James T Rutka

University of Toronto, Toronto, Ontario, Canada

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Publications (509)2037.24 Total impact

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    ABSTRACT: Epilepsy surgery can be successful in children with extensive congenital or early acquired focal or hemispheric brain lesion on magnetic resonance imaging (MRI) despite generalized interictal epileptiform discharges (IEDs). The aim of this study was to assess if rapid eye movement (REM) sleep reduced generalized IEDs and revealed lateralized IEDs to identify the epileptogenic hemisphere in children with generalized IEDs and normal/subtle changes on MRI. We studied 20 children with generalized IEDs on scalp electroencephalography (EEG) and normal/subtle changes on MRI who underwent intracranial video-EEG for epilepsy surgery. We assessed a minimum of 100 IEDs during REM, non-REM, and wakefulness, and assigned the distribution (generalized, left, or right hemisphere) to each IED. The number of lobes in the resected areas and seizure outcome were compared between 20 children with generalized IEDs and a comparison group of 28 children without generalized IEDs. The mean occurrence rate of generalized IEDs during REM (37%) was significantly lower than that during non-REM (67%, p < 0.001) and wakefulness (54%, p = 0.003). The number of children whose largest number of IEDs was lateralized in REM was significantly higher than that in non-REM (15 vs. 3 children, 75% vs. 15%, p < 0.001). The hemisphere with lateralized IEDs among three states corresponded with the surgical side in 16 children with generalized IEDs. Seventeen children (85%) with generalized IEDs and 27 (96%) without generalized IEDs underwent resective surgery. Multilobar resection was required for 16 children (94%) with generalized IEDs more frequently than 7 children (26%) without generalized IEDs (p < 0.001). Thirteen children (77%) with generalized IEDs and 19 (73%) without generalized IEDs were seizure-free with a mean of 3.3 years of follow-up. Our study demonstrates the importance of assessing REM in children with generalized IEDs as it reveals lateralized epileptogenic spikes. Seizure freedom may be achieved with multilobar resection in these children with generalized IEDs and normal/subtle changes on MRI. Generalized IEDs in children with normal/subtle changes on MRI should not preclude surgical resection. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
    Epilepsia 07/2015; DOI:10.1111/epi.13081 · 4.58 Impact Factor
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    ABSTRACT: There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC). We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery. A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery. Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 ± 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1- and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom. In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber. EEG, electroencephalographyEZ, epileptic zoneIPD, individual participant dataTSC, tuberous sclerosis complex.
    Neurosurgery 06/2015; DOI:10.1227/NEU.0000000000000875 · 3.03 Impact Factor
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    ABSTRACT: We report on our experience in performing peri-insular functional hemispherectomy (PIH) in very young infants with catastrophic epilepsy. We retrospectively reviewed the medical charts of all infants with catastrophic epilepsy that underwent PIH under the age of 4 months at our institution. Four infants (three female, one male) were included (median age at time of surgery 2.9 months, range from 2.4 to 4.2 months; median patient's weight at time of surgery 5650 g, range from 4300 to 7500 g). None of the patients experienced hemodynamic instability during surgery. All four patients were given red blood cell replacement (median 435 ml, range from 230 to 800 ml), three of the four patients experienced coagulopathy during surgery and were given platelet cells transfusion in one (50 ml) and fresh frozen plasma in two patients (191 and 320 ml). Two patients experienced severe complications that, however, did not cause a permanent morbidity due to prompt diagnosis and correct management. After a median follow-up time of 4.3 years (range from 1.3 to 7.9 years), three of four patients are completely seizure free. The remaining patient is experiencing brief daily staring episodes. All of them have a hemiparesis but are fully ambulatory and have a useful upper limb function. In catastrophic epilepsy, PIH within the first months of life is feasible provided that an experienced multidisciplinary team is involved. Awareness of surgical challenges and potential complications is indispensible when the life-threatening nature of the epilepsy compels neurosurgeons to operate at this very young age.
    Child s Nervous System 06/2015; DOI:10.1007/s00381-015-2794-3 · 1.16 Impact Factor
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    ABSTRACT: Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.
    Oncotarget 05/2015; · 6.63 Impact Factor
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    ABSTRACT: Infants with Sturge-Weber syndrome (SWS) are considered for surgery if they develop seizures and the seizures prove medically refractory. The authors report on 2 infants (15 and 19 months old) with SWS who underwent scalp video electroencephalography (EEG) and subsequent functional hemispherotomy for intractable partial motor seizures due to extensive left hemispheric angiomatosis. They presented with similar interictal and ictal EEG findings. Ictal EEG showed abrupt high-amplitude delta slow waves, without evolution on the contralateral hemisphere before the build-up of ictal EEG changes on the lesional hemisphere. The patients became seizure free after hemispherotomy. The ictal contralateral slow waves were not a sign of an ictal hemisphere and may indicate prominent ischemic changes resulting from a steal phenomenon of hemispheric angiomatosis during seizure.
    Journal of Neurosurgery Pediatrics 05/2015; DOI:10.3171/2014.12.PEDS14238 · 1.37 Impact Factor
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    ABSTRACT: Myxopapillary ependymoma (MPE) is a distinct histological variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumour lysates consisting of assays measuring Pyruvate Kinase M activity (PKM), Hexokinase activity (HK), and lactate production. At a gene expression level, we demonstrate that spinal Grade II and MPE are molecularly and biologically distinct. These findings are supported by specific copy number alterations occurring in each histological variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with up-regulation of HIF-1α. These findings were validated by western blot analysis demonstrating increased protein expression of HIF-1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; DOI:10.1158/1078-0432.CCR-14-2650 · 8.19 Impact Factor
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    ABSTRACT: OBJECT Choroid plexus carcinomas (CPCs) are rare brain tumors originating from the ventricular choroid plexus. They account for 2%-4% of all pediatric brain tumors and are most frequently seen in very young children. This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss. Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue. At the Hospital for Sick Children in Toronto, this empirical finding led to the strategy of neoadjuvant chemotherapy to minimize blood loss and maximize cytoreduction. The authors undertook this study to assess the potentially beneficial effect of neoadjuvant chemotherapy on blood loss during surgery for CPCs. METHODS In this retrospective cohort review, the demographic, clinical, and treatment parameters of 22 consecutive patients diagnosed with CPC are presented. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit. RESULTS Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2-5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy. CONCLUSIONS In children with CPC, the administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival.
    Journal of Neurosurgery Pediatrics 05/2015; DOI:10.3171/2014.12.PEDS14372 · 1.37 Impact Factor
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    ABSTRACT: Glioblastomas are progressive brain tumors with devastating proliferative and invasive characteristics. Ion channels are the second largest target class for drug development. In this study, we investigated the effects of the TRPM7 inhibitor carvacrol on the viability, resistance to apoptosis, migration, and invasiveness of the human U87 glioblastoma cell line.The expression levels of TRPM7 mRNA and protein in U87 cells were detected by RT-PCR, western blotting and immunofluorescence. TRPM7 currents were recorded using whole-cell patch-clamp techniques. An MTT assay was used to assess cell viability and proliferation. Wound healing and transwell experiments were used to evaluate cell migration and invasion. Protein levels of p-Akt/t-Akt, p-ERK1/2/t-ERK1/2, cleaved caspase-3, MMP-2 and phosphorylated cofilin were also detected.TRPM7 mRNA and protein expression in U87 cells is higher than in normal human astrocytes. Whole-cell patch-clamp recording showed that carvacrol blocks recombinant TRPM7 current in HEK293 cells and endogenous TRPM7-like current in U87 cells. Carvacrol treatment reduced the viability, migration and invasion of U87 cells. Carvacrol also decreased MMP-2 protein expression and promoted the phosphorylation of cofilin. Furthermore, carvacrol inhibited the Ras/MEK/MAPK and PI3K/Akt signaling pathways.Therefore, carvacrol may have therapeutic potential for the treatment of glioblastomas through its inhibition of TRPM7 channels.
    Oncotarget 04/2015; · 6.63 Impact Factor
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    ABSTRACT: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 04/2015; DOI:10.1016/S1470-2045(15)70114-2 · 24.73 Impact Factor
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    ABSTRACT: OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell-specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI-guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.
    Journal of Neurosurgery 04/2015; 122(6):1-10. DOI:10.3171/2015.2.JNS132507 · 3.15 Impact Factor
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    Marine Drugs 04/2015; 13(4):2505-2525. DOI:10.3390/md13042505 · 3.51 Impact Factor
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    ABSTRACT: Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.
    Acta Neuropathologica 03/2015; 129(3):449-57. DOI:10.1007/s00401-015-1389-0 · 9.78 Impact Factor
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    ABSTRACT: Medulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYC- overexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma.
    Oncotarget 02/2015; 6(5):3359-74. · 6.63 Impact Factor
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    ABSTRACT: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P <.001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
    Journal of Clinical Oncology 02/2015; DOI:10.1200/JCO.2014.58.3922 · 18.43 Impact Factor
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    ABSTRACT: The general principle of epilepsy surgery is to achieve seizure freedom without causing any neurological deficit that would outweigh the clinical benefit. To achieve this, the epileptogenic zone, which is the part of the brain responsible for seizure generation, as well as the anatomic location of the eloquent cortex must be precisely identified in order to spare those functions during excision of the epileptogenic tissue. Major technical advances over the last decade have continuously contributed to increase our ability to map the brain and identify these critical areas. These technologies and innovations that can be routinely used today include non--invasive studies such as magnetoencephalography (MEG), functional MRI (fMRI), simultaneous EEG-fMRI, and nuclear medicine based methods like PET and SPECT as well as invasive studies through chronically implanted electrodes. Electrodes can be either placed subdurally via burr holes and craniotomies or via frame--based and frameless stereotactic methods within the brain. Apart from a continuous change in these insertion techniques, the most valuable advances here include recordings on high frequency bandwidth (100-600 Hz EEG) that are capable to delineate high--frequency oscillations (HFOs). These HFOs have been recognized as a biomarker for epileptogenic tissue. All of these technical advances have made epilepsy surgery a truly multidisciplinary field and surgeons have to be able to understand and interpret all of the gathered data. Moreover, this development has influenced surgical approaches and techniques and epilepsy surgery today includes a wide variety of procedures. These can be subdivided into resective, disconnective and neuromodulation procedures and vary from a small, targeted lesionectomy to disconnection/resection of one hemisphere. This review will give an overview of the available surgical techniques today and will focus on how the technical advances enable us to map the brain and delineate the critical areas.
    Journal of neurosurgical sciences 02/2015; · 0.78 Impact Factor
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    ABSTRACT: Epilepsy is associated with disruption of integration in distributed networks, together with altered localization for functions such as expressive language. The relation between atypical network connectivity and altered localization is unknown. In the current study we tested whether atypical expressive language laterality was associated with the alteration of large-scale network integration in children with medically-intractable localization-related epilepsy (LRE). Twenty-three right-handed children (age range 8-17) with medically-intractable LRE performed a verb generation task in fMRI. Language network activation was identified and the Laterality index (LI) was calculated within the pars triangularis and pars opercularis. Resting-state data from the same cohort were subjected to independent component analysis. Dual regression was used to identify associations between resting-state integration and LI values. Higher positive values of the LI, indicating typical language localization were associated with stronger functional integration of various networks including the default mode network (DMN). The normally symmetric resting-state networks showed a pattern of lateralized connectivity mirroring that of language function. The association between atypical language localization and network integration implies a widespread disruption of neural network development. These findings may inform the interpretation of localization studies by providing novel insights into reorganization of neural networks in epilepsy. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cortex 01/2015; 65C:83-88. DOI:10.1016/j.cortex.2014.12.016 · 6.04 Impact Factor
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    ABSTRACT: OBJECT While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). METHODS The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. RESULTS Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. CONCLUSIONS The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups.
    Journal of Neurosurgery Pediatrics 12/2014; 15(3):1-7. DOI:10.3171/2014.9.PEDS14280 · 1.37 Impact Factor
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    ABSTRACT: We analyzed the spatial distribution and concordance of fast (>10Hz) and slow (<5Hz) electroencephalogram (EEG) components of ictal activities and interictal epileptiform discharges (IIED) recorded by intracranial video EEG (IVEEG) in children with epileptic spasms (ES). We studied eight children with ES, who underwent IVEEG before resective surgery for epilepsy. We quantified the root-mean-square (RMS) amplitude of the fast and slow components of ictal activities during ES and IIED. We compared the concordance between the spatial distributions of the fast and slow components of ES and IIED. There was a larger concordance between the spatial distributions of the fast and slow components in IIED than in ES (p=0.0206 and 0.0401). The spatial concordance between the fast and slow EEG components was significantly different between ES and IIED. The mechanisms underlying the generation of slow EEG components may differ between ES and IIED. The slow EEG components of ES might indicate an extensive epileptic network involving remote symptomatic zones for ES in either the cortical or subcortical areas. The high spatial concordance between the fast and slow components of IIED suggests the involvement of a local inhibitory process within the epileptic cortex. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 12/2014; DOI:10.1016/j.clinph.2014.12.005 · 2.98 Impact Factor
  • James Rutka
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    ABSTRACT: Abstract The Science-in-Backstage interviews aim to share experiences by global medical and life sciences thought leaders on emergent technologies and novel scientific, medical, and educational practices, situating them in both a historical and contemporary science context so as to "look into the biotechnology and innovation futures" reflexively and intelligently. OMICS systems diagnostics and personalized medicine are greatly impacting brain surgery, not to forget the training of the next generation of neurosurgeons. What do the futures hold for the practice of, and education in 21(st) century brain surgery in the age of OMICS systems science, personalized medicine, and the use of simulation in surgeon training? James Rutka is a clinician scientist and a world leader in diagnosis and treatment of brain tumors. He is Professor and Chair of the Department of Surgery at the Faculty of Medicine, University of Toronto, a President Emeritus of the American Association of Neurological Surgeons, and Editor-in-Chief of the Journal of Neurosurgery. Professor Rutka was interviewed for the global medical, biotechnology, and life sciences readership of the OMICS: A Journal of Integrative Biology to speak on these pressing questions in his personal capacity as an independent senior scholar. The issues debated in the present interview are of broad relevance for 21(st) century surgery and postgenomics medicine. The interviewers were Professor Joseph B. Martin, Harvard Medical School Dean Emeritus in Boston and Joint Dean of Medicine at Bahçeşehir University in İstanbul, and the author of "Alfalfa to Ivy: Memoir of a Harvard Medical School Dean," and Professor Türker Kılıç, Dean of Medicine at Bahçeşehir University in İstanbul, and an elected member of the Turkish Academy of Sciences.
    Omics A Journal of Integrative Biology 11/2014; 18(12). DOI:10.1089/omi.2014.0151 · 2.73 Impact Factor
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    ABSTRACT: Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here we report that the analysis of several large non-overlapping cohorts of medulloblastoma patients reveal MET kinase as a marker of sonic hedgehog (SHH) driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that SHH medulloblastoma patients may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma.
    Cancer Research 11/2014; 75(1). DOI:10.1158/0008-5472.CAN-13-3629 · 9.28 Impact Factor

Publication Stats

12k Citations
2,037.24 Total Impact Points

Institutions

  • 1993–2015
    • University of Toronto
      • • Department of Surgery
      • • Division of Neurosurgery
      • • Hospital for Sick Children
      • • Faculty of Medicine
      Toronto, Ontario, Canada
  • 1990–2015
    • SickKids
      • • Division of Neurosurgery
      • • Department of Paediatric Laboratory Medicine (DPLM)
      Toronto, Ontario, Canada
  • 2013
    • University of Florida Health Science Center-Jacksonville
      Jacksonville, Florida, United States
  • 2011–2012
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • Nationwide Children's Hospital
      Columbus, Ohio, United States
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
    • University of Toyama
      • Department of Neurosurgery
      Тояма, Toyama, Japan
  • 2008
    • Baylor College of Medicine
      • Department of Neurosurgery
      Houston, TX, United States
    • University of Tehran
      Teheran, Tehrān, Iran
  • 2006
    • Translational Genomics Research Institute
      • Division of Neurogenomics
      Phoenix, Arizona, United States
  • 2003
    • University of Manitoba
      Winnipeg, Manitoba, Canada
  • 1995
    • The University of Calgary
      Calgary, Alberta, Canada
    • The Royal Children's Hospital
      Melbourne, Victoria, Australia
  • 1992
    • University Medical Center Utrecht
      • Department of Neurosurgery
      Utrecht, Provincie Utrecht, Netherlands
  • 1987–1990
    • University of California, San Francisco
      • • Department of Neurological Surgery
      • • Division of Hospital Medicine
      San Francisco, CA, United States
  • 1987–1988
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States