Citations

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

AbstractObjectiveThis study aimed to evaluate the diagnostic accuracy of dried blood spot (DBS) compared with conventional serum Aquaporin‐4‐IgG (AQP4‐IgG) testing.MethodsProspective multicenter diagnostic study was conducted between April 2018 and October 2023 across medical centers in the United States, Uganda, and the Republic of Guinea. Neuromyelitis optica spectrum disorder (NMOSD) patients and controls collected blood on filter paper cards along with concurrent serum samples. These samples underwent analysis using flow cytometric live‐cell‐based assays (CBA) and enzyme‐linked immunosorbent assay (ELISA) to determine AQP4 serostatus. The accuracy of AQP4‐IgG detection between DBS and serum (gold standard) was compared.ResultsAmong 150 participants (47 cases, 103 controls), there was a strong correlation between DBS and serum samples (Spearman's correlation coefficient of 0.82). The AUC was 0.97 (95% CI: 0.92–0.99). AQP4‐IgG detection through DBS showed 87.0% sensitivity (95% CI: 0.74–0.95) and 100% specificity (95% CI: 0.96–1.00) using CBA, and 65.2% sensitivity (95% CI: 0.43–0.84) and 95.2% specificity (95% CI: 0.76–0.99) using ELISA. Serum ELISA demonstrated 69.6% sensitivity (95% CI: 0.47–0.87) and 98.4% specificity (95% CI: 0.91–0.99). The stability of DBS in detecting AQP4‐IgG persisted over 24 months for most cases.InterpretationThe DBS represents a viable alternative for detecting AQP4‐IgG in resource‐limited settings to diagnose NMOSD, offering high sensitivity and specificity comparable to serum testing. Moreover, DBS has low shipping costs, is easy to administer, and is suitable for point‐of‐care testing.

Background There is a paucity of literature analyzing data for return to sport (RTS) and return to work (RTW) in the setting of direct anterior approach (DAA) total hip arthroplasty (THA). Objective The aims of this systematic review are to identify existing literature and to aggregate rates of RTS/RTW following DAA THA in a meta-analysis. Methods A query of major databases yielded 1819 initial studies. A random-effects model approach was implemented for meta-analysis. Moderator effects were assessed with respect to patient demographics and functional outcomes. Results Five studies reporting RTS after DAA THA were identified, representing a total of 204 patients with a mean age of 60.2±7.5 years and mean follow up of 31.8±9.5 months. Pooled rate of RTS was 76%(95% confidence interval [CI], 63%-86%;range 58%-100%). Pooled rate of return to the same sport was 77%(95%CI, 64%-86%;range of 62%-100%). Pooled rate of RTS to the same intensity was 58%(95%CI, 48%-68%;range of 41%-68%). Meta-regression demonstrated no significant correlations between independent variables and RTS characteristics. Three studies reported RTW rates. Rates of RTW within 3-months were 30%, 45%, and 60%. One study reported rate of RTW of 79% at 6-months and 87% at 12-months. One study demonstrated a mean time to RTW of 38±24.8 days. Conclusion Pooled rate of RTS is satisfactory following DAA THA and are comparable to rates of RTS aggregated without delineating surgical approach. Data supporting RTW rates following DAA THA limited, and thus more primary studies are needed to establish if this approach confers an advantage of faster RTS/RTW.

Goals: To determine long-term efficacy and safety of tCS for treatment of EoE. Background: Maintenance therapy with topical corticosteroids (tCS) is recommended for eosinophilic esophagitis (EoE), but data for long-term use are still needed. Study: This retrospective cohort study assessed newly diagnosed patients with EoE who were treated with a tCS and had a follow-up endoscopy with biopsy after at least 5 years. Histologic symptomatic and endoscopic responses were extracted from medical records. Patients who did and did not have long-term tCS treatment were compared at baseline, and outcomes for patients were assessed at their last endoscopy while on tCS. Results: Of 431 patients with EoE treated with tCS, 104 met inclusion criteria for long-term use. For patients with long-term tCS use, the median time (IQR) on tCS was 6.5 years (5.4 to 8.8 y). At the last endoscopy, 54% had histologic response (<15 eos/hpf), but those with excellent adherence had a histologic response of 64%. Endoscopic severity also decreased with improved adherence which was strongly associated with EREFS (1.7 vs. 2.8 vs. 4.0 for excellent, good, and poor adherence; P<0.001). Symptomatic response was 68% overall, but only 40% in those with poor adherence (P=0.07). Complications of taking tCS were uncommon (adrenal insufficiency: 1%; osteopenia: 1%; and esophageal candidiasis: 4% at final endoscopy). Conclusions: Long-term tCS (median 6.5 y) were generally effective, especially with better adherence, and also safe, with only rare serious complications. These data can be used to help patients make clinical decisions about chronic tCS use in EoE.

Summary Cannabis use is becoming increasingly common, both for recreational and medical purposes. However, there is a paucity of data regarding cannabis use in the context of eosinophilic esophagitis (EoE). We aimed to determine the impact of cannabis use on presentation and treatment response in EoE. To this end, we conducted a retrospective cohort study at a large academic medical center of newly diagnosed EoE patients age ≥ 12 years. Self-reported cannabis use status, baseline characteristics, and treatment response to topical corticosteroids and dietary therapy data were extracted. Bivariate and multivariable analyses were used to compare cannabis users and non-users at time of EoE diagnosis and to assess treatment response. Of 983 EoE patients, 80 reported using cannabis, with the majority reporting daily use and administration by inhalation. Baseline symptoms and peak eosinophil count were similar between cannabis users and non-users; cannabis users were less likely to have baseline endoscopic findings of exudates, edema, and stricture, and lower total Endoscopic Reference Score. On multivariable analysis, younger age, male sex, non-White race, and psychiatric diagnosis were independently associated with history of cannabis use at EoE presentation and stricture was independently associated with cannabis non-use. Post-treatment symptom and histologic responses were similar between cannabis users and non-users though there was a higher odds of post-treatment endoscopic inflammatory features with cannabis use. In conclusion, despite presenting with milder initial endoscopic findings, cannabis users exhibited greater inflammatory findings after treatment, highlighting a potential negative influence of cannabis use on EoE management.

Abstract Background Live cell-based assays (CBA) are considered the gold-standard methodology for detecting pathogenic antibodies targeting neural cell surface antigens. However, the adoption of these methods in clinical laboratories has been limited by their manual nature and low throughput. Here, we describe the development and validation of an automated system utilizing a live flow cytometry-based CBA to detect AQP4-IgG. Establishing AQP4-IgG serostatus is a critical component of the diagnostic criteria for Neuromyelitis optica spectrum disorders (NMOSD) as it enables the differentiation of NMOSD from Multiple Sclerosis where there may be significant clinical overlap. The accurate diagnosis of the correct disease state is vital, as the prognosis and treatment approach differ significantly for these two conditions. Two redundant systems were built that automatically receive reagents (live cells in suspension, buffers, diluents, secondary antibodies, and patients’ samples) and generate flow cytometer ready 96-well plates (each containing up to 45 serum or CSF samples tested in duplicate). Methods We assessed the analytical performance of an AQP4-IgG live flow cytometry-based CBA on these new automated systems. We measured intra- and inter-assay imprecision at three levels in 5x5 format and for end-point titer assessment, accuracy (20 positive and 20 negative sera; 5 positive and 5 negative CSF; established on the current manual assay), reference range (20 negative sera and 20 negative CSF from disease controls), analytical sensitivity (LOB and LOD) and specificity (high IgG containing serum specimens), within-plate draft (1 positive sample near the diagnostic cut-off [IgG-binding index of 2.0] that was tested across the entire plate), instrument to instrument correlation (42 positive samples/dilutions tested simultaneously on both systems), and total throughput for both CSF and Serum. Results Imprecision testing yielded the following results: Serum Intra/Inter precision level 1 (IBI = 2) CV% (current method:4.6%/20.7%), (system 1: 3.1%/18.4%), (system 2: 2.6%/22.5%), serum Intra/Inter precision level 2 (IBI=4) CV% (current method:4.9%/23.3%), (system 1: 3.2%/21.9%), (system 2: 2.6%/24.1%), and serum Intra/Inter precision level 3 (IBI =10) pos CV% (current method:6.0%/31.1%), (system 1: 3.8%/27.4%), (system 2: 4.2%/29.4%), and CSF Intra/Inter precision (IBI =2) CV% (System 1: 11.7%/16.8%), (system 2: 6.1%/10.7%). The median end-point titers for all four samples assessed matched within one end-point titer. For accuracy, 100% qualitative agreement between current and both automated systems, and titration accuracy (5 positive serums, 1 positive CSF) all matched within one titer between current and both automated systems. All reference range samples were negative. LOB/LOD in serum (Current: 0.85/1.11), (System 1: 0.82/0.95), (system 2: 0.82/0.96) and CSF (Current: 1.06/1.52), (System 1: 1.02/1.38), (system 2: 1.02/1.64) were comparable. All high IgG samples were negative. Plate drift analysis showed improved whole plate %CV: (Current:6.52%), (system 1: 4.51%), (system 2: 3.46%). Instrument to instrument comparison utilizing linear regression indicated strong agreement across the two systems (slope = 0.93 and R2= 0.95). Assessment of throughput based on real-time timings indicated a maximum output of approximately &gt;700 patient samples per 24hrs per system. Conclusions An automated system for performing live CBAs provides equivalent to superior analytical performance compared to pre-existing manual methods with improved testing capacity.