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1.  Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy 
Neuro-Oncology  2014;17(3):448-456.
Background
Multimodal therapy has improved survival for some childhood CNS tumors. However, whether risk for subsequent neoplasms (SNs) also increases is unknown. We report the cumulative incidence of, and risk factors for, SNs after a childhood primary CNS tumor and determine whether treatment that combines radiation therapy (RT) with chemotherapy increases risk for SNs.
Methods
Analyses included 2779 patients with a primary CNS tumor treated at St Jude Children's Research Hospital between 1985 and 2012. Cumulative incidence and standardized incidence ratios (SIRs) were estimated for SNs confirmed by pathology report. Cumulative incidence among the 237 five-year medulloblastoma survivors treated with multimodal therapy (RT + chemotherapy) was compared with a historical cohort of 139 five-year survivors treated with RT but no chemotherapy in the Childhood Cancer Survivor Study.
Results
Eighty-one survivors had 97 SNs. The cumulative incidence of first SN was 3.0% (95% CI: 2.3%–3.9%) at 10 years, and 6.0% (95% CI: 4.6%–7.7%) at 20 years from diagnosis. Risks were highest for subsequent glioma, all grades (SIR = 57.2; 95% CI: 36.2–85.8) and acute myeloid leukemia (SIR = 31.8; 95% CI: 10.2–74.1). Compared with RT alone, RT + chemotherapy did not increase risk for SNs (hazard ratio: 0.64; 95% CI: 0.38–1.06). Among five-year survivors of medulloblastoma treated with multimodal therapy, cumulative incidence of SN was 12.0% (95% CI: 6.4%–19.5%) at 20 years, no different than survivors treated with RT alone (11.3%, P = .44).
Conclusion
The cumulative incidence of SNs continues to increase with time from treatment with no obvious plateau, but the risk does not appear to be higher after exposure to multimodal therapy compared with RT alone. Continued follow-up of survivors as they age is essential.
doi:10.1093/neuonc/nou279
PMCID: PMC4483102  PMID: 25395462
chemotherapy; childhood CNS tumor survivors; medulloblastoma; radiation; subsequent neoplasms
2.  Successive Distinct High-Grade Gliomas in L-2-hydroxyglutaric Aciduria 
SUMMARY
Patients with L-2-hydroxyglutaric aciduria are at risk for developing cerebral neoplasms, particularly gliomas, as one of the optical isomers of the known oncometabolite, 2-hydroxyglutarate is produced in L-2-hydroxyglutaric aciduria. To illustrate the concept of sustained oncogenic potential in permanent exposure to L-2-hydroxyglutarate in brain tissue, we present the medical history of a patient with L-2-hydroxyglutaric aciduria who underwent surgery to remove a right temporal anaplastic astrocytoma and developed an anatomically distinct, but histopathologically similar, tumor in the left frontal region 40 months later. This is the first reported case of successive distinct gliomas in a patient with L-2-hydroxyglutaric aciduria. While this implies a significant, cumulative lifetime risk for cerebral neoplasms in patients with this rare organic aciduria, it also allows further insight into a unique mechanism of tumorigenesis in the brain.
doi:10.1007/s10545-014-9782-8
PMCID: PMC4657728  PMID: 25338511
L-2-hydroxyglutaric aciduria; cerebral neoplasm; magnetic resonance imaging; positron emission tomography; IDH1 mutation
3.  Localized TRPA1 channel Ca2+ signals stimulated by reactive oxygen species promote cerebral artery dilation 
Science signaling  2015;8(358):ra2.
Reactive oxygen species (ROS) can have divergent effects in cerebral and peripheral circulations. We found that Ca2+-permeable transient receptor potential ankyrin 1 (TRPA1) channels were present and colocalized with NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 2 (NOX2), a major source of ROS, in the endothelium of cerebral arteries but not in other vascular beds. We recorded and characterized ROS-triggered Ca2+ signals representing Ca2+ influx through single TRPA1 channels, which we called “TRPA1 sparklets.” TRPA1 sparklet activity was low under basal conditions but was stimulated by NOX-generated ROS. Ca2+ entry during a single TRPA1 sparklet was twice that of a TRPV4 sparklet and ~200 times that of an L-type Ca2+ channel sparklet. TRPA1 sparklets representing the simultaneous opening of two TRPA1 channels were more common in endothelial cells than in human embryonic kidney (HEK) 293 cells expressing TRPA1. The NOX-induced TRPA1 sparklets activated intermediate-conductance, Ca2+-sensitive K+ channels, resulting in smooth muscle hyperpolarization and vasodilation. NOX-induced activation of TRPA1 sparklets and vasodilation required generation of hydrogen peroxide and lipid-peroxidizing hydroxyl radicals as intermediates. 4-Hydroxy-nonenal, a metabolite of lipid peroxidation, also increased TRPA1 sparklet frequency and dilated cerebral arteries. These data suggest that in the cerebral circulation, lipid peroxidation metabolites generated by ROS activate Ca2+ influx through TRPA1 channels in the endothelium of cerebral arteries to cause dilation.
doi:10.1126/scisignal.2005659
PMCID: PMC4745898  PMID: 25564678
4.  Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections 
Purpose
High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors.
Methods
Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations ([MTX]) were collected. Delayed plasma excretion was defined as [MTX] ≥1μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until [MTX] <0.1μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling.
Results
Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m2 (41.1 CV%) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (p<0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity.
Conclusions
Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than one year may need additional monitoring to avoid toxicity.
doi:10.1007/s00280-014-2614-6
PMCID: PMC4282603  PMID: 25342291
Methotrexate; Pharmacokinetics; Pseudocyst; Toxicity; Cerebrospinal Fluid
5.  Spatial Distortion Due to Field Inhomogeneity in 3.0 Tesla Intraoperative MRI 
The Neuroradiology Journal  null;27(4):387-392.
Summary
We describe a 14-year-old boy with a pilocytic astrocytoma of the left caudate head. Preoperative localization MR imaging (MRI) was performed in the operating room, and spatial distortion was noted felt to be related to head positioning relative to the isocenter of the magnetic field. The distortion artifact was subtle enough to be difficult to detect, but large enough to change the location of the lesion potentially leading to a non-diagnostic stereotactic biopsy. Repeat imaging after changing the head position to allow scanning closer to the isocenter of the magnetic field showed decreased distortion, an improvement greater than that using the manufacturer's distortion correction algorithm on the initial images. Intraoperative MRI, and its requisite limitations in positioning, requires vigilance to detect possible distortion that could alter surgical outcomes if not identified and corrected prospectively.
doi:10.15274/NRJ-2014-10081
PMCID: PMC4236867  PMID: 25196608
magnetic resonance imaging; intraoperative MRI; brain tumor; artifact
6.  Highly cited publications in pediatric neurosurgery: part 2 
Purpose
Citation counting can be used to evaluate the impact an article has made on its discipline. This study characterizes the most cited articles related to clinical pediatric neurosurgery as of July 2013.
Methods
A list of search terms was computed using Thomson Reuters Web of Science® (WOS) to capture the 100 most cited articles in the overall literature and the top 50 articles from 2002 to 2012 related to clinical pediatric neurosurgery from non-dedicated pediatric neurosurgical journals. The following information was recorded for each article: number of authors, country of origin, citation count adjusted for number of years in print, topic, and level of evidence.
Results
The 100 most cited articles appeared in 44 journals. Publication dates ranged from 1986 to 2008; two were class 1 evidence, nine class 2, 26 class 3, and 52 class 4. Citations ranged from 90 to 321 (mean=131); average time-adjusted citation count was 10. The 50 most cited articles from 2002 to 2012 appeared in 31 journals; four were class 2 evidence, 15 class 3, and 21 class 4. Citations ranged from 68 to 245 (mean=103); average time-adjusted citation count was 13.
Conclusion
Overall, papers from non-pediatric neurosurgical journals had higher citation counts and improved level of evidence grades compared to articles from pediatric neurosurgical periodicals. An original paper related to clinical pediatric neurosurgery in a non-pediatric neurosurgical journal having a total citation count of 100–150 or more and an average citation count of 10–15 per year or more can be considered a high-impact publication.
doi:10.1007/s00381-013-2293-3
PMCID: PMC4530008  PMID: 24113776
Citation; Analysis; Articles; Pediatric; Neurosurgery
7.  Highly cited publications in pediatric neurosurgery 
Object
The number of citations a publication receives can be used as a surrogate for the impact that article has made on its discipline. This study identifies and characterizes the most cited articles in pediatric neurosurgical journals as of April 2013.
Methods
We examined four clinical pediatric neurosurgery journals. The 100 most cited articles in the overall literature and the top 50 articles from 2002 to 2012 were examined. The following information was recorded for each article: number of authors, country of origin, citation-count adjusted for number of years in print, topic, and level of evidence.
Results
The 100 most cited articles appeared in three of the four journals: Child's Brain, Pediatric Neurosurgery and Child's Nervous System. Publication dates ranged from 1975 to 2006; 21 were prospective studies, 64 were retrospective, and 81 were either class 4 evidence (case series, n=70) or review articles (n=11). Citations ranged from 65 to 193 (mean of 90); average adjusted citation count per year was 4.5. The 50 most cited articles from 2002 to 2012 appeared in Child's Nervous System, Pediatric Neurosurgery, and JNS: Pediatrics. Four were prospective studies, 25 were retrospective, and 38 of the total (76 %) were either class 4 evidence (n=24) or review articles (n=14). Citations ranged from 41 to 125 (mean of 54); average adjusted citation count per year was 6.3.
Conclusion
An original paper in pediatric neurosurgery having a total citation count of 50 or more, and an average citation count of 5 per year or more can be considered a high impact publication.
doi:10.1007/s00381-013-2228-z
PMCID: PMC4530009  PMID: 23900628
Citation; Analysis; Articles; Pediatric; Neurosurgery
8.  Diffusion tensor imaging to guide surgical planning in intramedullary spinal cord tumors in children 
Neuroradiology  2014;56(2):169-174.
BACKGROUND AND PURPOSE
Intramedullary spinal cord neoplasms (ISCN) in children provide diagnostic, treatment and management dilemmas. Resection results in the best chance for disease control, but the greatest risk of neurologic deficit. We hypothesize that diffusion tensor imaging (DTI) and diffusion tensor-fiber tracking (DT-FT) can help characterize margins of pediatric ISCN to aid in surgical planning.
METHODS
This HIPAA compliant retrospective study was performed after Institutional Review Board approval. Patients with ISCN from a single tertiary care pediatric institution were identified, and patients with preoperative DTI were evaluated.
RESULTS
Ten patients (8 males, 2 females) with ISCN with preoperative DTI were identified. The mean age was 11.1 ± 6.2 years (range 2 – 18 years). Eight tumors demonstrated DTI and DT-FT evidence of splayed cord tracts, and two demonstrated evidence of infiltration of cord tracts. The eight patients with splayed tracts underwent resection, with seven achieving gross-total resection and one subtotal resection. The two patients with infiltration of white matter tracts underwent biopsy of their lesion.
DISCUSSION
DTI of pediatric ISCN can aid in defining the margins of the tumor and relationship to the intrinsic white matter structures of the spinal cord. Splaying and displacement of fiber tracts appears to predict a discrete margin to the tumor and resectability, while infiltration of the white matter tracts suggests biopsy may be more advisable.
doi:10.1007/s00234-013-1316-9
PMCID: PMC4504212  PMID: 24395215
9.  C11ORF95-RELA FUSIONS DRIVE ONCOGENIC NF-KB SIGNALING IN EPENDYMOMA 
Neuro-Oncology  2014;16(Suppl 3):iii16.
BACKGROUND: The nuclear factor-kB (NF-kB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kB activity in cancer. METHODS: To identify additional genetic alterations that drive ependymoma, we sequenced the whole genomes (WGS) of 41 tumours and matched normal blood, and the transcriptomes (RNAseq) of 77 tumours. The transforming significance of alterations were tested in mouse NSCs that we showed previously to be cells of origin of ependymoma. RESULTS: Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kB 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-kB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. CONCLUSIONS: 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. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.
doi:10.1093/neuonc/nou206.57
PMCID: PMC4144525
10.  Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma 
Nature genetics  2009;41(4):465-472.
We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.
doi:10.1038/ng.336
PMCID: PMC4454371  PMID: 19270706
11.  Mesenchymal Chondrosarcoma in Children and Young Adults: A Single Institution Retrospective Review 
Sarcoma  2015;2015:608279.
Background. Mesenchymal chondrosarcoma is an aggressive, uncommon histologic entity arising in bone and soft tissues. We reviewed our institutional experience with this rare diagnosis. Methods. We conducted a retrospective chart review on patients with mesenchymal chondrosarcoma over a 24-year period. Clinicopathologic and radiographic features were reviewed. Results. Twelve patients were identified. Nine were females; median age was 14.5 years (1.2–19.7 years). The most common site was the head/neck (7/12). Disease was localized in 11/12 patients (one with lung nodules). Six with available tissue demonstrated NCOA2 rearrangement by FISH. Six underwent upfront surgical resection, and six received neoadjuvant therapy (2 chemotherapy alone and 4 chemotherapy and radiation). All patients received adjuvant chemotherapy (most commonly ifosfamide/doxorubicin) and/or radiation (median dose 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival and overall survival were 68.2% (95% CI 39.8%, 96.6%) and 88.9% (95% CI 66.9%, 100%). Two patients had distant recurrences at 15 and 42 months, respectively. Conclusion. Aggressive surgical resection of mesenchymal chondrosarcoma with chemoradiotherapy yields excellent local control and may reduce likelihood of late recurrence. Characterization of downstream targets of the HEY1-NCOA2 fusion protein, xenograft models, and drug screening are needed to identify novel therapeutic strategies.
doi:10.1155/2015/608279
PMCID: PMC4469840  PMID: 26146478
12.  Emotional and Behavioral Functioning After Conformal Radiation Therapy for Pediatric Ependymoma 
Purpose/Objectives
The standard of care for pediatric patients with ependymoma involves post-operative 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 CRT’s effect on emotional and behavioral functioning.
Methods and Materials
A 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 five years after CRT. Emotional and behavioral functioning was assessed via the Child Behavior Checklist.
Results
Prior to CRT, emotional and behavioral functioning was commensurate with that 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.
Conclusions
The use of photon CRT for ependymoma is associated with relatively stable emotional and behavioral functioning during the first five years after treatment. The exception is an increase in attention problems. Results suggest that intervening earlier in the survivorship period – during the first year post-treatment – may be beneficial.
doi:10.1016/j.ijrobp.2013.12.006
PMCID: PMC4261227  PMID: 24462384
ependymoma; conformal radiation therapy; emotional and behavioral functioning; pediatric brain tumors
13.  Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience 
Object
Whereas diffuse intrinsic pontine gliomas generally have a short symptom duration and more cranial nerve involvement, focal brainstem gliomas are commonly low grade, with fewer cranial neuropathies. Although these phenotypic distinctions are not absolute predictors of outcome, they do demonstrate correlation in most cases. Because there is a limited literature on focal brainstem gliomas in pediatric patients, the objective of this paper was to report the management and outcome of these tumors.
Methods
The authors reviewed the records of all children diagnosed with radiographically confirmed low-grade focal brainstem gliomas from 1986 to 2010. Each patient underwent biopsy or resection for tissue diagnosis. Eventfree survival (EFS) and overall survival were evaluated. Univariate analysis was conducted to identify demographic and treatment variables that may affect EFS.
Results
Fifty-two patients (20 girls, 32 boys) with follow-up data were identified. Median follow-up was 10.0 years, and the median age at diagnosis was 6.5 years (range 1–17 years). The tumor locations were midbrain (n = 22, 42%), pons (n = 15, 29%), and medulla (n = 15, 29%). Surgical extirpation was the primary treatment in 25 patients (48%). The 5- and 10-year EFS and overall survival were 59%/98% and 52%/90%, respectively. An event or treatment failure occurred in 24 patients (46%), including 5 deaths. Median time to treatment failure was 3.4 years. Disease progression in the other 19 patients transpired within 25.1 months of diagnosis. Thirteen of these patients received radiation, including 11 within 2 months of primary treatment failure. Although children with intrinsic tumors had slightly better EFS at 5 years compared with those with exophytic tumors (p = 0.054), this difference was not significant at 10 years (p = 0.147). No other variables were predictive of EFS.
Conclusions
Surgery suffices in many children with low-grade focal brainstem gliomas. Radiation treatment is often reserved for disease progression but offers comparable disease control following biopsy. In the authors’ experience, combining an assessment of clinical course, imaging, and tumor biopsy yields a reasonable model for managing children with focal brainstem tumors.
doi:10.3171/2012.11.PEDS12317
PMCID: PMC4349190  PMID: 23289916
focal brainstem glioma; low grade; radiation treatment; outcomes; oncology; event-free survival
14.  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.
doi:10.1177/0883073812464817
PMCID: PMC4264380  PMID: 23143722
brain tumor; craniopharyngioma; headache; migraine; hydrocephalus
15.  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.
doi:10.1097/WNR.0000000000000276
PMCID: PMC4232293  PMID: 25371284
Broca’s area; cortical stimulation mapping; high gamma activity; presurgical language mapping; speech production area
16.  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.
doi:10.1038/ng.2938
PMCID: PMC4056452  PMID: 24705251
17.  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.
Summary
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
18.  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.
doi:10.1038/nature13109
PMCID: PMC4050669  PMID: 24553141
19.  DISEASE CONTROL AFTER REDUCED VOLUME CONFORMAL AND INTENSITY-MODULATED RADIATION THERAPY FOR CHILDHOOD CRANIOPHARYNGIOMA 
PURPOSE
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.
METHODS AND MATERIALS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1016/j.ijrobp.2012.10.030
PMCID: PMC3594571  PMID: 23245282
Radiotherapy; Pediatrics; Brain Tumor; Craniopharyngioma; Adaptive Therapy
20.  Supratentorial Ependymoma: Disease Control, Complications and Functional Outcomes after Irradiation 
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1016/j.ijrobp.2012.10.033
PMCID: PMC3705553  PMID: 23245280
21.  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.
doi:10.3389/fnhum.2014.00657
PMCID: PMC4140211  PMID: 25191260
magnetoencephalography; non-invasive; language mapping; sedation; epilepsy; children
22.  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
23.  Epilepsy: neuroinflammation, neurodegeneration, and APOE genotype 
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/2051-5960-1-41
PMCID: PMC3893449  PMID: 24252240
Alzheimer’s disease; Apolipoprotein E (ApoE); APOE genotype; Caspase 3; Epilepsy; Neuroinflammation
24.  SEQUENCING OF LOCAL THERAPY AFFECTS THE PATTERN OF TREATMENT FAILURE AND SURVIVAL IN CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMORS OF THE CENTRAL NERVOUS SYSTEM 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ijrobp.2011.02.059
PMCID: PMC3530399  PMID: 21601374
Atypical teratoid rhabdoid tumor; Local failure; Radiation therapy; Therapeutic sequencing; Pattern of failure
25.  Dysembryoplastic Neuroepithelial Tumors and Cognitive Outcome: cure at a price? 
Cancer  2010;116(23):5461-5469.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/cncr.25528
PMCID: PMC3556450  PMID: 20672357
Dysembryoplastic neuroepithelial tumors (DNETs); pediatric; recurrence; neuropsychologic outcome

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