Single-agent bevacizumab is efficacious in the management of recurrent or refractory pediatric LGG with radiographic and clinical responses similar to those reported for bevacizumab-based therapies.

MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N = 11) or highgrade CNS tumors (N = 3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N = 9) or in combination (N = 5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with lowgrade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinasedriven CNS tumors. Our observations need to be confirmed in a clinical trial setting.

Visual field deficits can be a consequence of brain tumor location or treatment. The prevalence of unrecognized visual field deficits in children diagnosed with brain tumors is not known. All children at a single tertiary care pediatric children's hospital diagnosed with a primary brain tumor were tested for visual field deficits by a child neurologist and neuro-ophthalmologist over 16 months. Children with reproducible visual field deficits on two separate occasions were included in the analysis. Patients with optic glioma, craniopharyngioma, or previously known visual field deficits were excluded. Fourteen of 92 (15.2%) children (average 8.9 years, 8 girls) had undiagnosed visual field deficits. Average time between diagnosis of tumor and unrecognized visual field deficit was 3.7 years (range 0-13 years). Unrecognized visual field deficits were not associated with age (P = 0.27) or gender (P = 0.38). Visual field deficits were attributed to direct tumor infiltration (n = 8), postoperative complications (n = 5) and post-radiation edema (n = 1). Deficits included bitemporal hemianopsia (n = 2), homonymous hemianopsia (n = 9), quadrantanopsia (n = 2), and concentric visual field loss (n = 1.) Tumor location included temporal lobe (n = 9), parietal lobe (n = 2), posterior fossa (n = 2), hypothalamic-chiasmatic (n = 2) and multifocal areas (n = 4). Children with temporal lobe tumors were more likely to have unrecognized visual field deficits (P = 0.004). In all 14 patients, visual field deficits were determined by examination only and were not reported by either the patient or caregiver regardless of age. The prevalence of unrecognized visual field deficits in children with brain tumors can be surprisingly high. Serial neuro-ophthalmologic evaluation of children with brain tumors is often required to diagnose a visual field deficit since patient or caregiver reporting may be limited.

Successful use of immune checkpoint inhibitors in a variety of cancers has generated interest in using this approach in pediatric brain tumors. We performed a retrospective review of 10 consecutive children (6 boys, 4 girls; ages, 2 to 17 y), with recurrent or refractory pediatric brain tumors (5 high-grade glioma, 1 lowgrade glioma, pineoblastoma, medulloblastoma, ependymoma, and CNS embryonal tumor, NOS) treated at Rady Children's Hospital San Diego from 2015 to 2017 with the immune checkpoint inhibitor nivolumab (3 mg/kg every 2 wk). Eight of 10 patients received prior chemotherapy and 9 radiation therapy. Nine patients had radiographic disease progression (median, 2.5 doses). Median time to progression was 5.5 weeks (1.6 to 24 wk). Three patients (2 with high-grade glioma, 1 with CNS embryonal tumor NOS) showed a partial response to treatment at the primary tumor site and 2 of 3 had progression of metastatic disease. Grade 2 toxicities were observed without dose limiting side effects. Tumor mutation burden (TMB) was low to intermediate (median, 1.3; range, 0 to 6.3). Median survival for PD-L1 positive patients was 13.7 weeks versus 4.2 weeks for PD-L1 negative patients (ρ = 0.08) nivolumab was well tolerated in our series of pediatric recurrent brain tumors with some transient partial responses in patients with positive PD-L1 expression and higher TMB. Our findings suggest that the use of immune checkpoint inhibitors in pediatric brain tumor patients should be limited to those with elevated PD-L1 expression and TMB.

Object Pediatric low-grade glioma (LGG) is the most common brain tumor of childhood. Except for the known association of gross-total resection and improved survival rates, relatively little is known about the clinical and radiographic predictors of recurrent disease and the optimal frequency of surveillance MRI. The authors sought to determine the clinical and radiographic features associated with recurrent or progressive disease in a single-institutional series of children diagnosed with primary CNS LGG. Methods The authors performed a retrospective analysis of data obtained in 102 consecutive patients diagnosed at Rady Children's Hospital–San Diego between 1994 and 2010 with a biopsy-proven LGG exclusive of a diagnosis of neurofibromatosis. Tumor location, patient age, sex, and symptomatology were correlated with tumor progression or recurrence. Magnetic resonance imaging characteristics and neuroimaging surveillance frequency were analyzed in those children with progressive or recurrent disease. Results Forty-six of 102 children diagnosed with an LGG had evidence of recurrent or progressive disease between 2 months and 11 years (mean 27.3 months) after diagnosis. In the larger group of 102 children, gross-total resection was associated with improved progression-free survival (p = 0.012). The location of tumor (p = 0.26), age at diagnosis (p = 0.69), duration of symptoms (p = 0.72), histological subtype (p = 0.74), sex (p = 0.53), or specific chemotherapeutic treatment regimen (p = 0.24) was not associated with tumor progression or recurrence. Sixty-four percent of children with recurrent or progressive disease were asymptomatic, and recurrence was diagnosed by surveillance MRI alone. All children less than 2 years of age in whom the tumor was diagnosed were asymptomatic at the time of progression (p = 0.04). Thirteen percent (6 of 46) of the children had disease recurrence 5 years after initial diagnosis; all of them had undergone an initial subtotal resection. Tumor progression was associated with either homogeneous or patchy T1-weighted post–Gd administration MRI enhancement in 94% of the cases (p = 0.0001). Conclusions Children diagnosed with recurrent LGG may be asymptomatic at the time of recurrence. The authors' findings support the need for routine neuroimaging in a subset of children with LGGs, even when gross-total resection has been achieved, up to 5 years postdiagnosis. The authors found that T1-weighted MR images obtained before and after Gd administration alone may be sufficient to diagnose LGG recurrence and may represent an effective strategy worthy of further validation in a larger multiinstitutional cohort.

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Medulloblastoma with extensive nodularity is a rare subtype of the most common malignant childhood brain tumor and has been associated with more favorable prognosis. The authors report the case of a 10-month-old girl with a posterior fossa tumor of excessive nodularity with decreased diffusivity on diffusion-weighted magnetic resonance imaging sequences and robust grape-like postgadolinium contrast enhancing features. The unique neuroradiographic features were confirmed by histopathology and a diagnosis of medulloblastoma with extensive nodularity was made. This case highlights the importance of recognizing this unique medulloblastoma subtype preoperatively, as the more favorable outcome may preclude less aggressive medical management.

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