Lisa McLeod

Abstract BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − 2 once weekly; 600 mg maximum) in patients with BRAF -altered, relapsed/refractory pLGG. Arm 2 ( n = 60) is an extension cohort, which provided treatment access for patients with RAF -altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF -altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .

Importance: US national guidelines discourage the use of continuous pulse oximetry monitoring in hospitalized children with bronchiolitis who do not require supplemental oxygen. Objective: Measure continuous pulse oximetry use in children with bronchiolitis. Design, Setting, and Participants: A multicenter cross-sectional study was performed in pediatric wards in 56 US and Canadian hospitals in the Pediatric Research in Inpatient Settings Network from December 1, 2018, through March 31, 2019. Participants included a convenience sample of patients aged 8 weeks through 23 months with bronchiolitis who were not receiving active supplemental oxygen administration. Patients with extreme prematurity, cyanotic congenital heart disease, pulmonary hypertension, home respiratory support, neuromuscular disease, immunodeficiency, or cancer were excluded. Exposures: Hospitalization with bronchiolitis without active supplemental oxygen administration. Main Outcomes and Measures: The primary outcome, receipt of continuous pulse oximetry, was measured using direct observation. Continuous pulse oximetry use percentages were risk standardized using the following variables: nighttime (11 pm to 7 am), age combined with preterm birth, time after weaning from supplemental oxygen or flow, apnea or cyanosis during the present illness, neurologic impairment, and presence of an enteral feeding tube. Results: The sample included 3612 patient observations in 33 freestanding children's hospitals, 14 children's hospitals within hospitals, and 9 community hospitals. In the sample, 59% were male, 56% were white, and 15% were black; 48% were aged 8 weeks through 5 months, 28% were aged 6 through 11 months, 16% were aged 12 through 17 months, and 9% were aged 18 through 23 months. The overall continuous pulse oximetry monitoring use percentage in these patients, none of whom were receiving any supplemental oxygen or nasal cannula flow, was 46% (95% CI, 40%-53%). Hospital-level unadjusted continuous pulse oximetry use ranged from 2% to 92%. After risk standardization, use ranged from 6% to 82%. Intraclass correlation coefficient suggested that 27% (95% CI, 19%-36%) of observed variation was attributable to unmeasured hospital-level factors. Conclusions and Relevance: In a convenience sample of children hospitalized with bronchiolitis who were not receiving active supplemental oxygen administration, monitoring with continuous pulse oximetry was frequent and varied widely among hospitals. Because of the apparent absence of a guideline- or evidence-based indication for continuous monitoring in this population, this practice may represent overuse.

BACKGROUND AND OBJECTIVES: Croup is a clinical diagnosis, and the available evidence suggests that, except in rare cases, ancillary testing, such as radiologic imaging, is not helpful. Given the paucity of inpatient-specific evidence for croup care, we hypothesized that there would be marked variability in the use of not routinely indicated resources (NRIRs). Our primary study objective was to describe the variation and predictors of variation in the use of NRIRs. METHODS: This was a retrospective cohort study that used the Pediatric Health Information System database of generally healthy inpatients with croup aged 6 months to 15 years who were admitted between January 1, 2012 and September 30, 2014. We measured variability in the use of NRIRs: chest and lateral neck radiographs, viral testing, parenteral steroids, and antibiotics. Risk-adjusted analysis was used to compare resource utilization adjusted for hospital-specific effects and average case mix. RESULTS: The cohort included 26 hospitals and 6236 patients with a median age of 18 months. Nine percent of patients required intensive care services, and 3% had a 30-day readmission for croup. We found marked variability in adjusted and unadjusted utilization across hospitals for all resources. In the risk-adjusted analysis, hospital-specific effects rather than patient characteristics were the main predictor of variability in the use of NRIRs. CONCLUSIONS: We observed an up to fivefold difference in NRIR utilization attributable to hospital-level practice variability in inpatient croup care. This study highlights a need for inpatient-specific evidence and quality-improvement interventions to reduce unnecessary utilization and to improve patient outcomes.

STUDY DESIGN: A comparative effectiveness database study. OBJECTIVE: The aim of this study was to describe variation in use of adjuvant therapies for managing postoperative pain in in patients undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) and determine association between use of these therapies and patient outcomes. SUMMARY OF BACKGROUND DATA: Variation in postoperative pain management for children undergoing PSF for AIS likely impacts outcomes. Minimal evidence exists to support strategies that most effectively minimize prolonged intravenous (IV) opioids and hospitalizations. METHODS: We included patients aged 10 to 18 years discharged from one of 38 freestanding children's hospitals participating in a national database from December 1, 2012, to January 5, 2015, with ICD9 codes indicating scoliosis and PSF procedure. Use of ketorolac, gamma aminobutyric acid (GABA) analogues (GABAa), and benzodiazepines was compared across hospitals. Hierarchical logistic regression adjusting for confounders and accounting for clustering of patients within hospitals was used to estimate association between these therapies and odds of prolonged duration of IV opioids, prolonged length of stay (LOS), and early readmissions. RESULTS: Across hospitals, use of ketorolac and GABAa was highly variable and increased over time among 7349 subjects. Use of ketorolac was independently associated with significantly lower odds of prolonged LOS [odds ratio (OR) 0.75, 95% confidence interval (95% CI) 0.64-0.89] and prolonged duration of IV opioid (OR 0.84, 95% CI 0.73-0.98). GABAa use was significantly associated with decreased odds of prolonged IV opioid use (OR 0.63, 95% CI 0.53-0.75). Readmission rate at 30 days was 1.6% and most strongly associated with prolonged LOS. CONCLUSION: In this national cohort of children with AIS undergoing PSF, patients who received postoperative ketorolac or GABAa were less likely to have prolonged IV opioid exposure. Given the rapid increase in use of adjuvant therapies without strong evidence, resources should be devoted to multicenter trials in order to optimize effectiveness and outcomes. LEVEL OF EVIDENCE: 3.