Faculty Bibliography

BACKGROUND AND PURPOSE/UNASSIGNED:After surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. METHODS/UNASSIGNED:In this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. RESULTS/UNASSIGNED:Median follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9-40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. CONCLUSION/UNASSIGNED:FSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson's r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPKpathway alterations, and patients with relatively high CBF

Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2, 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or ampliconbased electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Preliminary analysis of samples demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201, and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (15% tumor reduction) at 30 months on treatment from diagnosis. In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG

OBJECTIVES/OBJECTIVE:Child life specialists and music therapists have a unique and integral role in providing psychosocial care to pediatric patients and families. These professionals are trained to provide clinical interventions that support coping and adjustment and reduce the risk of psychological trauma related to hospital visits and health care encounters. The researchers devised a multimodal approach using a combined child life and music therapy intervention to address procedure-related distress in patients receiving intravenous (IV) placement in the pediatric emergency department. The aim of this study was to investigate the efficacy of this collaborative intervention by evaluating parental perception of their child's distress. METHODS:This study was a prospective analysis investigating the impact of a child life and music therapy intervention on children aged 4 to 11 years old receiving an IV placement in the pediatric emergency department. Efficacy was evaluated by comparing scores between a 4-question pretest and subsequent 4-question posttest that asked the child's parent to evaluate how they anticipated their child would respond to the procedure, and then to evaluate how they perceived their child to have responded after the procedure. Qualitative data were collected in the form of open-ended comments, which were accommodated at the end of the posttest. Data were analyzed by the Cochran-Mantel-Haenszel method for testing repeated ordinal responses and the PROC GENMOD procedure in the SAS system software. RESULTS:A total of 41 participants were enrolled in this study. Results of the statistical analysis revealed significant differences between all pre- and posttest scores (P < 0.05), and significant likelihood that the patient would improve relative to the 4 questions, as a result of the child life and music therapy intervention. CONCLUSIONS:Improvement was demonstrated across all 4 questions, suggesting that the child life and music therapy intervention supported healthy, adaptive coping and helped to minimize distress experienced by patients during IV placement. These results underscore the importance and potential clinical impact of child life psychological preparation and psychotherapy-based music therapy interventions in reducing distress in pediatric patients during common medical procedures.

This article provides recommendations for pediatric readiness, scope of services, competencies, staffing, emergency preparedness, and transfer of care coordination for urgent care centers (UCCs) and retail clinics that provide pediatric care. It also provides general recommendations for the use of telemedicine in these establishments.With continuing increases in wait times and overcrowding in the nation's emergency departments and the mounting challenges in obtaining timely access to primary care providers, a new trend is gaining momentum for the treatment of minor illness and injuries in the form of UCCs and retail clinics. As pediatric visits to these establishments increase, considerations should be made for the type of injury or illnesses that can be safely treated, the required level training and credentials of personnel needed, the proper equipment and resources to specifically care for children, and procedures for safe transfer to a higher level of care, when needed. When used appropriately, UCCs and retail clinics can be valuable and convenient patient care resources.

BACKGROUND:Bullying is an important public health issue with broad implications. Although this issue has been studied extensively, there is limited emergency medicine literature addressing bullying. The emergency department (ED) physician has a unique opportunity to identify children and adolescents that are victims of bullying, and make a difference in their lives. OBJECTIVE:Our aim is to discuss the role of the emergency physician (EP) in identifying patients who have been victims of bullying and how to provide effective management as well as referral for further resources. DISCUSSION/CONCLUSIONS:This document provides a framework for recognizing, stabilizing, and managing children who have experienced bullying. With the advent of social media, bullying behavior is not limited to in-person situations, and often occurs via electronic communication, further complicating recognition because it may not impart any physical harm to the child. Recognition of bullying requires a high level of suspicion, as patients may not offer this history. After the stabilization of any acute or overt indications of physical injury, along with obtaining a history of the mechanism of injury, the EP has the opportunity to identify the existence of bullying as the cause of the injury, and can address the issue in the ED while collaborating with "physician-extenders," such as social workers, toward identifying local resources for further support. CONCLUSIONS:The ED is an important arena for the assessment and management of children who have experienced bullying. It is imperative that EPs on the front lines of patient care address this public health epidemic. They have the opportunity to exert a positive impact on the lives of the children and families who are the victims of bullying.

A well-appearing 3-year-old boy presented to the pediatric emergency department 2 hours after a presumed hydrocarbon ingestion. He was referred to the emergency department by his pediatrician after consultation with the local poison control center after possibly ingesting ylang ylang (Cananga odorata) fragrance oil. The child was asymptomatic with a normal physical examination. Point-of-care lung ultrasound identified focal hydrocarbon pneumonitis in the right lung and demonstrated resolution of these findings. Utilization of point-of-care ultrasound resulted in a shorter emergency department length of stay and the avoidance of radiation exposure from serial chest x-rays.

BACKGROUND: Chest x-ray (CXR) is the test of choice for diagnosing pneumonia. Lung ultrasound (LUS) has been shown to be accurate for diagnosing pneumonia in children and may be an alternative to CXR. Our objective was to determine the feasibility and safety of substituting LUS for CXR when evaluating children with suspected pneumonia. METHODS: We conducted a randomized control trial comparing LUS to CXR in 191 children from birth to 21 years of age with suspected pneumonia in an emergency department. Patients in the investigational arm received a LUS. If there was clinical uncertainty after ultrasound, clinicians had the option to obtain CXR. Patients in the control arm underwent sequential imaging with CXR followed by LUS. Primary outcome was the rate of CXR reduction; secondary outcomes were missed pneumonia, subsequent unscheduled healthcare visits, and adverse events between investigational and control arms. RESULTS: There was a 38.8% reduction (95% CI, 30.0 to 48.9%) in CXR among investigational subjects compared to no reduction (95% CI, 0.0 to 3.6%) in the control group. Novice and experienced clinician-sonologists achieved 30.0% and 60.6% reduction in CXR use, respectively. There were no cases of missed pneumonia among all study participants (investigational arm 0%; 95% CI: 0.0-2.9%; control arm 0%; 95% CI 0.0-3%) or differences in adverse events, or subsequent unscheduled healthcare visits between arms. CONCLUSIONS: It may be feasible and safe to substitute LUS for CXR when evaluating children with suspected pneumonia with no missed cases of pneumonia or increase in rates of adverse events.

Hip pain and fever in children include a broad differential. Most concerning is the possible diagnosis of a septic joint, which carries significant morbidity. We describe the case of a 13-year-old boy with fever and hip pain who was referred to the emergency department with concern for septic hip. The etiology was later discovered to be pyomyositis from methicillin-resistant Staphylococcus aureus. In areas with high prevalence of community-acquired methicillin-resistant Staphylococcus aureus, it is important for physicians to be aware of this rare, but potentially complicated condition.