications, such as prednisone or antipsychotics. In this era of precision medicine, it is essential to identify patients at the highest risk of weight gain as a result of medication use. Pharmacogenomics could play an important role in obesity management by optimizing use of antiobesity medications as well as minimizing adverse weight gain. This review aims to provide a comprehensive analysis of the current literature on the role of pharmacogenomics in obesity and medication‐induced weight gain. In summary, there are more robust studies of medication associated with weight gain and pharmacogenomics, and more studies are needed to understand the role of pharmacogenomics in antiobesity medications.

Background Serum levels of vascular cell adhesion molecule‐1 (VCAM‐1) are reflective of endothelial activation. Although VCAM‐1 has been implicated in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), the prospective association of VCAM‐1 with development of clinically overt heart failure (HF) across ejection fraction categories is unclear. Methods and Results In MESA (the Multi‐Ethnic Study of Atherosclerosis), we evaluated the association of VCAM‐1 at examination 2 (2002–2004) with incident HF (HFpEF and HF with reduced ejection fraction) after adjustment for cardiovascular risk factors. Incident HF was independently adjudicated as first hospitalization for symptomatic HF. Among 2297 participants (mean age, 63 years; women, 53%), those with higher VCAM‐1 were more likely to be White race, had higher blood pressure, and had lower kidney function. Over a median of 14.4 years, there were 102 HF events (HFpEF=65; HF with reduced ejection fraction=37). After covariate adjustment, each doubling of VCAM‐1 was associated with incident HF (hazard ratio [HR], 1.94; 95% CI, 1.17–3.23; P =0.01). This association appeared stronger among current/former smokers compared with never smokers. On evaluation of HF subtypes, VCAM‐1 was associated with incident HFpEF (HR, 1.97; 95% CI, 1.04–3.72; P =0.04) but not with incident HF with reduced ejection fraction, although risk estimates were consistent (HR, 1.82; 95% CI, 0.79–4.21; P =0.16). Conclusions In a multiethnic cohort, VCAM‐1 was significantly associated with incident HF over long‐term follow‐up. These findings suggest a potential role for endothelial activation in driving clinical HF, and specifically HFpEF. Therapies that decrease endothelial activation may prevent the progression from cardiovascular risk factors to clinical HF.

Abstract Aim Female urethral stricture disease is rare and has several surgical approaches including endoscopic dilations (ENDO), urethroplasty with local vaginal tissue flap (ULT) or urethroplasty with free graft (UFG). This study aims to describe the contemporary management of female urethral stricture disease and to evaluate the outcomes of these three surgical approaches. Methods This is a multi‐institutional, retrospective cohort study evaluating operative treatment for female urethral stricture. Surgeries were grouped into three categories: ENDO, ULT, and UFG. Time from surgery to stricture recurrence by surgery type was analyzed using a Kaplan–Meier time to event analysis. To adjust for confounders, a Cox proportional hazard model was fit for time to stricture recurrence. Results Two‐hundred and ten patients met the inclusion criteria across 23 sites. Overall, 64% ( n = 115/180) of women remained recurrence free at median follow‐up of 14.6 months (IQR, 3–37). In unadjusted analysis, recurrence‐free rates differed between surgery categories with 68% ENDO, 77% UFG and 83% ULT patients being recurrence free at 12 months. In the Cox model, recurrence rates also differed between surgery categories; women undergoing ULT and UFG having had 66% and 49% less risk of recurrence, respectively, compared to those undergoing ENDO. When comparing ULT to UFG directly, there was no significant difference of recurrence. Conclusion This retrospective multi‐institutional study of female urethral stricture demonstrates that patients undergoing endoscopic management have a higher risk of recurrence compared to those undergoing either urethroplasty with local flap or free graft.

1087 Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in >20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]