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1.  Headaches in Children With Craniopharyngioma 
Journal of child neurology  2012;28(12):1622-1625.
Craniopharyngioma frequently involves intracranial pain-sensitive structures. We retrospectively studied prevalence, associated risk factors, and outcome of headaches in children with craniopharyngioma. Fisher exact test and multivariate analysis were used to study association of study variables. Of the 51 craniopharyngioma patients treated at our institution from January 1994 to December 2005, 40 (78%) reported headaches (35 [68%] before tumor diagnosis). Migraine headaches were diagnosed in 32 (63%) and tension-type headaches in 11 patients (22%). The median follow-up period was 2.7 years. At the last follow-up, 38 (75%) were headache free. Presence of hydrocephalus, distortion of circle of Willis, and large tumor volume were associated with headache, and the last 2 variables were also associated with more severe and frequent headaches. Radiation treatment and insertion of Ommaya reservoir were associated with reduced headache frequency. In conclusion, headaches are common in patients with craniopharyngioma and are likely related to tumor size and volume. In most patients, headaches improve with successful tumor treatment.
PMCID: PMC4264380  PMID: 23143722
brain tumor; craniopharyngioma; headache; migraine; hydrocephalus
2.  Variation in the topography of the speech production cortex verified by cortical stimulation and high gamma activity 
Neuroreport  2014;25(18):1411-1417.
Supplemental Digital Content is available in the text.
In this study, we have addressed the question of functional brain reorganization for language in the presence and absence of anatomical lesions in two patients with epilepsy using cortical stimulation mapping and high gamma (HG) activity in subdural grid recordings. In both, the expressive language cortex was defined as the cortical patch below the electrode(s) that when stimulated resulted in speech arrest, and during speech expression tasks generated HG activity. This patch fell within the borders of Broca’s area, as defined anatomically, in the case of the patient with a lesion, but outside that area in the other, lesion-free patient. Such results highlight the necessity for presurgical language mapping in all cases of surgery involving the language-dominant hemisphere and suggest that HG activity during expressive language tasks can be informative and helpful in conjunction with cortical stimulation mapping for expressive language mapping.
PMCID: PMC4232293  PMID: 25371284
Broca’s area; cortical stimulation mapping; high gamma activity; presurgical language mapping; speech production area
3.  The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma 
Nature genetics  2014;46(5):444-450.
Pediatric high-grade glioma (HGG) is a devastating disease with a two-year survival of less than 20%1. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPG (32%), in addition to the previously reported frequent somatic mutations in histone H3, TP53 and ATRX in both DIPG and NBS-HGGs2-5. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, 2, or 3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase/RAS/PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59%, respectively, of pediatric HGGs, including DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.
PMCID: PMC4056452  PMID: 24705251
4.  Same Day Tri-Modality Functional Brain Mapping Prior to Resection of a Lesion Involving Eloquent Cortex: Technical Feasibility 
The neuroradiology journal  null;26(5):548-554.
Non-invasive functional evaluation of the brain complements structural MRI imaging and has largely supplanted invasive techniques such as awake craniotomy. Techniques used for functional mapping of the brain include BOLD-functional MRI (fMRI), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). We describe the case of a right-handed patient with a lesion centered in the left inferior perirolandic cortex who underwent fMRI, MEG, and TMS on a single day to facilitate maximal lesion resection while preserving eloquent cortex and eloquent white matter tracts.
PMCID: PMC4202830  PMID: 24199815
brain tumor; functional MRI; magnetoencephalography; transcranial magnetic stimulation; image-guided navigation; multimodality
5.  C11orf95-RELA fusions drive oncogenic NF-κB signaling in ependymoma 
Nature  2014;506(7489):451-455.
The nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
PMCID: PMC4050669  PMID: 24553141
To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and determine factors that predict for tumor progression.
Eighty-eight children (median age 8.5 years, range 3.2–17.6 years) received conformal or intensity-modulated radiation therapy between 1998 and 2009. This included those prospectively treated from 1998 to 2003 using a 10 mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003 yielding two groups of patients: those treated with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and the frequency of weekly surveillance MR imaging during radiation therapy. The median follow-up was 5 years.
There was no difference comparing progression-free survival based on CTV margin (>5mm vs. ≤ 5mm) at 5 years, 88.1 + 6.3% vs. 96.2 + 4.4% (P=0.6386). There was no difference based on the planning target volume (PTV) margin (or combined CTV+PTV). The PTV was systematically reduced from 5 to 3mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race (P=0.0175), absent CSF shunting requirement (P=0.0066), and the number of surveillance imaging studies during treatment (P=0.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression.
These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating the differences in outcome based on host factors to explain the results.
PMCID: PMC3594571  PMID: 23245282
Radiotherapy; Pediatrics; Brain Tumor; Craniopharyngioma; Adaptive Therapy
7.  Supratentorial Ependymoma: Disease Control, Complications and Functional Outcomes after Irradiation 
Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single institution series provides valuable information about disease control for supratentorial ependymoma and the complications of supratentorial irradiation in children.
Methods and Materials
A total of 50 children with newly diagnosed supratentorial ependymoma were treated with adjuvant radiation therapy (RT); 36 were using conformal methods after 1996. The median age at RT was 6.5 years (range, 1–18.9). The entire group was characterized according to sex (girls = 27), race (Caucasian = 43), extent of resection (gross-total = 46), and tumor grade (anaplastic = 28). The conformal RT group was prospectively evaluated for neurological, endocrine and cognitive effects.
With a median follow-up of 9.1 years from the start of RT for survivors (range 0.2–23.2), the 10-year progression-free and overall survival were 73% + 7% and 76% + 6%, respectively. None of the evaluated factors was prognostic for disease control. Local and distant failures were evenly divided among the 16 patients who experienced progression. Eleven patients died from disease and one from CNS necrosis. Seizure disorders were present in 17 patients and 4 were considered to be clinically disabled. Clinically significant cognitive effects were limited to children with difficult to control seizures. Average values for IQ and academic achievement (reading, spelling, and math) were within the range of normal through 10 years of follow-up. Central hypothyroidism was the most commonly treated endocrinopathy.
RT may be administered with acceptable risks for complications in children with supratentorial ependymoma. These results suggest that outcomes for these children are improving and that complications may be limited by use of focal irradiation methods.
PMCID: PMC3705553  PMID: 23245280
8.  Assessment of hemispheric dominance for receptive language in pediatric patients under sedation using magnetoencephalography 
Non-invasive assessment of hemispheric dominance for receptive language using magnetoencephalography (MEG) is now a well-established procedure used across several epilepsy centers in the context of pre-surgical evaluation of children and adults while awake, alert and attentive. However, the utility of MEG for the same purpose, in cases of sedated patients, is contested. Establishment of the efficiency of MEG is especially important in the case of children who, for a number of reasons, must be assessed under sedation. Here we explored the efficacy of MEG language mapping under sedation through retrospective review of 95 consecutive pediatric patients, who underwent our receptive language test as part of routine clinical evaluation. Localization of receptive language cortex and subsequent determination of laterality was successfully completed in 78% (n = 36) and 55% (n = 27) of non-sedated and sedated patients, respectively. Moreover, the proportion of patients deemed left hemisphere dominant for receptive language did not differ between non-sedated and sedated patients, exceeding 90% in both groups. Considering the challenges associated with assessing brain function in pediatric patients, the success of passive MEG in the context of the cases reviewed in this study support the utility of this method in pre-surgical receptive language mapping.
PMCID: PMC4140211  PMID: 25191260
magnetoencephalography; non-invasive; language mapping; sedation; epilepsy; children
9.  Increased Neuronal β-Amyloid Precursor Protein Expression in Human Temporal Lobe Epilepsy: Association with Interleukin-1α Immunoreactivity 
Journal of neurochemistry  1994;63(5):1872-1879.
Levels of immunoreactive β-amyloid precursor protein and interleukin-1α were found to be elevated in surgically resected human temporal lobe tissue from patients with intractable epilepsy compared with postmortem tissue from neurologically unaffected patients (controls). In tissue from epileptics, the levels of the 135-kDa β-amyloid precursor protein isoform were elevated to fourfold (p < 0.05) those of controls and those of the 130-kDa isoform to threefold (p < 0.05), whereas those of the 120-kDa isoform (p > 0.05) were not different from control values. β-Amyloid precursor protein-immunoreactive neurons were 16 times more numerous, and their cytoplasm and proximal processes were more intensely immunoreactive in tissue sections from epileptics than controls (133 ± 12 vs. 8 ± 3/mm2; p < 0.001). However, neither β-amyloid precursor protein-immunoreactive dystrophic neurites nor β-amyloid deposits were found in this tissue. Interleukin-1α-immunoreactive cells (microglia) were three times more numerous in epileptics than in controls (80 ± 8 vs. 25 ± 5/mm2; p < 0.001), and these cells were often found adjacent to β-amyloid precursor protein-immunoreactive neuronal cell bodies. Our findings, together with functions established in vitro for interleukin-1, suggest that increased expression of this protein contributes to the increased levels of β-amyloid precursor protein in epileptics, thus indicating a potential role for both of these proteins in the neuronal dysfunctions, e.g., hyperexcitability, characteristic of epilepsy.
PMCID: PMC3833617  PMID: 7931344
β-Amyloid precursor protein; Epilepsy; Interleukin-1
10.  Epilepsy: neuroinflammation, neurodegeneration, and APOE genotype 
Precocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ϵ4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome. Frozen and paraffin-embedded tissue samples resected from superior temporal lobes of 92 patients undergoing temporal lobectomies as a treatment for medication-resistant temporal lobe epilepsy were used in this study. To determine if epilepsy-related changes reflect those in another neurological condition, analogous tissue samples harvested from 10 autopsy-verified Alzheimer brains, and from 10 neurologically and neuropathologically normal control patients were analyzed using immunofluorescence histochemistry, western immunoblot, and real-time PCR to determine genotype effects on neuronal number and size, neuronal and glial expressions of amyloid β (Aβ) precursor protein (βAPP), Aβ, apolipoprotein E (ApoE), S100B, interleukin-1α and β, and α and β secretases; and on markers of neuronal stress, including DNA/RNA damage and caspase 3 expression.
Allelic combinations of APOE influenced each epilepsy-related neuronal and glial response measured as well as neuropathological change. APOE ϵ3,3 conferred greatest neuronal resilience denoted as greatest production of the acute phase proteins and low neuronal stress as assessed by DNA/RNA damage and caspase-3 expression. Among patients having an APOE ϵ2 allele, none had Aβ plaques; their neuronal sizes, like those with APOE ϵ3,3 genotype were larger than those with other genotypes. APOE ϵ4,4 conferred the weakest neuronal resilience in epilepsy as well as in Alzheimer patients, but there were no APOE genotype-dependent differences in these parameters in neurologically normal patients.
Our findings provide evidence that the strength of the neuronal stress response is more related to patient APOE genotype than to either the etiology of the stress or to the age of the patient, suggesting that APOE genotyping may be a useful tool in treatment decisions.
PMCID: PMC3893449  PMID: 24252240
Alzheimer’s disease; Apolipoprotein E (ApoE); APOE genotype; Caspase 3; Epilepsy; Neuroinflammation
To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT).
Methods and Materials
Pediatric 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.
Thirty-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 progression before 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.
Delayed 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.
PMCID: PMC3530399  PMID: 21601374
Atypical teratoid rhabdoid tumor; Local failure; Radiation therapy; Therapeutic sequencing; Pattern of failure
12.  Dysembryoplastic Neuroepithelial Tumors and Cognitive Outcome: cure at a price? 
Cancer  2010;116(23):5461-5469.
Dysembryoplastic neuroepithelial tumors (DNETs) are benign glioneuronal tumors that occur in children. These tumors are characterized by seizures, lack of neurologic deficits, and a seemingly benign course after resection.
We conducted a retrospective review of data relating to 11 children diagnosed with DNET between January 1988 and December 2007 at St. Jude Children's Research Hospital. This report documents the clinical features, neurocognitive function, and treatment outcomes in our institutional series.
Our patient cohort included 8 boys and 3 girls (median age at diagnosis, 10 years); all patients presented with seizures: 4 complex partial, 3 generalized tonic clonic, 2 absence, 1 partial simple, and 1 not classified. Of the 11 patients, 1 died of cardiac fibrosis, and tumors recurred or progressed in 4 (36%). Seizure control was achieved in all patients but 1. Of the 9 patients who completed neuropsychologic testing, only 3 (23%) functioned at or above the expected level of same-age peers.
The high recurrence and progression rates of DNETs and the high rate of abnormal neurocognitive test results in this study highlight the need for regular follow-up and appropriate academic counseling of children with these tumors.
PMCID: PMC3556450  PMID: 20672357
Dysembryoplastic neuroepithelial tumors (DNETs); pediatric; recurrence; neuropsychologic outcome
13.  Surgical management of tumors producing the thalamopeduncular syndrome of childhood 
Thalamopeduncular tumors arise at the junction of the inferior thalamus and cerebral peduncle and present with a common clinical syndrome of progressive spastic hemiparesis. Pathologically, these lesions are usually juvenile pilocytic astrocytomas and are best treated with resection with the intent to cure. The goals of this study are to define a common clinical syndrome produced by thalamopeduncular tumors and to discuss imaging characteristics as well as surgical adjuncts, intraoperative nuances, and postoperative complications relating to the resection of these neoplasms.
The authors present a retrospective review of their experience with 10 children presenting between 3 and 15 years of age with a thalamopeduncular syndrome. Formal preoperative MR imaging was obtained in all patients, and diffusion tensor (DT) imaging was performed in 9 patients. Postoperative MR imaging was obtained to evaluate the extent of tumor resection. A prospective analysis of clinical outcomes was then conducted by the senior author.
Pilocytic astrocytoma was the pathological diagnosis in 9 cases, and the other was fibrillary astrocytoma. Seven of 9 pilocytic astrocytomas were completely resected. Radical surgery was avoided in 1 child after DT imaging revealed that the corticospinal tract (CST) coursed through the center of the tumor, consistent with the infiltrative nature of fibrillary astrocytoma as identified by stereotactic biopsy. In 8 patients, tractography served as an important adjunct for designing a surgical approach that spared the CST. In 6 cases the CSTs were pushed anterolaterally, making a transsylvian approach a poor choice, as was evidenced by the first patient in the series, who underwent operation prior to the advent of tractography, and who awoke with a dense contralateral hemiparesis. Thus, subsequent patients with this deviation pattern underwent a transcortical approach via the middle temporal gyrus. One patient exhibited medial deviation of the tracts and another had lateral deviation, facilitating a transtemporal and a transfrontal approach, respectively.
The thalamopeduncular syndrome of progressive spastic hemiparesis presenting in children with or without symptoms of headache should alert the examiner to the possibility of a tumoral involvement of CSTs. Preoperative tractography is a useful adjunct to surgical planning in tumors that displace motor pathways. Gross-total resection of pilocytic astrocytomas usually results in cure, and therefore should be entertained when developing a treatment strategy for thalamopeduncular tumors of childhood.
PMCID: PMC3531960  PMID: 21631193
thalamopeduncular astrocytoma; juvenile pilocytic astrocytoma; diffusion tensor imaging; tractography; pediatric neurosurgery; congenital
14.  Characterization, treatment, and outcome of intracranial neoplasms in the first 120 days of life 
Journal of child neurology  2011;26(8):988-994.
Little is known about brain tumors in early infancy. We reviewed the records of 27 patients (12 boys and 15 girls) diagnosed within 120 days of birth. The median age was 66 days (range, 0–110 days) at diagnosis. All patients underwent surgery; 18 received adjuvant chemotherapy, and 3 received adjuvant chemotherapy and radiation therapy. The median follow-up was 2.1 years (range, 0.2–21.6 years). At last encounter, 15 patients were alive, and 11 had no evidence of disease. Ten patients died of progressive disease, and 2 died of treatment-related complications. All survivors experienced late effects, including endocrine, neurologic, and cognitive deficits. Of the 13 patients who completed neurocognitive assessments, 7 had an IQ score less than 70. Children in whom brain tumors arise during early infancy can be cured with conventional therapy; however, contemporary approaches can adversely affect long-term function, and families need to be aware when making therapeutic decisions.
PMCID: PMC3174527  PMID: 21532007
neonatal; congenital; early infancy; brain tumors
15.  Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience 
BMC Medicine  2012;10:35.
Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype.
Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.
Tissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17).
Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).
Please see related article:
PMCID: PMC3352297  PMID: 22502727
Amyloid beta (Aβ); Alzheimer disease; APOE genotype; DNA damage; epilepsy; interleukin-1; neuroinflammation; phosphorylated tau; synaptophysin; TUNEL
16.  Subtypes of medulloblastoma have distinct developmental origins 
Nature  2010;468(7327):1095-1099.
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor1–4. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype)3–8. 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)1,3,4, 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 tumors infiltrate the dorsal brainstem, while SHH-subtype tumors 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 that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence 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.
PMCID: PMC3059767  PMID: 21150899
17.  Proximal dentatothalamocortical tract involvement in posterior fossa syndrome 
Brain  2009;132(11):3087-3095.
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.
PMCID: PMC2781745  PMID: 19805491
posterior fossa; cerebellum; mutism; medulloblastoma
18.  Evolution of Neurological Impairment in Pediatric Infratentorial Ependymoma Patients 
Journal of neuro-oncology  2009;94(3):391-398.
Infratentorial ependymoma is a common central nervous system tumor of childhood and in patients > 1 year 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.
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.
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 60 month survival.
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.
PMCID: PMC2731005  PMID: 19330288
ependymoma; children; conformal radiation; neurological impairment
19.  Phase II Trial of Conformal Radiation Therapy for Pediatric Low-Grade Glioma 
Journal of Clinical Oncology  2009;27(22):3598-3604.
The use of radiotherapy in pediatric low-grade glioma (LGG) is controversial, especially for young patients. We conducted a phase II trial of conformal radiation therapy (CRT) to estimate disease control by using a 10-mm clinical target volume (CTV) margin.
Materials and Methods
Between August 1997 and August 2006, 78 pediatric patients with LGG and a median age of 8.9 years (range, 2.2 to 19.8 years) received 54 Gy CRT by using a 10-mm CTV and by targeting with systematic magnetic resonance imaging (MRI) registration. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Sixty-seven patients had documented or presumed WHO grade 1 tumors, 25 patients had prior chemotherapy, and 13 patients had neurofibromatosis type 1.
During a median follow-up of 89 months, 13 patients experienced disease progression. One patient experienced marginal treatment failure, eight experienced local failures, and four experienced metastatic failure. The mean and standard error 5- and 10-year event-free (87.4% ± 4.4% and 74.3% ± 15.4%, respectively) and overall (98.5% ± 1.6% and 95.9% ± 5.8%, respectively) survival rates were determined. The mean and standard error cumulative incidences of local failure at 5 and 10 years were 8.7% ± 3.5% and 16.4% ± 5.4%, respectively. The mean and standard error cumulative incidence of vasculopathy was 4.79% ± 2.73% at 6 years, and it was higher for those younger than 5 years of age (P = .0105) at the time of CRT.
This large, prospective series of irradiated children with LGG demonstrates that CRT with a 10-mm CTV does not compromise disease control. The results suggest that CRT should be delayed in young patients to reduce the risk of vasculopathy.
PMCID: PMC3525947  PMID: 19581536
20.  A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET 
Neuro-Oncology  2009;11(1):33-40.
We undertook this study to estimate the event-free survival (EFS) of patients with newly diagnosed supratentorial primitive neuroectodermal tumor (SPNET) treated with risk-adapted craniospinal irradiation (CSI) with additional radiation to the primary tumor site and subsequent high-dose chemotherapy supported by stem cell rescue. Between 1996 and 2003, 16 patients with SPNET were enrolled. High-risk (HR) disease was differentiated from average-risk (AR) disease by the presence of residual tumor (M0 and tumor size > 1.5 cm2) or disseminated disease in the neuraxis (M1–M3). Patients received risk-adapted CSI: those with AR disease received 23.4 Gy; those with HR disease, 36–39.6 Gy. The tumor bed received a total of 55.8 Gy. Subsequently, all patients received four cycles of high-dose cyclophosphamide, cisplatin, and vincristine with stem cell support. The median age at diagnosis was 7.9 years; eight patients were female. Seven patients had pineal PNET. Twelve patients are alive at a median follow-up of 5.4 years. The 5-year EFS and overall survival (OS) estimates for all patients were 68% ± 14% and 73% ± 13%. The 5-year EFS and OS estimates were 75% ± 17% and 88% ± 13%, respectively, for the eight patients with AR disease and 60% ± 19% and 58% ± 19%, respectively, for the eight with HR disease. No deaths were due to toxicity. High-dose cyclophosphamide-based chemotherapy with stem cell support after risk-adapted CSI results in excellent EFS estimates for patients with newly diagnosed AR SPNET. Further, this chemotherapy allows for a reduction in the dose of CSI used to treat AR SPNET without compromising EFS.
PMCID: PMC2718957  PMID: 18796696
autologous stem cell rescue; craniospinal radiotherapy; dose-intensive chemotherapy; event-free survival; risk-adapted therapy; supratentorial PNET
21.  M1 Medulloblastoma: High Risk at any Age 
Journal of neuro-oncology  2008;90(3):351-355.
The prognosis for children with M1 medulloblastoma (positive CSF cytology) has not been well-defined.
We retrospectively reviewed the records of 285 newly diagnosed medulloblastoma patients treated between 1984 and 2006. Older children received post-operative craniospinal and tumor bed irradiation; radiotherapy for younger children depended on treatment era and physician/family preference.
55 patients were <3 years old and 230 patients were = 3 years old at diagnosis. We detected significant (p<0.0001) associations between M1 disease and EFS for the entire cohort and for both younger and older patients. Among younger children, M1 patients had lower EFS than M0 (p=0.0044).
Children <3 years old with M1 medulloblastoma fared poorly in our small series. Survival for older children with M1 disease treated with higher-dose CSI was better than that of M2/M3 patients, but still less than optimal; our findings do not support reduction in therapy for either cohort.
PMCID: PMC2597631  PMID: 18704266
medulloblastoma; cytology; infant; survival; metastatic; prognosis

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