Cynthia J. Campen

Cranial Irradiation Increases Risk of Stroke in Pediatric Brain Tumor Survivors

Background and Purpose— The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor. Methods— Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment January 1, 1993, to December 31, 2002, and at least 2 visits with neuro-oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack. Results— Of 431 subjects, 14 had 19 events of stroke or transient ischemic attack over a median follow-up of 6.3 years. The incidence rate was 548/100 000 person-years. Overall, 61.5% of subjects received radiation, including 13 of 14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/transient ischemic attack hazard ratio for any brain irradiation was 8.0 (95% CI, 1.05–62; P=0.045); for the circle of Willis, radiation was 9.0 (95% CI, 1.2–70; P=0.035); and for focal noncircle of Willis, radiation was 3.4 (95% CI, 0.21–55; P=0.38). Conclusions— The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.

Subependymal Giant Cell Astrocytoma (SEGA) Treatment Update

Opinion statementRates of regrowth after resection of subependymal giant cell astrocytoma (SEGA) are low, making surgical resection a successful and permanent therapeutic strategy. In addition to surgical resection of SEGAs, other treatment options now include medications and Gamma Knife™ therapy. Advising patients on medical versus surgical management of SEGAs is currently not easy. SEGAs have been reported to regrow if mTOR inhibitor therapy is stopped, raising the possibility that long-term medication may be required to prevent tumor growth and hydrocephalus. The question of regrowth following medication withdrawal will need to be addressed in more patients to help establish the optimal duration of therapy. The risks of surgery include acute morbidity and the permanent need for ventriculoperitoneal shunting, which must be balanced against the adverse effects of mTOR inhibitors, including immunosuppression (infections, mouth sores), hypercholesterolemia, and the need for chronic drug monitoring. Some additional benefits of mTOR inhibition in patients with tuberous sclerosis complex, however, may include shrinkage of angiofibromas and angiomyolipomas as well as a possible decrease in seizure burden. Recent reports of successful nonsurgical treatment of SEGAs are promising, and it is hoped that further specifics on dosing, duration, and long-term outcome will help patients and physicians to make informed therapeutic choices.Present treatment recommendations for SEGAs include routine surveillance neuroimaging and close clinical follow-up, paying particular attention to signs and symptoms of acute hydrocephalus. If symptoms arise, or if serial neuroimaging demonstrates tumor growth, neurosurgical intervention is recommended. When gross total resection is impossible, rapamycin and everolimus should be considered, but may not offer a durable response.

Intellectual Outcome in Molecular Subgroups of Medulloblastoma

Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Childrens National Health System (Washington, DC), or the Lucile Packard Childrens Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma.

Headache as a risk factor for neurovascular events in pediatric brain tumor patients

Objective: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. Methods: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0–21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. Results: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7–9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8–15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7–5.5 years). Conclusions: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.

Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors

Objective To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction. Study design We analyzed retrospectively arterial spin‐labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure. Results Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%‐23% lower, varying by anatomic region, all adjusted P < .05), whereas patients with PA (all treated with surgery alone) had normal CBF. ADC was decreased specifically in the hippocampus and amygdala of patients with MB and within the amygdala of patients with PA but otherwise remained normal after therapy. In the patients with tumor previously evaluated for IQ, regional ADC, but not CBF, correlated with IQ (R2 = 0.33‐0.75). Conclusions The treatment for MB, but not PA, was associated with globally reduced CBF. Treatment in both tumor types was associated with diffusion abnormalities of the mesial temporal lobe structures. Despite significant perfusion abnormalities in patients with MB, diffusion, but not perfusion, correlated with cognitive outcomes.

Reduced Cerebral Arterial Spin-Labeled Perfusion in Children with Neurofibromatosis Type 1

BACKGROUND AND PURPOSE: Neurofibromatosis type 1 is associated with increased risk for stroke, cerebral vasculopathy, and neurocognitive deficits, but underlying hemodynamic changes in asymptomatic children remain poorly understood. We hypothesized that children with neurofibromatosis type 1 have decreased cerebral blood flow. MATERIALS AND METHODS: Arterial spin-labeled CBF was measured in 14 children with neurofibromatosis type 1 (median age, 9.7 years; mean, 10.2 years; range, 22 months to 18 years) and compared with age-matched control subjects on 3T MR imaging. Three-dimensional pseudocontinuous spin-echo arterial spin-labeled technique was used. Measurements were obtained at cortical gray matter of bilateral cerebral hemispheres and centrum semiovale by use of the ROI method. Comparison by Mann-Whitney test was used, with Bonferroni-adjusted P values ≤.004 judged as significant. RESULTS: We identified 7 of 12 areas with significantly diminished arterial spin-labeled CBF in patients with neurofibromatosis type 1 compared with control subjects. These areas included the anterior cingulate gyrus (P = .001), medial frontal cortex (P = .004), centrum semiovale (P = .004), temporo-occipital cortex (P = .002), thalamus (P = .001), posterior cingulate gyrus (P = .002), and occipital cortex (P = .001). Among patients with neurofibromatosis type 1, there were no significant differences in these regions on the basis of the presence of neurofibromatosis type 1 spots or neurocognitive deficits. CONCLUSIONS: Reduced cerebral perfusion was seen in children with neurofibromatosis type 1, particularly in the posterior circulation and the vascular borderzones of the middle and posterior cerebral arteries.

Ependymoma: An Overview

Ependymoma, a central nervous system tumor in the glioma family, is composed of neoplastic ependymal cells. Most ependymomas are WHO grade II, slow-growing tumors, but grades range from WHO grade I-III. Location and grade vary by patient age, with adult tumors typically spinal and grade I, and pediatric tumors mainly in the posterior fossa and grade II. Prognostic features include: age, location, grade and extent of resection with adult, spinal, grade I tumors having the best prognosis; and pediatric, intracranial, grade III tumors having the worst prognosis. Treatment is typically composed of surgical resection with or without radiotherapy, while chemotherapy has very little proven efficacy in ependymoma.

Epidemiology of Pediatric Central Nervous System Tumors

Tumors of the central nervous system (CNS) comprise a broad and diverse collection of neoplasms within pediatric oncology. Yet when taken together pediatric brain and spine tumors represent the most common childhood cancer with an incidence of 5.57 per 100,000 annually and are a leading cause of cancer-related death in patients under 19 years of age (Ostrom et al. 2014; Siegel et al. 2015). Factors such as genetic predisposition, age, and sex play an increasingly significant role in understanding presentation, management, and etiology of childhood brain tumors. Although long-standing observations regarding general patterns of CNS tumors continue to be clinically useful, the introduction of molecular subtypes, such as in medulloblastoma and ependymoma, and the discovery of epigenetic regulators, such as in diffuse intrinsic pontine gliomas (DIPG) and other diffuse midline gliomas with H3K27M mutations, have repurposed epidemiological findings and reconceptualized CNS tumor classification (Louis et al. 2016). The elucidation of the molecular profile of pediatric CNS tumors has made it clear that epidemiology, viewed through a prism of genetics and epigenetics, can offer even greater insights into this incredibly challenging group of tumors. Epidemiology today considers not only environmental, parental, and birth factors that may increase the risk of pediatric CNS tumors, but also germline and molecular features that are causal or pathognomonic of tumor types and subtypes.

Comment: Genotype–phenotype correlations in NF1: A case for routine genetic testing

Neurofibromatosis 1 (NF1), a genetic syndrome with a prevalence of 1/1,000–1/3,500 people, predisposes to intellectual disability, social–behavioral and learning problems, and tumors. Although the NF gene was identified in 1990, genotypic–phenotypic correlations have proven elusive. Known correlations include deletion of the entire NF1 gene (severe phenotype), missense mutations (spinal neurofibromatosis) and exon 17 base pair in-frame deletion c.2970-2972 (mild phenotype), and clustering of mutations in the 5′-end in patients with optic pathway gliomas.1 Clinicians and researchers alike would benefit from better mutation predictors of clinical outcomes, not only for streamlining appropriate surveillance and intervention, but to direct research, both tumoral and cognitive.

Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis

OBJECTIVE Pediatric spinal astrocytomas are rare spinal lesions that pose unique management challenges. Therapeutic options include gross-total resection (GTR), subtotal resection (STR), and adjuvant chemotherapy or radiation therapy. With no randomized controlled trials, the optimal management approach for children with spinal astrocytomas remains unclear. The aim of this study was to conduct a systematic review and meta-analysis on pediatric spinal astrocytomas. METHODS The authors performed a systematic review of the PubMed/MEDLINE electronic database to investigate the impact of histological grade and extent of resection on overall survival among patients with spinal cord astrocytomas. They retained publications in which the majority of reported cases included astrocytoma histology. RESULTS Twenty-nine previously published studies met the eligibility criteria, totaling 578 patients with spinal cord astrocytomas. The spinal level of intramedullary spinal cord tumors was predominantly cervical (53.8%), followed by thoracic (40.8%). Overall, resection was more common than biopsy, and GTR was slightly more commonly achieved than STR (39.7% vs 37.0%). The reported rates of GTR and STR rose markedly from 1984 to 2015. Patients with high-grade astrocytomas had markedly worse 5-year overall survival than patients with low-grade tumors. Patients receiving GTR may have better 5-year overall survival than those receiving STR. CONCLUSIONS The authors describe trends in the management of pediatric spinal cord astrocytomas and suggest a benefit of GTR over STR for 5-year overall survival.