Citations

ObjectiveEosinophilic granulomatosis with polyangiitis (EGPA) is part of a group of vasculitides commonly referred to as antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), in addition to granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal‐limited vasculitis. Patients with EGPA characteristically have asthma and marked peripheral eosinophilia with only approximately 30% to 35% of patients being myeloperoxidase (MPO)‐ANCA positive, distinguishing it from other forms of AAV (1,2). The aim of this systematic review is to support the development of the American College of Rheumatology/Vasculitis Foundation guideline for the management of EGPA.MethodsA systematic review was conducted of the literature for seven forms of primary systemic vasculitis (GPA, MPA, EGPA, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, and Takayasu arteritis). The search was done for articles in English using Ovid Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing population/patients, intervention, comparator, and outcomes (PICO) questions, with studies presenting the highest level of evidence given preference. Two independent reviewers conducted a title/abstract screen and full‐text review for each eligible study.ResultsThe initial search, conducted in August 2019, included 13 800 articles, of which 2596 full‐text articles were reviewed. There were 190 articles (addressing 34 PICO questions) reporting on the diagnosis and management of EGPA.ConclusionThis comprehensive systematic review synthesizes and evaluates the accuracy of commonly used tests for EGPA as well as benefits and toxicities of different treatment options.

AbstractObjectiveCareer paths leading to department chair positions are elusive. Women represent only 11% of academic emergency department (ED) chairs. It is unclear whether the pathway to chair is different for men and women; the characteristics, achievements, and qualifications among those who become ED chairs is unknown.MethodsThis study is a cross‐sectional analysis of curriculum vitae (CV) of current ED chairs in departments with Accreditation Council for Graduate Medical Education (ACGME)‐accredited residency programs. Former women chairs were included due to paucity of current women chairs. Statistics were calculated using bivariate and multivariate analysis.ResultsOf 163 eligible chairs, 88 CV (54%) were obtained, including six former women chairs. A majority (86.4%) self‐identified as White/Caucasian, 21.5% were women, 46% were chief residents, 28.4% completed additional postgraduate degrees, and 21.8% were fellowship trained. At time of chair appointment, 58% were professor rank, 53.5% held ED operations roles, and 32% served as vice chair. Women were more likely to be in educational (53% vs. 22%) versus operational (26% vs. 61%, p = 0.02) roles. Women obtained more advanced degrees (47% vs. 25%, p = 0.02), were awarded more nonfederal grants (median = 7 vs. 3, p = 0.04), and achieved more national committee leadership (median = 4 vs. 1, p = 0.02). There were no gender differences in fellowship training, awards, leadership training programs, publications, federal grants, or national/international lectures after adjusting for years in practice.ConclusionWhile the majority of chairs held prior leadership roles in ED operations, only one in five women chairs did, suggesting gender differences in the path to chair attainment. These differences in paths may contribute to persistent gender disparities in ED chairs and may be influenced by career path choices, implicit bias, and structural barriers.

Abstract Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively). Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute’s virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.

TPS264 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. M, an investigational Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. Data suggest margetuximab coordinately enhances both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. Retifanlimab (also known as MGA012 or INCMGA00012) is a humanized, hinge-stabilized, IgG4 Κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. Tebotelimab (also known as MGD013) is a humanized Fc-bearing bispecific tetravalent DART® protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC patients, and induced a 44% objective response rate (ORR) in a double-positive biomarker population. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC patients. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study (NCT04082364). The first single arm, CTX-free cohort A, evaluates M+retifanlimab in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) patients. After 40 patients are evaluated for response/safety, additional patients will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) patients are enrolled irrespective of PD-L1 status. Part 1 of cohort B randomizes patients to 1 of 4 arms (50 patients each): control arm (T+CTX) or 1 of 3 experimental arms (M+CTX; M+CTX+retifanlimab; M+CTX+tebotelimab). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Clinical trial information: NCT04082364.

AbstractThree sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5–5.3, p = .001] and 2.5 [CI: 1.4–4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17–0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post‐treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post‐treatment. These differences are important when choosing endpoints for clinical trials.

Background: Foam-mediated external suction (FMES) has previously shown to improve tissue microcirculation. We hypothesized that preconditioning fasciocutaneous perforator flaps with FMES would augment perfusion and demonstrate greater capillary recruitment. Methods: Gluteal perforator flaps were designed on sixteen 400 g rats. Continuous FMES at −125 mm Hg was applied on one side (intervention) to precondition tissue for 5 days, with the contralateral side as a paired control. In group A, we assessed changes following pretreatment, after surgery, and 7 days postprocedure, and in group B, we evaluated changes during preconditioning alone. In group A (N = 8), control and intervention flaps were assessed using laser-assisted indocyanine green fluorescence angiography. In group B, flap regions were assessed using 4-dimensional computed tomographic angiography. All flaps were analyzed for microvessel density using micro–computed tomography and histological assessment using hematoxylin and eosin and CD3 immunohistochemistry. Results: Thirty-two flaps were included in this study (N = 16 intervention and matched controls). Four-dimensional computed tomographic angiography demonstrated 17% greater tissue perfusion in preconditioned flaps (mean, 78.7 HU; SD, 8.8) versus controls (mean, 67.3 HU; SD, 15.7; P < 0.01). Laser-assisted indocyanine green fluorescence angiography showed a 30% higher mean absolute intensity in preconditioned flaps versus controls (P < 0.01). Postsurgery mean absolute intensity in preconditioned flaps remained 21% higher than in controls (P = 0.03). Preconditioned flaps demonstrated a 2-fold increase in mean vessel volume of 9.1 mm3 (SD, 7) versus 4.5 mm3 (SD, 3) in controls (P = 0.04); there was a 33% higher mean area fraction of CD31 in preconditioned flaps, 3.9% (SD, 3) versus 2.9% (SD, 3) in controls (P = 0.03). Conclusion: FMES preconditioning has the potential to augment vascularity of tissue for flap harvest; however, further experimental studies are required to optimize strategies and evaluate long-term effects for clinical applications.

PURPOSE: IMpower133 (ClinicalTrials.gov identifier: NCT02763579 ), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported. PATIENTS AND METHODS: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m 2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted. RESULTS: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status. CONCLUSION: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.