RESUMEN
BACKGROUND: Despite appropriate therapeutic interventions, progressive optic pathway glioma (OPG) in children may result in loss of vision and other neurologic morbidities. Molecularly targeted therapy against the MAP kinase pathway holds promise in improving outcomes while resulting in lower treatment-related toxicities. We report two children with refractory OPG who had a substantial and early reversal of their neurologic deficits and an impressive imaging response of their tumor to BRAFV600E inhibition therapy. METHODS: Two children with OPG (BRAFV600E-mutated pilocytic astrocytoma) who did not respond to at least one frontline therapy were treated with the oral BRAFV600E inhibitor vemurafenib. RESULTS: Both children had substantial visual compromise before start of therapy, with one child additionally having motor deficits. Both had an early improvement in their vision, and the second child showed a demonstrable improvement in motor weakness. This was accompanied by a decrease in tumor size, which was sustained at 6 months from therapy. Neither child had significant toxicities except for mild skin sensitivity to vemurafenib. CONCLUSIONS: BRAFV600E inhibitor therapy can potentially reverse visual and neurologic decline associated with progressive OPG. The clinico-radiologic response appears to be prompt and marked. Ongoing clinical trials using BRAFV600E inhibitors can help confirm these early promising findings.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas , Mutación/genética , Glioma del Nervio Óptico , Proteínas Proto-Oncogénicas B-raf/genética , Recuperación de la Función/efectos de los fármacos , Vemurafenib/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Preescolar , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Glioma del Nervio Óptico/diagnóstico por imagen , Glioma del Nervio Óptico/tratamiento farmacológico , Glioma del Nervio Óptico/genética , Recuperación de la Función/genética , Resultado del TratamientoRESUMEN
Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.
Asunto(s)
Neoplasias Encefálicas/patología , Genes myb , Predisposición Genética a la Enfermedad , Glioma/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Adulto , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Niño , Preescolar , Proteínas de Unión al ADN , Femenino , Ganglioglioma/genética , Ganglioglioma/patología , Glioma/patología , Humanos , Lactante , Masculino , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al ARN , Transactivadores/genética , Factores de Transcripción , Adulto JovenRESUMEN
Isolated optic nerve glioma is a rare tumor with no consensus for the best therapeutic approach. Therefore, tumor control and preservation of visual function remain a challenge. In this retrospective study, we describe our experience over 30 years in a single-institutional cohort of children with isolated optic nerve glioma, focusing on treatments and visual outcomes. Seventeen children were followed for a median period of 8 years (range, 2-22 years). Diagnosis was based on typical neuroradiologic findings, and 3 patients had histologic confirmation of their tumors. In our study, conservative management preserved the vision of most patients with neurofibromatosis type 1 (NF1). NF1-related optic nerve gliomas were less often treated but were associated with a lower probability of progression and with occasional spontaneous regression. Sporadic tumors more frequently exhibited aggressive clinical behavior with a higher propensity for posterior extension, often requiring surgical intervention.