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Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index–4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index–4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors. Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed. The median age at diagnosis was 2.3 years (y) old [range 11 months (m)–8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1–4). The median time on treatment was 11 m (range 4–20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life. Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.

Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

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Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers.We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients.None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules.Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as ≥15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%–47%), with median time to response of 4.5 months (range, 3–12). In responders, reduction in VS volumes ranged from −15.7% to −23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%–58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%–82.1%) and 70.6% (95% CI, 43.1%–86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.

Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors. We studied 106 low-grade CNS neoplasms in a cohort of primarily pediatric patients to identify the prevalence and clinicopathologic significance of these alterations. Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma. KIAA1549:BRAF gene fusions confirmed by sequencing included the previously reported ones involving exons 1–16/9–18 (49%), 1–15/9–18 (35%), and 1–16/11–18 (8%) and 2 fusions with novel breakpoints: 1–15/11–18 (6%) and 1–17/10–18 (1%). DNA sequencing identified BRAFV600E mutations in 8% of tumors. BRAFG468A mutations were absent. KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001). We did not identify significantly improved progression-free survival in tumors with fusions. In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors. The prognostic and therapeutic significance of this alteration is unclear and merits further study.

A population-based registry was used to ascertain whether neuroimaging findings of children with cerebral palsy could predict the occurrence of certain comorbidities. Neuroimaging findings and comorbidities data were extracted from the Quebec Cerebral Palsy Registry for children born in a 4-year birth interval (1999-2002) covering half of the province's population. Neuroimaging studies were classified into 10 mutually exclusive categories (periventricular white matter injury/leukomalacia, cerebral malformation, cerebral vascular accident, deep gray matter injury, superficial gray matter injury, diffuse gray matter injury, intracranial hemorrhage, infection, nonspecific findings, and normal). Comorbidities studied included cortical blindness, severe auditory impairment, inability to communicate verbally, assisted feeding, and the presence of afebrile seizures in the prior 12 months. Neuroimaging results were available for a total of 213 children. Only deep gray matter injury (defined as signal abnormality or volume loss in subcortical gray matter, n = 9) was significantly (P < 0.05) linked with the occurrence of both the inability to communicate verbally (n = 5, 55.6% vs n = 46, 22.5%, P = 0.04) and with a higher mean number of comorbidities (1.67 vs 0.70, P < 0.01), and therefore with increased burden of comorbidities. These findings may improve our ability to prognosticate the outcome of children with cerebral palsy, enabling targeted early direct interventions.

The impact of treatment given upon discharge on the “bounce back” rate was ascertained in children presenting at the emergency department for treatment of status migrainosus. All children ages 8 to 17 years old presenting to an emergency department in 2008 who were treated for status migrainosus and discharged home were included. Of the total of 187 patients, 21 patients (11.2%) bounced back. Treatment given was not associated with the bounce back rate. The only factors reaching significance were the presence of a migraine equivalent in 28.6% of patients who bounced back as compared with only 6.7% in patients without recurrence ( P = .006); brain imaging study in the emergency department (52.4% vs 16.9%, P = .001); and an arranged physician follow-up (66.6% vs 36.3%, P = .01). The results appear to suggest that no current treatment given to children presenting to the emergency department with status migrainosus seems to alter the immediate recurrence rate.

This report describes a 6-year-old boy with disseminated low-grade astrocytoma and ventriculo-peritoneal shunt, who developed recurrent ascites while receiving sorafenib on a clinical trial. Laboratory analysis of the peritoneal fluid showed no elevation of protein content and no evidence of underlying infection or tumor dissemination. This report highlights ascites as a previously unrecognized adverse reaction to sorafenib in a patient with a ventriculo-peritoneal shunt. We conclude that such patients should be closely monitored for this complication when treated with sorafenib.

Recurrent pediatric low-grade astrocytoma (PLGA) represents a major clinical problem in neuro-oncology, and novel, less toxic and more effective therapies are needed.1 Recently, our increased understanding of the key molecular pathways driving PLGA growth and the increasing availability of targeted therapies for those pathways have led to great interest in exploring molecular targeted therapies for PLGA. Pilocytic astrocytoma (PA) is the most common histological subtype of PLGA. Patients with neurofibromatosis type 1 (NF1) are predisposed to developing PAs, predominantly in the optic tract (ie, optic pathway gliomas [OPGs]).2 NF1 is characterized by the loss of the NF1 gene product neurofibromin, resulting in activation of the RAS/RAF/MEK/ERK signaling pathway.3 The majority of sporadic PAs harbor a unique tandem duplication at chromosome 7q34, which produces a fusion gene between KIAA1549 and the kinase domain of BRAF that result in constitutive BRAF and ultimately MAPK activation. In recent genomic studies, almost all PAs that do not harbor KIAA-BRAF have been shown to harbor other genetic lesions that also result in constitutive MAPK pathway activation, such as activating genetic hits in FGFR1, NTRK2, and RAF1.4,5 PLGAs express pro-angiogenic factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF]), and their receptors (VEGFR and PDGFR).6–8 Bevacizumab, a VEGF inhibitor, has recently shown very encouraging activity in PLGA.9,10 Sorafenib is an oral, small-molecule multikinase inhibitor with potent in vitro activity against both wild-type and mutant (V600E) BRAF.11 Recent preclinical data showed that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with sorafenib.12 Sorafenib also exerts anti-angiogenic activity via inhibition of VEGFR-1/2/3, PDGFRβ, Flt-3, and c-kit, which has been studied in a variety of preclinical models13,14 as well as in clinical studies using dynamic, contrast-enhanced MRI.15 Because sorafenib is a potent inhibitor of several key molecular pathways that are relevant in PLGAs and encouraging preclinical data,12 we conducted this prospective phase II clinical trial to assess the objective response rate to sorafenib in patients with PLGA.

There is increasing reliance on oncoprotein assays such as the β-subunit of human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) for diagnosis or confirmation of histology of central nervous system (CNS) germ cell tumors (GCT), but the relative diagnostic sensitivity and reliability of assays from serum (S), lumbar (L), and ventricular (V) cerebrospinal fluid (CSF) are uncertain.A total of 86 patients with CNS GCT were identified from our database. Fourteen patients had contemporaneous β-hCG and/or AFP measurements from serum, ventricular, and lumbar CSF at diagnosis (n = 13) or relapse (n = 1), constituting the subjects for this report. Their primary tumor sites were: pineal (n = 8), suprasellar (n = 1), or both (n = 5). Their mean age at diagnosis was 16.0 years (range 9.1-25.9). The male:female sex ratio was 13:1.For the germinoma-treated patients (n = 8), the median (range) β-hCG values (S, V, L) were 0 (0-6.9), 7.0 (0-57.4), 8.3 (0-34.0) mIU/ml. For patients managed as mixed malignant GCT (MMGCT) (n = 6), the median (range) β-hCG values (S, V, L) were 3.9 (0-58.0), 3.6 (0-147.0), 61.8 (0-358.0) mIU/ml. The median (range) AFP values were 7.5 (0-27,400.0), 2.0 (0-2,981.0), 3.0 (0-14,015.0) ng/ml. Lumbar CSF β-hCG values were equal or greater than those in ventricular CSF or serum in 12 of 13 cases (92.3%). All patients with MMGCT had lumbar AFP equal or greater than the ventricular CSF values, while serum AFP values remained highest.Ventricular CSF values cannot be considered a replacement for lumbar CSF. Lumbar CSF is the most reliable source of tumor markers to establish baseline and follow-up diagnostic endpoints.