A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas.

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas.

Treatment Approach for Metastatic Intracranial Germinoma: A Multi-Institutional Experience.

Background: Germinoma is the most common intracranial germ cell tumor (IGCT) in children and young adults. Treatment with 24 Gy craniospinal irradiation (CSI) with boost to 40 Gy alone results in excellent survival, irrespective of disease stage. For localized germinoma, recent studies have demonstrated the efficacy of pre-irradiation induction chemotherapy in decreasing the field and dose of radiation therapy (RT) needed for cure.

Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.

Purpose: There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population.

Advances in Treatment of Diffuse Midline Gliomas.

Purpose Of Review: Diffuse midline gliomas (DMGs) generally carry a poor prognosis, occur during childhood, and involve midline structures of the central nervous system, including the thalamus, pons, and spinal cord.

Recent Findings: To date, irradiation has been shown to be the only beneficial treatment for DMG. Various genetic modifications have been shown to play a role in the pathogenesis of this disease.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort.

Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.

We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53) but showed alterations in TP53 pathway members PPM1D and MDM4.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

Background: The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained.

Methods: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy.

Liquid biopsy detection of genomic alterations in pediatric brain tumors from cell-free DNA in peripheral blood, CSF, and urine.

Background: The ability to identify genetic alterations in cancers is essential for precision medicine; however, surgical approaches to obtain brain tumor tissue are invasive. Profiling circulating tumor DNA (ctDNA) in liquid biopsies has emerged as a promising approach to avoid invasive procedures. Here, we systematically evaluated the feasibility of profiling pediatric brain tumors using ctDNA obtained from plasma, cerebrospinal fluid (CSF), and urine.

Outcomes after first relapse of childhood intracranial ependymoma.

Background: Ependymoma is the third most common malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor. Approaches to therapy for relapsed ependymoma are varied.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

Background: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG).

Methods: Everolimus was administered at 5 mg/m once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded.

Increasing value of autopsies in patients with brain tumors in the molecular era.

Background: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report.

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross-sectional study.

Background: MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors.

Anaplastic Astrocytoma in a Child With Coffin-Siris Syndrome and a Germline SMARCE1 Mutation: A Case Report.

Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS.

Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets.

Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG.

Establishing a Preclinical Multidisciplinary Board for Brain Tumors.

Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.

Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor.

The permanent defects in bone growth observed in preclinical studies of hedgehog (Hh) pathway inhibitors were not substantiated in early phase clinical studies of vismodegib in children. Consequently, vismodegib advanced into pediatric trials for malignancies suspected of being driven by aberrant activation of the Hh pathway. In one multicenter phase II trial, vismodegib was added to the therapy regimen for newly diagnosed Hh pathway activated medulloblastoma.

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival.

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Chicago's Ann & Robert H. Lurie Children's Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database.

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors.

Background: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established.

Methods: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels.