Frederick A. Boop

Subtypes of medulloblastoma have distinct developmental origins.

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

A RETROSPECTIVE STUDY OF SURGERY AND REIRRADIATION FOR RECURRENT EPENDYMOMA

PURPOSEnTo report disease control for patients with recurrent ependymoma (EP) treated with surgery and a second course of radiation therapy (RT(2)).nnnPATIENTS AND METHODSnThirty-eight pediatric patients (median age, 2.7 years) with initially localized EP at the time of definitive RT underwent a second course of RT after local (n = 21), metastatic (n = 13), or combined (n = 4) failure. Reirradiation included radiosurgery (n = 6), focal fractionated reirradiation (n = 13), or craniospinal irradiation (CSI; n = 19).nnnRESULTSnInitial time to failure was 16 months, and median age at second treatment was 4.8 years. Radiosurgery resulted in significant brainstem toxicity and one death (median dose, 18 Gy). Progression-free survival ratio was greater than unity for 4 of 6 patients; there was one long-term survivor. Three of 13 patients treated using focal fractionated reirradiation (median combined dose, 111.6 Gy) experienced metastasis. The CSI was administered to 12 patients with metastatic failure, 3 patients with local failure, and 4 patients with combined failure. The 4-year event-free survival rate was 53% +/- 20% for 12 patients with metastatic failure treated with CSI. Failure after CSI was observed in 1 of 3 patients with a history of local failure and 3 of 4 patients with a history of combined failure.nnnCONCLUSIONnPatients with locally recurrent EP experience durable local tumor control, but remain at risk of metastasis. Patients with metastatic EP failure may receive salvage therapy that includes a component of CSI. Durability of disease control and long-term effects from this approach require further follow-up.

Proximal dentatothalamocortical tract involvement in posterior fossa syndrome

Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, -71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates -24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.

Functional MRI and Wada Determination of Language Lateralization: A Case of Crossed Dominance

Summary:u2003 The Wada test has historically been the conventional procedure for determining language lateralization before neurosurgery. However, functional magnetic resonance imaging (fMRI) offers a less invasive alternative to the Wada procedure. Research indicates that the two techniques used together may provide comparable, and sometimes complementary, information that results in improved prediction of postsurgical language ability. We present a case in which use of fMRI in conjunction with Wada testing provided complementary information about language lateralization before neurosurgical resection of a mesial temporal subependymoma for seizure control in a patient with schizencephaly.

Seizures in children with primary brain tumors: Incidence and long-term outcome

PURPOSEnTo estimate the incidence and long-term outcome of brain tumor related seizures in children and to identify risk factors for adverse seizure outcome.nnnMETHODSnAnalysis of medical records of children treated for brain tumor and seizures in a single institution. Children were identified from hospital database and neurology clinic records. Seizure status was characterized for the 6 months prior to most recent follow-up.nnnRESULTSnMedian follow-up after first seizure of the 157 analyzed children was 3.3 years. Tumor location was supratentorial in 81% and posterior fossa in 19%. Initial anti-epileptic drugs were phenytoin (n=52), carbamazepine (n=38), phenobarbital (n=14), gabapentin (n=31), or others (n=22). Seizures were controlled in 65% of the children and uncontrolled in 35% (17% intractable). Gabapentin showed a trend toward better seizure control (p=0.06). Neurologic deficit, T2 peri-cavity hyperintensity, and EEG slow waves were independently predictive of uncontrolled seizures by multivariate analysis.nnnCONCLUSIONSnT2 peri-cavity hyperintensity, focal neurologic deficits, and EEG slow waves predict poor seizure control in children with brain tumors. Seizures can be controlled in most patients with brain tumors. Gabapentin use as first anti-epileptic drug needs to be studied prospectively.

Sequencing of Local Therapy Affects the Pattern of Treatment Failure and Survival in Children With Atypical Teratoid Rhabdoid Tumors of the Central Nervous System

PURPOSEnTo assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT).nnnMETHODS AND MATERIALSnPediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated.nnnRESULTSnThirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT.nnnCONCLUSIONSnDelayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.

Evolution of neurological impairment in pediatric infratentorial ependymoma patients

Background Infratentorial ependymoma is a common central nervous system tumor of childhood and in patients >1xa0year of age is treated with maximally feasible surgical resection and radiotherapy. Because of this tumor typically arises within the 4th ventricle and can invade the brainstem, patients are at risk for significant neurological impairment. Purpose To characterize the incidence, evolution, and persistence of neurologic impairment in children with infratentorial ependymoma following maximal safe surgery and conformal or intensity-modulated radiation therapy (CRT/IMRT). Patients and Methods After surgical resection, 96 children with non-metastatic infratentorial ependymoma were enrolled on a phase II study of image-guided radiation therapy and were prospectively followed with interval comprehensive neurological examinations. Late adverse neurological severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Results The most common deficits detected at baseline examination were limb dysmetria, cranial nerve VI/VII palsy, limb paresis, dysphagia, and truncal ataxia/hypotonia. When present, gait dysfunction and dysphagia were often severe. Oculomotor dysfunction, facial paresis, dysphagia, and gait impairment improved over time. With the exception of hearing loss, in the survivor cohort, very few severe late effects (CTCAE Grade 3/4/5) were present at 60xa0months survival. Conclusion In general, neurological deficits were maximal in the post-operative period and either remained stable or improved during radiation and the post-treatment evaluation period. With the exception of hearing, the majority of chronic residual neurological deficits in this at-risk population are mild and only minimally intrude upon daily life.

Diffusion tensor imaging of brainstem tumors: axonal degeneration of motor and sensory tracts

OBJECTnDiffusion tensor (DT) imaging has been used to predict postoperative motor function in patients with supratentorial tumors. The authors sought to determine whether DT imaging and white matter tractography could detect axonal degeneration in patients with brainstem tumors.nnnMETHODSnA cross-sectional, retrospective study of 7 patients with brainstem tumors and 8 healthy volunteers was performed. The DT imaging data were normalized and regions of interest (ROIs) with the highest probability of sensory and motor connections were selected using the Talairach Atlas to identify the 3D millimetric coordinates of white matter tracts. An iterative process involving fractional anisotropy (FA), apparent diffusion coefficients (ADCs), and color maps was developed to precisely select ROIs in the bilateral sensory and motor tracts. The FA and ADC values were calculated for each ROI.nnnRESULTSnThe FA values of sensory and motor tracts significantly differed between the patient and healthy volunteer groups (p < 0.05), whereas no significant changes were found in the splenium or genu of the corpus callosum. The FA values were altered proximal and distal to the brainstem tumors with a bimodal peak of antegrade decreased FA involving second- and third-order sensory axons and retrograde decreased FA of motor axons.nnnCONCLUSIONSnThis study demonstrates changes in diffusion properties of sensory and motor tracts consistent with degeneration to further characterize brainstem tumors in children, and the results warrant the planning of prospective trials. The rigorous methods the authors describe may provide valuable information when planning biopsies or debulking of unusual brainstem tumors, as well as improve prognostication of the possible functional tract recovery following therapy.

Emotional and Behavioral Functioning After Conformal Radiation Therapy for Pediatric Ependymoma

PURPOSEnThe standard of care for pediatric patients with ependymoma involves postoperative radiation therapy. Prior research suggests that conformal radiation therapy (CRT) is associated with relative sparing of cognitive and academic functioning, but little is known about the effect of CRT on emotional and behavioral functioning.nnnMETHODS AND MATERIALSnA total of 113 patients with pediatric ependymoma underwent CRT using photons as part of their enrollment on an institutional trial. Patients completed annual evaluations of neurocognitive functioning during the first 5 years after CRT. Emotional and behavioral functioning was assessed via the Child Behavior Checklist.nnnRESULTSnBefore CRT, emotional and behavioral functioning were commensurate with those of the normative population and within normal limits. After 5 years, means remained within normal limits but were significantly below the normative mean. Linear mixed models revealed a significant increase in attention problems over time. These problems were associated with age at diagnosis/CRT, tumor location, and extent of resection. A higher-than-expected incidence of school problems was present at all assessment points after baseline.nnnCONCLUSIONSnThe use of photon CRT for ependymoma is associated with relatively stable emotional and behavioral functioning during the first 5 years after treatment. The exception is an increase in attention problems. Results suggest that intervening earlier in the survivorship period-during the first year posttreatment-may be beneficial.

Eight-second MRI scan for evaluation of shunted hydrocephalus

IntroductionPediatric patients harboring shunts placed early in life are subjected to numerous radiographic studies during development of their central nervous system. Radiation is detrimental to these young patients. MRI avoids the risk of radiation but is thought more difficult due to the increased time a young patient must lie motionless during scan acquisition. Optimal radiographic interrogation would be quick, radiation-free, and allow adequate ventricular evaluation.MethodsWe queried the electronic medical records system of the senior author (SE) for the terms “hydrocephalus” and “shunt malfunction.” All patients currently younger than 18xa0years were included. In the last 5xa0years, pediatric patients have been evaluated in an office setting with a limited MRI sequence (T1 sagittal, T2 axial, T1 axial, and DWI) lasting a total of 178xa0s. In the event of significant motion artifact, the total sequence is abandoned and an 8-sxa0T2 diffusion-weighted scan is performed.ResultsForty-four patients were included in the study (20 males, average age 10.4xa0yrs). Eighty-eight rapid acquisition scans were obtained. Adequate ventricular evaluation was performed without sedation in every case. In each instance where there was motion, the 8-s scan provided adequate ventricular evaluation.ConclusionRapid acquisition MRI scanning avoids the deleterious cumulative effects of radiation in pediatric patients and allows adequate evaluation of the ventricles without the need for sedation.