Abstract Background Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial. Methods FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO) and RANO-LGG criteria. The data cutoff was June 5, 2023. Results Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set. Conclusions Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients.
Abstract BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − 2 once weekly; 600 mg maximum) in patients with BRAF -altered, relapsed/refractory pLGG. Arm 2 ( n = 60) is an extension cohort, which provided treatment access for patients with RAF -altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF -altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .
The incidence of childhood central nervous system tumors in infants is about 6 per 100 000 children. Recent studies have showed recurrent fusion of the neurotrophic tyrosine receptor kinase (NTRK) gene in 10% of non-brainstem high grade glioma in very young children suggesting an oncogenic effect of the NTRK fusion genes. In this report, we present a rare, severe case of a full-term neonate who was noted to have widely splayed sutures and a bulging fontanelle at birth who was found to have infant-type hemispheric glioma with NTRK1 fusion with course complicated by seizures refractory to medical treatment. Patient was deemed a poor surgical candidate due to the size of the mass and thus parents opted for comfort care.
Neonatal stroke is one of the leading causes of lifelong disability and has an incidence of 25 in 100,000 term live births. Neonatal arterial ischemic stroke (NAIS) is a subset with sequelae that can include cerebral palsy, global developmental impairments, and epilepsy. While NAIS remains rare, these adverse outcomes may be permanent and result in significant impact on the patients and their families. Potential etiologies include infection, malignancy, thromboembolic disease, and trauma. Neuroimaging findings generally demonstrate focal cerebral infarctions and possible spinal ischemia. Although cervical spinal infarcts are known to occur in conjunction with cerebral infarcts, we report a rare case of an isolated cervical spinal infarct in a neonate.
Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
Midbrain gliomas are a group of slow-growing, low-grade tumors that arise from the tectum and/or tegmentum. Clinical symptoms at diagnosis are usually due to aqueductal compression resulting in non-communicating hydrocephalus and managed by an endoscopic third ventriculostomy. In the majority of patients, diagnosis is based on imaging characteristics, and only a subset undergo biopsy or resection. As a result, little is known about the histopathological and molecular genetic spectrum of midbrain gliomas. We reviewed a series of 58 consecutive patients (age range birth-52 years) with midbrain gliomas treated at our institution over more than 30 years. Anatomically, these tumors appear to fall into two distinct radiographic categories: limited to the tectum and/or the periaqueductal gray matter of the tegmentum (Group A) and diffuse tumors that include the tectum and infiltrate the pons and/or thalamus (Group B). Twenty-one of our patients (Group A – 6, Group B – 12, unknown -- 3) had biopsies or surgical resection, and tissue was available for histologic and molecular analyses including methylation profiling and BRAF mutation analysis. Most tumors with available tissue, regardless of radiographic group, were found to be low-grade gliomas, primarily pilocytic astrocytomas (13 pilocytic astrocytomas, 7 other low grade gliomas). Most of our patients had a benign clinical course, with 10% requiring no treatment, and 34% receiving only endoscopic third ventriculostomy or ventriculoperitoneal shunt. Radiographic group was significantly associated with likelihood to progress and with progression-free survival, with only 12.5% of Group A tumors progressing but 46.4% of Group B tumors progressing (p=0.008). In addition, progression –free survival was significantly longer in Group A patients. Overall, survival in our cohort was 100% over more than 30 years, reinforcing that these are treatable tumors with generally excellent outcomes.
Purpose To investigate the rate of lesions of the corpus callosum (CC), specifically unidentified bright objects (UBOs) and gliomas, in a large cohort of Neurofibromatosis type 1 (NF1) patients.Methods We reviewed the medical records of 681 patients (aged 3 months to 86 years) followed at our institution from 2000-2023 with a diagnosis of NF1 and ≥ 1 brain MRI. Patients with UBOs or gliomas in the CC were identified and the change in lesions over time was recorded. RAPNO/RANO criteria were used to determine changes in size.Results Forty-seven patients had CC UBOs (9.2% of the 512 patients with any UBO). The majority of CC UBOs were in the splenium (66.0%), followed by the body (21.3%), and genu (12.8%). Seventeen patients had CC gliomas, two of whom had 2 gliomas, representing 10% of the 170 patients with any glioma. Seventeen of nineteen gliomas were in the splenium. Over follow-up, 8/19 remained stable, 3/19 decreased in size, and 8/19 increased in size. The mean percentage change in the product of the dimensions was 311.5% (ranging from -46.7% to 2566.6%). Of the 8 lesions that grew, only one required treatment.Conclusions There is a 6.9% and 2.5% prevalence of CC UBOs and gliomas, respectively, in our cohort of patients with NF1. Most lesions are present in the splenium, and while some gliomas demonstrate significant growth, they rarely require treatment. This work is the largest series of corpus callosal lesions in NF1 and adds to growing data to better inform appropriate follow-up.
