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OBJECTIVE To determine whether burden of multiple chronic conditions (MCCs) influences the risk of receiving inappropriate vs appropriate device therapies. DESIGN Retrospective cohort study. SETTING Seven US healthcare delivery systems. PARTICIPANTS Adults with left ventricular systolic dysfunction receiving an implantable cardioverter‐defibrillator (ICD) for primary prevention. MEASUREMENTS Data on 24 comorbid conditions were captured from electronic health records and categorized into quartiles of comorbidity burden (0‐3, 4‐5, 6‐7 and 8‐16). Incidence of ICD therapies (shock and antitachycardia pacing [ATP] therapies), including appropriateness, was collected for 3 years after implantation. Outcomes included time to first ICD therapy, total ICD therapy burden, and risk of inappropriate vs appropriate ICD therapy. RESULTS Among 2235 patients (mean age = 69 ± 11 years, 75% men), the median number of comorbidities was 6 (interquartile range = 4‐8), with 98% having at least two comorbidities. During a mean 2.2 years of follow‐up, 18.3% of patients experienced at least one appropriate therapy and 9.9% experienced at least one inappropriate therapy. Higher comorbidity burden was associated with an increased risk of first inappropriate therapy (adjusted hazard ratio [HR] = 1.94 [95% confidence interval {CI} = 1.14‐3.31] for 4‐5 comorbidities; HR = 2.25 [95% CI = 1.25‐4.05] for 6‐7 comorbidities; and HR = 2.91 [95% CI = 1.54‐5.50] for 8‐16 comorbidities). Participants with 8‐16 comorbidities had a higher total burden of ICD therapy (adjusted relative risk [RR] = 2.12 [95% CI = 1.43‐3.16]), a higher burden of inappropriate therapy (RR = 3.39 [95% CI = 1.67‐6.86]), and a higher risk of receiving inappropriate vs appropriate therapy (RR = 1.74 [95% CI = 1.07‐2.82]). Comorbidity burden was not significantly associated with receipt of appropriate ICD therapies. Patterns were similar when separately examining shock or ATP therapies. CONCLUSIONS In primary prevention ICD recipients, MCC burden was independently associated with an increased risk of inappropriate but not appropriate device therapies. Comorbidity burden should be considered when engaging patients in shared decision making about ICD implantation.

Background: Research has shown that individuals with mild cognitive impairment (MCI) value quality of life (QoL) above and beyond cognitive function or other potential outcomes in MCI. There is evidence supporting the negative impact of poor physical function on QoL ratings. Objective: The study explored whether a modified measure of self-efficacy for managing MCI and education mediated and/or moderated the relationship between physical function and QoL in persons with MCI. Methods: Baseline data from 200 participants with MCI were obtained from a larger study assessing the effectiveness of a behavioral intervention. Physical function was assessed by the Short Physical Performance Battery. QoL was assessed with the Quality of Life in Alzheimer’s Disease scale. Memory-related self-efficacy was assessed using a modified 9-item version of the Chronic Disease Self-Efficacy Scales. Mediation and moderation analyses tested the hypotheses that self-efficacy and education alter the association between physical function and QoL in individuals with MCI. All analyses were adjusted for age, cognitive severity, and sex. Results: Self-efficacy for managing MCI was a significant mediator of the association between physical function and perceived QoL. Individuals with better physical function reported higher self-efficacy which was associated with higher QoL ratings. Conclusions: Greater self-efficacy for managing MCI mediated the negative association between physical function and quality of life in this exploratory study. Interventions aimed at enhancing memory self-efficacy in MCI may improve perceived QoL, even in the presence of poor physical function. Future research is needed to investigate this further.

Obesity and hypertension independently promote pathological left ventricular remodelling (LVR) and left ventricular hypertrophy (LVH), but to what extent they do so when they do not coexist is unclear. We used data from the Cardiovision Brno 2030 study to assess—for the first time in a region where no investigations have been previously carried out—the independent association of obesity and hypertension with LV geometry, and to evaluate the effects of hypertension in normal weight patients and the effects of obesity in normotensive patients. Overall, 433 individuals, aged 25–65 years, with no history of cardiovascular disease and/or antihypertensive treatment, were stratified into four groups according to BMI and hypertension: normal weight non-hypertensive (NWNH), normal weight hypertensive (NWH), overweight/obese non-hypertensive (ONH) and overweight/obese hypertensive (OH). LVR was classified as normal, concentric LVR (cLVR), concentric LVH (cLVH) or eccentric LVH (eLVH). Linear regression analysis demonstrated that body mass index (BMI) and systolic blood pressure (SBP) are the main predictors of LV mass and that they interact: SBP had a stronger effect in overweight/obese (β = 0.195; p = 0.033) compared to normal weight patients (β = 0.134; p = 0.048). Hypertension increased the odds of cLVR (OR = 1.78; 95%CI = 1.04–3.06; p = 0.037) and cLVH (OR = 8.20; 95% CI = 2.35–28.66; p = 0.001), independent of age, sex and BMI. Stratified analyses showed that NWH had a greater odd of cLVH (OR = 7.96; 95%CI = 1.70–37.08; p = 0.008) and cLVR (OR = 1.62; 95%CI = 1.02–3.34; p = 0.047) than NWNH. In the absence of hypertension, obesity was not associated with LVM and abnormal LV geometry, suggesting that it is not per se a determinant of LVR. Thus, antihypertensive therapy still remains the first-line approach against LVH in hypertensive patients, though weight loss interventions might be helpful in those who are obese.

Introduction: Frailty and decreased physical performance are associated with poor outcomes after kidney transplant. Less is known about their relationship with pretransplant outcomes. The aim of this study was to characterize associations between frailty and physical performance with death on the kidney transplant waiting list. Design: Since December 2014, high-risk kidney transplant candidates at our center (age > 59, diabetic and/or history of >3 years dialysis) have undergone frailty and physical performance testing using Fried Criteria and the Short Physical Performance Battery. Results: Between December 2014 and November 2016, 272 high-risk candidates underwent testing and were approved for transplant. Both frailty and physical performance score were significantly associated with death on the waiting list (hazard ratio [HR]: 6.7, confidence interval [CI]: 1.5-30.1; P = .01; HR: 0.8 per 1-point increase, CI: 0.7-1.0; P = .02, respectively). The relationship between frailty, physical performance score, and death on the waiting list appeared to be independent of age, diabetes, or duration of dialysis. Discussion: Frailty and decreased physical performance appear to be independently associated with increased mortality on the kidney transplant waiting list. Further studies are needed to determine whether improving frailty and physical performance prior to transplant can decrease waiting list mortality.

Abstract Rationale The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)—versus surgical lung biopsy (SLB) as the current gold standard—in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5–8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01–0.44), percentage agreement = 38% (95% CI, 18–62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06–0.56), percentage agreement = 48% (95% CI, 26–70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27–0.75), percentage agreement = 62% (95% CI, 38–82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

TPS504 Background: Patients with high-risk MIBC have a poor prognosis. Radical cystectomy remains the standard treatment. Yet despite substantial improvements in surgical techniques, mortality from metastatic recurrence remains high. A large number of MIBC patients are ineligible for cisplatin-based chemotherapy or have persistent muscle-invasive disease despite neoadjuvant chemotherapy (NAC). Pembrolizumab, a PD-1 inhibitor, has demonstrated significant activity and is FDA-approved for patients with advanced/chemotherapy-refractory metastatic urothelial carcinoma. We hypothesize that pembrolizumab given post-cystectomy will improve overall survival (OS) and disease-free survival (DFS) in patients with high-risk MIBC. Methods: Patients must have histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract, have received NAC and have ≥ pT2 and/or pN+ at surgery or be cisplatin-ineligible and have ≥ pT3 and/or pN+ at surgery or have declined adjuvant cisplatin-based therapy and have ≥ pT3 and/or pN+ at surgery. Surgery could be radical cystectomy, nephrectomy, or ureterectomy. Patients are stratified by pathologic stage, central PD-L1 status, and prior NAC. Patients are randomized to receive pembrolizumab 240 mg every 3 weeks for 1 year, or observation. The dual primary objectives are to determine DFS and OS. Secondary objectives are to determine DFS and OS in PD-L1-positive and -negative patients and assess safety. Correlative objectives are to determine whether 12 immune gene signatures, tumor molecular subtypes, diversity of T-cell receptor (TCR) clonotypes, persistence of TCR clonotypes, tumor and neoantigen burden, HLA subtypes, and plasma HGF and VEGF levels with IL-10 and IL-17 are associated with OS and DFS. Quality of Life Correlative objectives are to compare health-related quality of life as assessed by the EORTC QLQ-C30. Clinical trial information: NCT03244384.

154 Background: Poly ADP-ribose polymerase inhibitors (PARPi) are being studied as a treatment option for men with mCRPC and deficient homologous recombination DNA repair. While the FDA has granted “breakthrough” designation status to olaparib for use in mCRPC patients with either BRCA1/2 or ATM mutations, it is not known if responsiveness to PARPi may be influenced by the mutation type. Because ATM functions as a sensor of DNA damage rather than a mediator of DNA repair, we hypothesized that patients with ATM mutations may not show robust responses to PARPi therapy compared to those with BRCA1/2 mutations. Methods: We conducted a retrospective analysis of mCRPC patients treated with off-label olaparib at Johns Hopkins Hospital and Mayo Clinic Scottsdale who had somatic or germline mutations in BRCA1/ 2 or ATM. The primary endpoint was PSA50 response. Secondary endpoints included overall survival (OS) and radiographic/clinical progression-free survival (PFS). Results: 40 men received olaparib for mCRPC of which 17 had pathogenic mutations (5 ATM-mutant, 12 BRCA1/2-mutant). Eleven (65%) had germline and 6 (35%) had somatic alterations. Five (29%) had Gleason sum ≤7 at diagnosis, 4 (24%) had Gleason sum 8, and 8 (47%) had Gleason sum ≥9. Three (18%) had metastatic disease at diagnosis. Mean age at start of olaparib therapy was 65.6 (range, 52-76) years. Prior chemotherapy was received by 59% of men, and prior abiraterone/enzalutamide by 88% of men. Eleven (65%) had extra-osseous metastases at start of therapy. PSA50 responses were achieved by 10/12 men (83%) with BRCA1/2 mutations and 0/5 men (0%) with ATM mutations (Fisher’s exact test, P= 0.003). Men with BRCA1/2 mutations had a median PFS of 12.3 mo versus 3.3 mo for those with ATM mutations (HR 0.14, 95%CI 0.03-0.60; P= 0.008). There was no difference in OS (HR 0.24, 95%CI 0.03-1.173; P= 0.16). Conclusions: Men with mCRPC harboring mutations in BRCA1/2 appear to have better PSA responses and longer PFS with olaparib compared to men with ATM mutations. ATM-mutant mCRPC patients may require alternative therapies ( e.g. chemotherapy, ATR inhibitors). Larger prospective studies are needed to confirm or refute these preliminary findings.