Citations

Background: Randomized clinical trials are often criticized for not reflecting real-world practice. To understand the effect of site and patient selection on trial generalizability, we examined US patient and hospital participation within the Dual Antiplatelet Therapy (DAPT) Study, a broadly inclusive trial of PCI patients, using a linked analysis with the CathPCI Registry®. Methods: Within the CathPCI Registry, we identified patients undergoing PCI between September 1, 2009 and July 1, 2011 - the period of DAPT Study enrollment. We compared US patients enrolled in DAPT to CathPCI Registry patients meeting DAPT inclusion criteria. Characteristics of US DAPT sites were also compared to those of hospitals not participating in DAPT. Standardized differences (%) for all variables were estimated, with those greater than 10% considered significant. Results: Among 1,139,932 NCDR patients undergoing PCI, 748374 (65.7%) met the enrollment criteria for DAPT, and 23495 (2.1%) were enrolled. Enrolled patients were younger and had lower rates of prior stroke, CHF and peripheral vascular disease, but were similar with respect to race and gender compared with eligible patients (Table). Of the 1276 hospitals within the NCDR, 309 (24.2%) participated in DAPT. Hospital characteristics differed markedly, with DAPT-participating hospitals being larger (mean beds 468 vs. 311), more often located in urban settings (61.2% vs. 42.6%), more often affiliated with training programs (53.7% vs. 34.1%), and with higher annual PCI volumes (mean annual hospital volume 858 vs. 378 PCIs) compared with non-DAPT hospitals. Conclusions: While liberal inclusion criteria may allow randomized trials to better simulate “real-world” clinical practice, the process of site selection may encourage participation of higher volume, urban hospital settings. These findings are relevant to clinical trial interpretation and implementation of evidence-based practice throughout the healthcare system.

AbstractObjectivesEosinophilic esophagitis (EoE) is often diagnosed in school‐age children between 6‐ and 9‐year‐old. There is less known about those who are diagnosed with EoE that are younger than 6 years old. The objective of this study is to compare clinical presentation, comorbidities, and outcomes based on age at diagnosis of EoE.MethodsSingle‐center retrospective chart review of children (<18 years) diagnosed with EoE between 2005 and 2020. We recorded demographics, clinical presentation, family history, past medical history, treatment, and endoscopic findings. Children in this cohort were classified based on age into three age groups: <2 years, 2−<6 years, and 6−<18 years.ResultsWe identified 256 children with EoE, the mean age (SD) at the time of diagnosis was 9 (5.2) years and 184 (72%) were male. We had 164 (64%) patients with available follow‐up esophagogastroduodenoscopies (EGDs) data (495 EGDs in total) of those 99/164 (60%) reached mucosal remission. In the very young children (<2 years) vomiting was the most common presentation, while poor weight gain was seen more in the 2−<6‐year group in comparison to the >6‐years. Food impaction and abdominal pain were most likely to present in older children 6−18 years. Combination therapy, as opposed to a single therapy, induced remission at a higher frequency in the <6‐year group in comparison to the 6−<18‐year group (85% vs. 66%).ConclusionEoE should be considered in younger children presenting with feeding difficulty and poor weight gain. Combination therapy seems to be more effective in younger children with EoE, but further studies with bigger sample size are needed to study the efficacy of the different combination therapies.

Abstract Several reports of concurrent MYC, BCL2, BCL6, and CCND1 rearrangements in high-grade B-cell lymphoma (HGBL) have been recently described. Herein, we aimed to delineate the scope of this entity through a review of HGBL with a “quadruple-hit” genetic profile identified at our institution. We performed a retrospective review (2015-2023) at our institution of B-cell lymphoma (BCL) cases that were evaluated with concurrent MYC, BCL2, and BCL6 break-apart and IGH::MYC and IGH::CCND1 dual-color dual-fusion fluorescence in situ hybridization studies. Of 203 cases meeting inclusion criteria, 2 (1%) with a quadruple-hit genetic profile were identified. Case 1 represented a 59-year-old female with widespread lymphadenopathy and a diagnosis of HGBL who exhibited primary refractoriness to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy. Case 2 represented a 58-year-old male with mediastinal and abdominal lymphadenopathy and a diagnosis of large BCL who died from disease after 1 cycle of DA-EPOCH-R chemotherapy. Similarly, a literature review of 7 previously reported cases of HGBL with a quadruple-hit profile also demonstrated aggressive disease behavior. Our study adds 2 new cases to the rarely encountered quadruple-hit HGBL, and a brief meta-analysis of the 9 available cases indicates aggressive disease behavior conferred by this constellation of genetic events.

Abstract Glioblastoma (GBM) tumors contain a subpopulation of glioma stem cells (GSC) which can escape therapeutic effects through self-renewal and invasion. Epidermal growth factor receptor (EGFR) mutations are the most common alteration in GBM (50%). One example includes extracellular domain missense mutations like G598V, A289V, and R108K (10-15%). These extracellular domain missense mutations increase ligand binding affinity, inducing a highly active receptor. Earlier reports have shown these EGFR missense mutations exhibit therapeutic resistance; however, the molecular mechanism of these missense mutations in GBM remains unknown. In this study, we show high oligodendrocyte transcription factor 2 (OLIG2) expression in GSCs with EGFR-G598V and EGFR-A289V missense mutations. OLIG2 is universally expressed in glioma and essential for reprogramming GBM cells into stem-like tumor cells. Here, we report GSCs with these point mutations display increased self-renewal, growth, invasion, and therapeutic resistance. In addition, EGFR-G598V and EGFR-A289V trigger distinct downstream signaling pathways in GSCs to regulate OLIG2 function. These missense mutation(s) also represent different pathway-based GBM subclassifications, where A289V induces a Neuronal subtype and G598V induces a Glycolytic/Plurimetabolic subtype. We hypothesize that GBM tumors harboring EGFR missense mutations (G598V, A289V) influence stem cell properties via multiple pathways to evade therapeutic effects and inhibiting these different signaling pathways will decrease therapeutic resistance in GBM. Understanding the mechanism of these EGFR mutations may lead to improved therapeutic strategies for GBM patients. Citation Format: Sidney Weaver, Aunay Miller, Mylan Blomquist, James McNamara, Keely Orndorff, Chris Sereduk, Jean Kloss, Joseph Loftus, Shwetal Mehta, Nhan L. Tran. EGFR missense mutation(s) induce OLIG2 expression to regulate glioma stem cells maintenance and therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5444.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Summary Non‐steroidal anti‐inflammatory drugs (NSAIDs) are one of the mainstays of multimodal pain management. While effective for acute pain control, recent pre‐clinical evidence has raised concerns regarding an association between NSAIDs and chronic pain and potential opioid use. Our objective was to explore the association between peri‐operative use of prescription NSAIDs and the need for continued opioid prescriptions lasting 90–180 days in previously opioid‐naïve patients undergoing total knee arthroplasty. A database of health claims in the USA was used to identify all opioid‐naïve adult patients who underwent primary knee arthroplasty between January 2010 and October 2021. We evaluated the magnitude of association between peri‐operative prescription NSAID claims and claims for opioids at 90 days postoperatively using multivariable logistic regression models. Secondary outcomes included: the magnitude of association between peri‐operative NSAID prescription and claims for opioids at 180 days postoperatively; and identifying other potential factors associated with opioid claims at 90 days postoperatively. After risk adjustment using multivariable logistic regression models in the 789,736‐patient cohort, the adjusted odds ratio (95%CI) for a continuous claim of opioids at 90 and 180 days postoperatively among patients with a peri‐operative NSAID prescription within 30 days was 1.32 (1.30–1.35), p < 0.001; and 1.12 (1.10–1.15), p < 0.001, respectively. This estimate of effect remained robust at 90 days after accounting for known potential confounders, including pre‐existing knee pain and acute postoperative pain severity. Similar analysis of other pain medications (e.g. paracetamol) did not detect such an association. This population‐based cohort study suggests that peri‐operative prescription NSAID use may be associated with continued opioid prescription claims at 90 and 180 days after knee arthroplasty, even after adjusting for other observed covariates for continuous opioid claims. These novel findings can inform clinical decision‐making for post‐surgical pain management, risk–benefit discussions with patients and future research.

ABSTRACT: Objective: Determine the risk of autoimmune disease in research-identified cases of autism spectrum disorder (ASD) compared with referents using a longitudinal, population-based birth cohort. Methods: ASD incident cases were identified from a population-based birth cohort of 31,220 individuals. Inclusive ASD definition based on DSM-IV-TR autistic disorder, Asperger syndrome, and pervasive developmental disorder, not otherwise specified, was used to determine ASD cases. For each ASD case, 2 age- and sex-matched referents without ASD were identified. Diagnosis codes assigned between birth and December 2017 were electronically obtained. Individuals were classified as having an autoimmune disorder if they had at least 2 diagnosis codes more than 30 days apart. Cox proportional hazards models were fit to estimate the hazard ratio (HR) between ASD status and autoimmune disorder. Results: Of 1014 ASD cases, 747 (73.7%) were male. Fifty ASD cases and 59 of the 1:2 matched referents were diagnosed with first autoimmune disorder at the median age of 14 and 17.1 years, respectively. ASD cases had increased risk of autoimmune disease compared with matched referents (HR 1.74; 95% confidence interval [CI], 1.21–2.52). The increased risk was statistically significant among male patients (HR 2.01; 95% CI, 1.26–3.21) but not among the smaller number of female subjects (HR 1.38; 95% CI, 0.76–2.50). Conclusion: This study provides evidence from a longitudinal, population-based birth cohort for co-occurrence of ASD and autoimmune disorders. Thus, children with ASD should be monitored for symptoms of autoimmune disease and appropriate workup initiated.

AbstractChildren with very early onset inflammatory bowel disease (VEO‐IBD) may respond differently to coronavirus disease 2019 (COVID‐19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO‐IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO‐IBD experience robust humoral immune response to COVID‐19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO‐IBD respond well and safely to SARS‐CoV‐2 vaccination.