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A prospective, single-arm clinical trial was conducted to evaluate an altruism-tailored educational intervention to improve parental attitudes and vaccine uptake in vaccine-hesitant parents.Vaccine-hesitant parents at two primary care sites, spanning two influenza seasons from 2020 to 2021 were provided an intervention (spoken and written communication) which highlighted altruistic benefits of accepting the seasonal influenza vaccine to optimize herd immunity to help protect pediatric cancer patients. Eligible parents included those with children eligible for the seasonal influenza vaccine, those who were proficient in English, and those with scores on the adjusted Vaccine Hesitancy Scale (aVHS) suggesting vaccine hesitancy (score ≥ 3). Enrollees completed a demographic questionnaire, underwent the educational intervention, and repeated the aVHS. Vaccination status at that visit was assessed. The primary outcome was change in aVHS scores obtained pre- and post-intervention. Influenza vaccine acceptance, along with demographic information, were also analyzed.We enrolled 510 parents of influenza vaccine eligible children and identified 73 vaccine-hesitant parents. There was an overall trend toward lower aVHS score, with a mean change in hesitancy score of -0.4 (P 0.01). 43/73 (58.9 %) of the cohort experienced a positive effect toward a lower aVHS score, and 27/73 (37.0 %) of vaccine hesitant subjects became non-hesitant on the aVHS. Several demographic characteristics were associated with vaccine hesitancy in the screening population: educational level lower than bachelor's degree (p = 0.03), household income 400 % of federal poverty level (p 0.01), unmarried (p = 0.02), and identifying with a political affiliation other than Democrat (p 0.01). However, no demographic characteristics were significantly associated with an individual becoming non-hesitant. Our altruism-tailored communication approach carried the largest positive impact on the altruism-specific question on the aVHS, decreasing the post-intervention response value by nearly 25 % (P 0.01).Our altruism-tailored communication approach significantly improved attitudes regarding childhood influenza vaccine among vaccine-hesitant parents.gov Identifier: NCT04568590.

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Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has disrupted normal health care utilization patterns worldwide, including decreasing emergency department (ED) visits for various medical emergencies. We examined whether this pattern was present in febrile pediatric oncology patients. In this single-center cohort study, we conducted a retrospective chart review of ED visits of febrile pediatric oncology patients during the first 4 months of the global SARS-CoV-2 pandemic and compared those data to the same time periods in the previous 2 years. During the first 5 months of the pandemic, 25 pediatric oncology patients with fever visited our ED; 65 children visited during the same time period in 2018; and 60 visited in 2019. Compared with 2018 and 2019, encounters for 2020 were decreased by 62% and 58%, respectively. A significantly higher percentage of febrile pediatric oncology patients (84%) were admitted to our hospital during the pandemic compared the previous years (58%). Of concern is the possibility that fear of exposure to coronavirus disease-19 (COVID-19) at our health care facility prompted caregivers of pediatric oncology patients to avoid seeking care for their child with fever. Consistent communication with families about the life-threatening nature of fever should be prioritized among pediatric oncology providers.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890

1. Thomas B. Russell, MD* 2. David E. Kram, MD, MCR* 1. *Section of Pediatric Hematology/Oncology, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC * AKI: : acute kidney injury ALL: : acute lymphoblastic leukemia HRD: : high-risk disease IRD: : intermediate-risk disease LRD: : low-risk disease TLS: : tumor lysis syndrome Along with knowledge of how to evaluate a pediatric patient with a suspected malignancy, general pediatricians must maintain a high level of suspicion of tumor lysis syndrome for initial management and timely patient referral. This syndrome is largely preventable, and certainly manageable, with prompt diagnosis and appropriate intervention. After completing this article, readers should be able to: 1. Define and diagnose tumor lysis syndrome (TLS). 2. Recognize the risk factors for TLS. 3. Stratify pediatric patients with cancer according to risk of developing TLS. 4. Identify interventions to prevent TLS. 5. Discuss management strategies for patients with TLS. Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency that occurs when cancer cells break down, either spontaneously or after initiation of cytotoxic chemotherapy, and release their intracellular contents into the bloodstream. This massive release of uric acid, potassium, and phosphorous, which under normal physiologic conditions are excreted in the urine, can lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. These metabolic derangements increase the risk of severe complications, including acute kidney injury (AKI), cardiac arrhythmias, seizures, and even death. TLS is the most common oncologic emergency, and it occurs most frequently in children with acute leukemia and non-Hodgkin lymphoma. TLS is often preventable; clinicians must maintain a high index of suspicion and rely on effective prevention and treatment strategies. This review will serve to update the readership on TLS in pediatric oncology patients, including the definition, common risk factors, epidemiology, pathophysiology, and clinical consequences, as well as preventive and management measures for children with suspected or newly diagnosed cancers. TLS consists of a constellation of laboratory findings, including hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and the consequential clinical …

For pediatric patients with high‐grade gliomas, standard‐of‐care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high‐grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3‐year‐old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal‐parietal‐temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard‐of‐care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas. Key Points Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome.Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome.Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP‐ribose) polymerase (PARP) inhibitors.Combining PARP inhibitors with temozolomide (standard‐of‐care treatment) revealed no adverse events or toxicities over the course of 18 months., This article reports the first case of a pediatric glioblastoma that maintained a durable response to a therapeutic strategy that included the PARP inhibitor olaparib, highlighting the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas.

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.1%) cases with known or novel alterations in BRAF or RAF1 detected in extracranial solid tumors, brain tumors, or hematological malignancies. Eighty percent (176/221) of these tumors had a known-activating short variant (98, 55.7%), fusion (72, 40.9%), or insertion/deletion (6, 3.4%). Among BRAF altered cancers, the most common tumor types were brain tumors (74.4%), solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%). RAF1 fusions containing intact RAF1 kinase domain (encoded by exons 10–17) were identified in seven tumors, including two novel fusions TMF1-RAF1 and SOX6-RAF1. Additionally, we highlight a subset of patients with brain tumor with positive clinical response to BRAF inhibitors, demonstrating the rationale for incorporating precision medicine into pediatric oncology. Implications for Practice Precision medicine has not yet gained a strong foothold in pediatric cancers. This study describes the landscape of BRAF and RAF1 genomic alterations across a diverse spectrum of pediatric cancers, primarily brain tumors, but also encompassing melanoma, sarcoma, several types of hematologic malignancy, and others. Given the availability of multiple U.S. Food and Drug Administration-approved BRAF inhibitors, identification of these alterations may assist with treatment decision making, as described here in three cases of pediatric cancer.

Dicentric (7;9)(p11-13;p11) is a rare but recurrent abnormality in pediatric and adult precursor B acute lymphoblastic leukemia (B-ALL). The rarity precludes a deep understanding of its biology and associated prognosis. However, recent findings have correlated dic(7;9) and PAX5 mutations, highlighting this cytogenetic event's involvement in leukemogenesis and may also shed light on the overall prognosis of dic(7;9) B-ALL.

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.

BACKGROUND Pediatric low-grade gliomas (LGG) not amenable to resection, while often indolent, represent a significant source of cancer-related morbidity and an unmet therapeutic need. Standardly, these patients are treated with sequential lines of chemotherapy, while delaying as long as possible radiation. Magnetic resonance-guided laser interstitial therapy (LITT) is a minimally invasive procedure that utilizes real-time MR thermography to ablate brain lesions. METHODS A 15-year-old girl was diagnosed with a suprasellar, hypothalamic LGG, BRAF V600E mutation positive. The tumor was unresectable, and due to progressive vision loss and headaches, the patient underwent treatment. Despite sequential trials of thioguanine/procarbazine/lomustine/vincristine, carboplatin/vincristine, dabrafenib, and combination dabrafenib/trametinib, the patient continued to experience debilitating headaches, malnutrition, school absenteeism, and overall poor quality-of-life. Using real-time, sequential MRI-thermometry and the Neuroblate cooled directional laser catheter, the bulk of the enhancing tumor was heated to a killing temperature. RESULTS At 1-year post LITT, the patient’s symptoms were dramatically improved, including greatly improved headaches, malnutrition, school absenteeism, and overall quality of life. LITT was generally well tolerated, though the patient had slight progressive left homonymous hemianopia, thought secondary to LITT impact on the optic tracts. The tumor progressively shrank over the year post-LITT to a peak of 42% volume reduction. CONCLUSION We report a case of a pediatric patient with an unresectable low grade glioma who underwent LITT with excellent clinical and radiographic effects. LITT should be considered for children with unresectable and morbid LGGs that fail to respond to more conventional therapies.

Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive condition in which affected patients carry biallelic germline mutations in the MMR genes. This highly penetrant syndrome results in nearly universal development of malignant neoplasms at a young age, most commonly pediatric brain tumors. Importantly, in addition to brain tumors, patients frequently develop multiple metachronous or even synchronous tumors making it impossible to treat these cancers with current chemotherapeutic approaches due to the complexity of different chemoradiation regimens required, resulting in excess toxicity and lack of efficacy. We first, assessed the metachronous (defined here as serial tumors diagnosed >1 year apart or after completion of definitive treatment for the initial tumor) or synchronous cancers (defined here as tumors diagnosed within a year of each other or during the definitive treatment for the initial tumor) in all patients within the consortium. Strikingly, 47% developed synchronous and/or metachronous cancers leading to patient demise. Molecular analysis revealed that all synchronous tumors (n=26) harbored a hypermutational burden accompanied by high genomic microsatellite instability and the relevant signatures. We therefore treated two patients with glioblastomas who had synchronous solid tumors with checkpoint inhibitors. In both patients, objective tumor response was associated with clinical benefit and prolonged survival. Biomarker analysis revealed increased tumor mutational burden, microsatellite instability and immune cell infiltration. These cases highlight the role of universal, mechanism based and tumor-agnostic approach to treat patients with brain tumors with additional synchronous cancers in the setting of cancer predisposition.

The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers that slowed down the pace of research and collaboration. Our network now includes 17 institutions working together to empower research. As of December 2019, over 3,600 subjects have been enrolled resulting in collection of over 45,000 specimens. Clinical data collection is longitudinal and includes medical history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, in freezing media, and fresh for the generation of pre-clinical models including cell lines. Blood is collected from the subject, with blood or saliva collected from the parents for germline comparison. Additionally, the Children’s Brain Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS and RNAseq, 221 proteomics, with annotated clinical data. All of this data, both generated raw and processed data, has been made available broadly to the scientific community via cloud-based platforms, including the Gabriella Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As of January 2020, we have 45 approved biospecimen requests and 80 genomic/molecular data requests. In summary, the Children’s Brain Tumor Network’s goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.

Background Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. Methods We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children’s Oncology Group (COG) induction therapy from 2014–2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. Results In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. Conclusions Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance.

A newborn presents with a large, bleeding mass on her left hand (Figure 1). Figure 1. ### Prenatal and Birth History: The infant was born through meconium-stained amniotic fluid and was initially nonvigorous. The trachea was suctioned, and heart rate remained less than 100 beats per minute. Positive-pressure ventilation with a bag and mask was initiated, and heart rate increased within 15 seconds. A large friable mass was noted arising from the ventral surface of the left hand. All digits were present and well formed but displaced by the mass. ### Vital Signs: ### Physical Examination

Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances in genomic technology and the outpouring of biological data over the last decade, clear insights into the molecular heterogeneity of these tumors are now well delineated. The major subtypes of ETs of the CNS in children include medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and embryonal tumors with multilayered rosettes (ETMR), which are now biologically and clinically characterized as different entities. These important developments have paved the way for treatments guided by risk stratification as well as novel targeted therapies in efforts to improve survival and reduce treatment burden.

BACKGROUND: Pediatric glioblastoma (GBM; WHO grade IV astrocytoma) continues to carry a poor prognosis. While the use of concurrent and adjuvant temozolomide (TMZ) has been adopted as a standard treatment in adults, there is no standard systemic therapy for pediatric GBM. Recent studies in adults suggest benefit to the addition of tumor treating fields (TTF) to standard TMZ-based chemoradiotherapy, while a recent study in children showed improvement with the addition of lomustine (CCNU) to standard TMZ-based chemoradiotherapy. No studies to this point have been published using the combination of TMZ, TTF, and CCNU in either adult or pediatric GBM. METHODS: A single patient was treated with aggressive local surgery achieving gross total resection. This was followed by 60 Gy in 30 fractions with concurrent temozolomide (75 mg/m2) given daily during radiotherapy. Post-radiation adjuvant therapy consisted of dose escalated temozolomide (160 mg/m2) given on days 1-5 of a 42-day cycle, CCNU (90 mg/m2) on day 1, and continuous tumor treating fields (started with cycle 1 of adjuvant chemotherapy). RESULTS: Chemoradiotherapy was tolerated well without grade III or IV toxicity. Thus far, the patient has received 2 cycles of adjuvant temozolomide/CCNU without grade III or IV toxicity. At 3 months post-radiotherapy, there is no evidence of tumor recurrence. CONCLUSION: We report the first case of a pediatric patient with GBM receiving a maintenance combination of TTF, TMZ, and CCNU after tumor resection and standard TMZ-based chemoradiotherapy. Prospective trials are necessary to validate the tolerability, safety, and efficacy of this aggressive combination therapy.

Extranodal marginal zone B-cell lymphomas (EMZLs), while relatively common in adults, are rare entities in the pediatric population. A subclass of the typically aggressive non-Hodgkin lymphomas, the few reported pediatric cases indicate that, as in adults, these tumors tend to be indolent. We present a case of EMZL arising in the conjunctivae in a 9-year-old male with bilateral disease. The patient was treated with surgical excision alone and has remained disease-free 6 years after the operation.

Extranodal marginal zone B-cell lymphomas (EMZLs), while relatively common in adults, are rare entities in the pediatric population. A subclass of the typically aggressive non-Hodgkin lymphomas, the few reported pediatric cases indicate that, as in adults, these tumors tend to be indolent. We present a case of EMZL arising in the conjunctivae in a 9-year-old male with bilateral disease. The patient was treated with surgical excision alone and has remained disease-free 6 years after the operation.