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OBJECTIVE Despite the known negative physiological impact of repeated mild head trauma events, their multiplicative impact on long-term seizure risk remains unclear. The objective of this study was to evaluate how multiple mild traumatic brain injuries (mTBIs) impact long-term seizure risk by testing 3 distinct machine learning approaches. Baseline and injury-specific characteristics were incorporated to enhance prognostication of individual seizure risk. METHODS Children with at least 1 mTBI event without prior evidence of seizure or antiepileptic drug treatment, from 2003 to 2021, were identified from a nationally sourced administrative claims database. The primary outcome of interest was a seizure event after mTBI, defined by qualifying principal diagnosis codes. Time-varying multivariable Cox regression was used to assess the impact of repeated mTBI. RESULTS A total of 156,118 children (mean age 11.7 ± 4.7 years) were included, with a median follow-up duration of 22.6 months (IQR 9.2–45.4 months). Among patients who experienced seizure after mTBI, the median time to seizure was 306 days. Seizures among those with radiographic findings and/or loss of consciousness occurred earlier (median time to seizure 112.5 days [imaging findings only, IQR 5–526.25 days], 80 days [loss of consciousness only, IQR 7–652 days], 22 days [both, IQR 5–192 days]). Both mTBI without and with short-term loss of consciousness resulted in increasing seizure risk with repeated trauma (HR 1.196, 95% CI 1.082–1.322; HR 2.025, 95% CI 1.828–2.244; respectively). The random survival forest approach achieved fixed-time areas under the receiver operating characteristic curve of 0.780 and 0.777 at 30 and 90 days after mTBI, and children predicted at high risk by the final model experienced a significantly higher burden of early seizure after mTBI (46.7% within the first 30 days vs 17.7% and 19.9% of children at low and medium risk). A simplified model using the top 12 contributing features achieved 95% of the full model’s performance in the validation set. CONCLUSIONS A novel machine learning model was developed and validated for personalized prediction of long-term seizure risk following multiple mTBIs. Model performance remained robust with a limited feature set, suggesting the feasibility of real-time incorporation into clinical workflows for individualized prognostication following each repeat mTBI event. In children predicted to be at high risk, early intervention should be considered.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.

ABSTRACTObjectivesCeliac disease (CeD), an autoimmune disorder triggered by gluten ingestion, induces intestinal inflammation and varied symptoms. Treatment entails a strict gluten‐free diet (GFD), posing challenges for students, especially in schools with limited food choices. Nonadherence worsens symptoms, yet research on CeD's impact on students is scarce.MethodsThe CeliacKIDS study, conducted across 11 United States academic medical centers, evaluated gluten exposure risk in pediatric CeD patients via a cross‐sectional survey from August 2020 to August 2021. Participants recruited from treating institutions were approved by respective Institutional Review Boards.ResultsOne hundred and sixty children aged 5–18 (65% female, 34% male, 1% other) participated. Only 12% had GF food options at school, 31% brought their own for celebrations, and 41% lacked gluten free (GF) snacks after school. Thirty‐six percent lacked a 504 plan, with 5% misinformed. Hand hygiene concerns included 24% using sanitizer and 10% rarely washing hands before eating. Sixty‐two percent disclosed CeD, 35% when prompted, and 3% refused, mainly 13‐year‐old males. Two percent hesitated to request GF options, and 2% consumed potentially gluten‐containing food from friends.ConclusionMany US schools provide GF accommodations under the Americans with Disabilities Act (ADA) but lack national standards. Diverse GF options and education on GF‐safe practices are crucial for GFD adherence. Discrepancies in parent–child perceptions emphasize the need for better communication. Adolescents, particularly females aged 12–13 with 2+ years on a GF diet, face higher risks. Transparent family–school communication is vital for optimizing the school experience and ensuring GFD adherence. Comprehensive nationwide school training is essential for celiac patients' well‐being.

Abstract Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n = 8) or Wilms tumor (n = 1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing–altered 1 subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875 to 1:4,843 but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and Wilms tumor are also associated with DICER1 GPVs, our results suggest that the tissues of origin for these tumors are uniquely tolerant of general miRNA loss. The miRNA processing–altered 1 pineoblastoma subtype is associated with older age of diagnosis and better outcomes than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest that genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, Wilms tumor, or other DICER1-/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are an essential systemic therapy for advanced melanoma. However, most melanomas develop resistance to ICI. Tumor-derived soluble PD-L1 (sPD-L1) and other soluble immunosuppressive factors drive checkpoint inhibitor resistance and correlate with inferior survival. We previously showed that therapeutic plasma exchange (TPE) removes sPD-L1 from circulation. Thus, we hypothesized that TPE-mediated removal of sPD-L1 and other immunosuppressive factors could overcome immunotherapy resistance in refractory melanoma. Methods: In this clinical trial (NCT04581382), we prospectively enrolled eighteen (18) patients with widely metastatic melanoma with progression despite anti-PD-1 ICI and elevated sPD-L1 by ELISA (≥1.7ng/mL). Each patient received radiotherapy to between one and three metastatic lesions (at least two unirradiated lesions) followed by three TPE sessions on consecutive days and re-challenge with checkpoint inhibitor. The primary safety and efficacy endpoints of the study were adverse events (AEs) and sPD-L1 reduction by TPE, respectively. Secondary endpoints included RECIST-based response in unirradiated lesions and overall survival. Correlative studies included kinetics of sPD-L1 and soluble immonsuppressive factors and dynamics of peripheral immune cell phenotypes. Results: Mean age was 62 (SD 13) and seven of eighteen (39%) were female. Mean baseline sPD-L1 was 26.31 ng/mL (40.01). The treatment was well-tolerated with one (6%) patient with grade 3 and 4 adverse events from a central line infection after TPE. Levels of sPD-L1 were significantly reduced by TPE (mean 80.2% reduction, p<0.0001). Two patients (11.1%) experienced complete response (CR), one (5.6%) partial response, three (16.7%) stable disease, and 12 (66.7%) progressive disease. In one case, immunotherapy was discontinued after two years due to no detectable lesions. Changes in tumor-reactive (TTR) GZMB+/CX3CR1+/CD11ahigh and other peripheral immune cell populations predicted overall survival in this cohort. In addition to sPD-L1, other soluble mediators of ICI resistance were also reduced by TPE and predicted overall survival in this cohort. Summary/Conclusion: sPD-L1 and other soluble immunoregulatory signaling molecules are important mediators of ICI resistance. SBRT and TPE can resensitize ICI-refractory melanoma by removing these factors. Patients with persistently elevated or rapid rebound of sPD-L1 following TPE experienced poor response and overall survival. Serial monitoring of sPD-L1 may predict response to ICI and multiple courses of TPE may be necessary. Our findings may apply in other ICI-resistant cancers with elevated sPD-L1. ClinicalTrials.gov registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1).

The novel Coronavirus Disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, created a need for evidence-based guidelines for the evaluation, management, and follow-up after infection. Data have become rapidly available, creating a challenge for medical providers to stay abreast of the ever-evolving recommendations. This article, written collaboratively by pediatric cardiovascular experts, pediatricians, and sports medicine specialists, is focused on SARS-CoV- 2-related pediatric cardiac manifestations. It aims to provide a systematic review of high-yield literature related to all cardiovascular entities as a tool for primary pediatric clinicians to utilize as they consider the cardiac consequences of acute SARS-CoV-2 infection, MIS-C, vaccine-related myocarditis, return-to-play, and long COVID-19 syndrome.

AbstractObjectivesThe prevalence of celiac disease (CeD) is increasing, yet it is still underdiagnosed, in part because of its heterogeneous presentation. Diagnostic criteria are evolving and management with strict adherence to a gluten‐free diet is challenging for many. We aimed to characterize the clinical presentation of CeD among a large multicenter cohort of pediatric patients and to identify factors associated with gluten‐free diet adherence.MethodsPatients with CeD aged 0–18 years were recruited from 11 United States health centers. Parents completed surveys about gluten‐free diet adherence and patient electronic health records were reviewed. Logistic regression analyses were performed to identify risk factors associated with gluten exposure.ResultsCharts were reviewed for 460 children with a median age of 6.4 years. Abdominal pain was reported in 57% of the cohort, but diverse symptoms were identified. Parent surveys were completed for 455 participants. Sixty‐five (14%) participants were at high risk for gluten exposure based on parental reports of weekly or daily gluten exposure or eating gluten by choice in the past year. Participants under the age of 5 years had a lower risk of gluten exposure, while participants without repeat serology testing 18 months after initial diagnosis were at higher risk of gluten exposure.ConclusionsIn a large, multicenter cohort of pediatric CeD patients, clinical presentation is highly variable, necessitating a high index of suspicion to make a diagnosis. Parent surveys indicate that 14% of patients are at high risk of gluten exposure, with patient age and lack of close follow‐up associated with gluten‐free diet adherence.