Gliomas in children and adolescents: investigation of molecular alterations with a potential prognostic and therapeutic impact.

PURPOSE: Gliomas represent the most frequent central nervous system (CNS) tumors in children and adolescents. However, therapeutic strategies for these patients, based on tumor molecular profile, are still limited compared to the wide range of treatment options for the adult population. We investigated molecular alterations, with a potential prognostic marker and therapeutic target in gliomas of childhood and adolescence using the next-generation sequencing (NGS) strategy. METHODS: We selected 95 samples with initial diagnosis of glioma from patients treated at Pediatric Oncology Institute-GRAACC/UNIFESP. All samples were categorized according to the 2021 World Health Organization Classification of Tumors of the CNS, which included 39 low-grade gliomas (LGGs) and 56 high-grade gliomas (HGGs). Four HGG samples were classified as congenital glioblastoma (cGBM). NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay® (OCCRA®) panel, from Thermo Fisher Scientific®. RESULTS: Genetic variants were identified in 76 of 95 (80%) tumors. In HGGs, the most common molecular alteration detected was H3F3A c.83A > T variant (H3.3 K27M) and co-occurring mutations in ATRX, TP53, PDGFRA, MET, and MYC genes were also frequently observed. One HGG sample was reclassified as supratentorial ependymoma ZFTA-fusion positive after NGS was performed. In LGGs, four KIAA1549-BRAF fusion transcripts were detected and this alteration was the most recurrent genetic event and favorable prognostic factor identified. Additionally, genetic variants in ALK and NTRK genes, which provide potential targets for therapy with Food and Drug Administration-approved drugs, were identified in two different cases of cGBM that were classified as infant-type hemispheric glioma, a newly recognized subgroup of pediatric HGG. CONCLUSION: Molecular profiling by the OCCRA® panel comprehensively addressed the most relevant genetic variants in gliomas of childhood and adolescence, as these tumors have specific patterns of molecular alterations, outcomes, and effectiveness to therapies.

Molecular profiling of pediatric and adolescent ependymomas: identification of genetic variants using a next-generation sequencing panel.

PURPOSE: Ependymoma (EPN) accounts for approximately 10% of all primary central nervous system (CNS) tumors in children and in most cases, chemotherapy is ineffective and treatment remains challenging. We investigated molecular alterations, with a potential prognostic marker and therapeutic target in EPNs of childhood and adolescence, using a next-generation sequencing (NGS) panel specific for pediatric neoplasms. METHODS: We selected 61 samples with initial diagnosis of EPN from patients treated at Pediatric Oncology Institute-GRAACC/UNIFESP. All samples were divided according to the anatomical compartment of the CNS - 42 posterior fossa (PF), 14 supratentorial (ST), and five spinal (SP). NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay® (OCCRA®) panel, from Thermo Fisher Scientific®. RESULTS: Genetic variants were identified in 24 of 61 (39.3%) tumors and over 90% of all variants were pathogenic or likely pathogenic. The most commonly variants detected were in CIC, ASXL1, and JAK2 genes and have not been reported in EPN yet. MN1-BEND2 fusion, alteration recently described in a new CNS tumor type, was identified in one ST sample that was reclassified as astroblastoma. Additionally, YAP1-MAMLD1 fusion, a rare event associated with good outcome in ST-EPN, was observed in two patients diagnosed under 2 years old. CONCLUSIONS: Molecular profiling by the OCCRA® panel showed novel alterations in pediatric and adolescent EPNs, which highlights the clinical importance in identifying genetic variants for patients' prognosis and therapeutic orientation.

Validated quantitative needs assessment differences in the management of children with central nervous system cancer between Brazil, an upper middle-income country, and the United States of America, a high income country.

BACKGROUND: Pediatric cancer cure rates differ among high-income countries (HIC) and upper middle-income countries (UMIC). We have compared individual capacities of two major referral pediatric centers from a HIC and an UMIC caring for children with central nervous system (CNS) cancer. METHODS: A quantitative needs assessment questionnaire and key informant interviews, distributed in March of 2017, were used to evaluate the treatment of children with CNS cancer at Grupo de Apoio ao Adolescente e à Criança com Câncer (GRAACC) children's cancer center in São Paulo, Brazil and Nationwide Children's Hospital (NCH) in Columbus, Ohio, United States of America (USA). RESULTS: Both hospitals had 24-hour pediatric oncology, nursing and intensivist coverage. Supportive care available at both institutions included social workers, psychologists, child life specialists, and physical/occupational/speech therapists. Differences included two part-time neuroradiologists and one pathologist specializing in neuropathology at IOP/GRAACC/UNIFESP, whereas eight full-time neuroradiologists and two neuropathologists at NCH/OSU. There were four pediatric neurosurgeons on staff at each hospital; however, there were only 2 operative days per week at IOP/GRAACC/UNIFESP, compared with 7 days at NCH/OSU. Additionally, time to initiation of radiation therapy at IOP/GRAACC/UNIFESP extended 2-4 weeks compared with less than 1 week at NCH/OSU. CONCLUSIONS: Center-specific differences in resources exist in highly specialized hospitals caring for children with CNS cancer in HIC and UMIC. This quantitative needs assessment may facilitate the development of targeted strategies for effective interventions to improve on the management of children with CNS cancers.