Early and Late Toxicities of Chimeric Antigen Receptor T-Cells.

As chimeric antigen receptor (CAR) T-cell therapy is increasingly integrated into clinical practice across a range of malignancies, identifying and treating inflammatory toxicities will be vital to success. Early experiences with CD19-targeted CAR T-cell therapy identified cytokine release syndrome and neurotoxicity as key acute toxicities and led to unified initiatives to mitigate the influence of these complications. In this section, we provide an update on the current state of CAR T-cell-related toxicities, with an emphasis on emerging acute toxicities affecting additional organ systems and considerations for delayed toxicities and late effects.

CAR T-cell detection scoping review: an essential biomarker in critical need of standardization.

The expansion and persistence of chimeric antigen receptor (CAR) T-cells in patients are associated with response, toxicity, and long-term efficacy. As such, the tools used to detect CAR T-cells following infusion are fundamental for optimizing this therapeutic approach. Nevertheless, despite the critical value of this essential biomarker, there is significant variability in CAR T-cell detection methods as well as the frequency and intervals of testing. Furthermore, heterogeneity in the reporting of quantitative data adds layers of complexity that limit intertrial and interconstruct comparisons. We sought to assess the heterogeneity of CAR T-cell expansion and persistence data in a scoping review using the PRISMA-ScR checklist. Focusing on 21 clinical trials from the USA, featuring a Food and Drug Administration-approved CAR T-cell construct or one of its predecessors, 105 manuscripts were screened and 60 were selected for analysis, based on the inclusion of CAR T-cell expansion and persistence data. Across the array of CAR T-cell constructs, flow cytometry and quantitative PCR were identified as the two primary techniques for detecting CAR T-cells. However, despite apparent uniformity in detection techniques, the specific methods used were highly variable. Detection time points and the number of evaluated time points also ranged markedly and quantitative data were often not reported. To evaluate whether subsequent manuscripts from a trial resolved these issues, we analyzed all subsequent manuscripts reporting on the 21 clinical trials, recording all expansion and persistence data. While additional detection techniques-including droplet digital PCR, NanoString, and single-cell RNA sequencing-were reported in follow-up publications, inconsistencies with respect to detection time points and frequency remained, with a significant amount of quantitative data still not readily available. Our findings highlight the critical need to establish universal standards for reporting on CAR T-cell detection, especially in early phase studies. The current reporting of non-interconvertible metrics and limited provision of quantitative data make cross-trial and cross-CAR T-cell construct comparisons extremely challenging. Establishing a standardized approach for collecting and reporting data is urgently needed and would represent a substantial advancement in the ability to improve outcomes for patients receiving CAR T-cell therapies.

Implementation of Febrile Infant Management Guidelines Reduces Hospitalization.

The clinical management of well-appearing febrile infants 7-60 days of age remains variable due in part to multiple criteria differentiating the risk of a serious bacterial infection. The purpose of this quality improvement study was to standardize risk stratification in the emergency department and length of stay in the inpatient unit by implementing an evidence-based clinical practice guideline (CPG). METHODS: The Model for Improvement was used to implement a CPG for the management of well-appearing febrile infants, with collaboration between pediatric emergency medicine and pediatric hospital medicine physicians. Interventions included physician education, process audit/feedback, and development of an electronic orderset. We used statistical process control charts to assess the primary aims of appropriate risk stratification and length of stay. RESULTS: Over a 34-month period, 168 unique encounters (baseline n = 65, intervention n = 103) were included. There was strong adherence for appropriate risk stratification in both periods: the proportion of low-risk patients admitted inappropriately decreased from 14.8% to 10.8%. Among admitted high-risk patients, the mean length of stay decreased from 49.4 to 38.2 hours, sustained for 18 months. CONCLUSION: CPG implementation using quality improvement methodology can increase the delivery of evidence-based care for febrile infants, leading to a reduction in length of stay for high-risk infants.

Epidermal growth factor receptor (EGFR) contributes to fetal lung fibroblast injury induced by mechanical stretch.

CONTEXT: Epidermal growth factor receptor (EGFR) is critical for normal fetal lung development. However, the role of this receptor in lung injury induced by mechanical ventilation is controversial. OBJECTIVE: To investigate in vitro whether EGFR plays a protective role or contributes to stretch-induced lung injury. METHODS: Fetal lung fibroblasts were isolated from wild-type and EGFR knockout mice and exposed to physiologic stretch (2.5% elongation) or injurious stretch (20% distention). Cells were evaluated for necrosis, apoptosis, proliferation and inflammation. RESULTS: Injurious stretch increased lactate dehydrogenase (LDH) release to similar degree in wild-type and knockout cells. In contrast, 20% stretch increased cleaved caspase-3 and decreased proliferating cell nuclear antigen (PCNA) only in wild-type cells. Furthermore, 20% stretch increased macrophage inflammatory protein-2 (MIP-2) and monocyte chemotactic protein-1 (MCP-1) by 3-5 fold in wild-type cells. In contrast, in knockout cells MIP-2 decreased by 50% and MCP-1 only increased by 60% when compared to physiologic stretch. CONCLUSION: Our data show a decrease of apoptosis and inflammation and absence of decreased proliferation after injurious stretch of fetal fibroblasts lacking EGFR. These data suggest that EGFR contributes to lung injury mediated by stretch. We speculate that EGFR may contribute to the arrest of lung development observed after mechanical ventilation by decreasing the population of lung fibroblasts.