James T Rutka

Publications (189)836.88 Total impact

• Article: Network analysis reveals patterns of antiepileptic drug use in children with medically intractable epilepsy.

  George M Ibrahim, James T Rutka, O Carter Snead
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  ABSTRACT: Network analysis is an emerging tool for the study of complex systems. Antiepileptic drug (AED) polytherapy in children with medically intractable epilepsy may be considered a complex system, given the heterogeneity of drug combinations that are frequently modified according to clinical indications. The current article presents a concise review of network theory and its application to the characterization of AED use in children with refractory epilepsy. Current and previous AEDs prescribed to 27 children with refractory, localization-related epilepsy were recorded, and network theory was applied to identify patterns of drug administration. Of the fifteen unique AEDs prescribed, levetiracetam possessed the highest betweenness centrality within the network. Furthermore, first generation AEDs were often discontinued, while lacosamide and topiramate were most likely to be initiated. We also identified three subnetworks of AEDs that were commonly coadministered. We conclude that network analysis is an effective method to characterize the complexity of AED administration patterns in children with epilepsy with many promising future applications.
  Epilepsy & Behavior 05/2013; 28(1):22-25. · 2.34 Impact Factor
• Article: Neurosurgical management of neurenteric cysts in children.

  Ibrahim H Al-Ahmed, Mohamed Boughamoura, Peter Dirks, Abhaya V Kulkarni, James T Rutka, James M Drake
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  ABSTRACT: Object Neurenteric cysts (NCs) are endothelium-lined structures of presumed endodermal origin. There have been few pediatric series of intracranial NCs reported previously. The authors present their experience in the management of these lesions. Methods A retrospective chart review of all cases of NCs identified between 1977 and 2007 was carried out. Demographics, details of clinical presentation, surgical therapy, and outcome data were extracted. Results Eleven cases were identified, involving 6 girls and 5 boys. The patients' average age was 4.6 years (range 1 day-14 years). Limb weakness was the most common presenting symptom. The location of the cysts was cervical in 2 cases, cervicothoracic in 4 cases, and thoracic in 3 cases. One cyst was anterior to the pons with extension to the left cerebellopontine angle and 1 cyst was at the craniocervical junction. Five patients had an apparently complete initial excision, with 1 recurrence. Four patients were initially treated with incomplete excision and/or cyst drainage, usually into an Ommaya reservoir. A neonate with a large cervicothoracic cyst died of multiple congenital anomalies without any intervention. All other patients were alive at last follow-up. One patient with a radiologically identified presumed cyst, which remained stable, was simply followed up. Several patients required multiple procedures and 1 patient developed hydrocephalus after aseptic meningitis and was treated with CSF shunting. Conclusions Neurenteric cysts are rare in the pediatric population. Total resection, if possible, provides the best long-term outcome. Incomplete excision may lead to multiple procedures, including cyst drainage, but can lead to long-term stability.
  Journal of Neurosurgery Pediatrics 03/2013; · 1.53 Impact Factor
• Article: Hemispherectomy: When half is better than the whole. Tuberous sclerosis complex.

  Aria Fallah, George M Ibrahim, James T Rutka
  Journal of Clinical Neuroscience 03/2013; 20(3):451, 478. · 1.25 Impact Factor
• Article: Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis.

  Aria Fallah, Gordon H Guyatt, O Carter Snead, Shanil Ebrahim, George M Ibrahim, Alireza Mansouri, Deven Reddy, Stephen D Walter, Abhaya V Kulkarni, Mohit Bhandari, Laura Banfield, Neera Bhatnagar, Shuli Liang, Federica Teutonico, Jianxiang Liao, James T Rutka
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  ABSTRACT: To perform a systematic review and individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Tuberous Sclerosis Complex undergoing resective epilepsy surgery. Electronic databases (MEDLINE, EMBASE, CINAHL and Web of Science), archives of major epilepsy and neurosurgery meetings, and bibliographies of relevant articles, with no language or date restrictions. We included case-control or cohort studies of consecutive participants undergoing resective epilepsy surgery that reported seizure outcomes. We performed title and abstract and full text screening independently and in duplicate. We resolved disagreements through discussion. One author performed data extraction which was verified by a second author using predefined data fields including study quality assessment using a risk of bias instrument we developed. We recorded all preoperative factors that may plausibly predict seizure outcomes. To identify predictors of a good seizure outcome (i.e. Engel Class I or II) we used logistic regression adjusting for length of follow-up for each preoperative variable. Of 9863 citations, 20 articles reporting on 181 participants were eligible. Good seizure outcomes were observed in 126 (69%) participants (Engel Class I: 102(56%); Engel class II: 24(13%)). In univariable analyses, absence of generalized seizure semiology (OR = 3.1, 95%CI = 1.2-8.2, p = 0.022), no or mild developmental delay (OR = 7.3, 95%CI = 2.1-24.7, p = 0.001), unifocal ictal scalp electroencephalographic (EEG) abnormality (OR = 3.2, 95%CI = 1.4-7.6, p = 0.008) and EEG/Magnetic resonance imaging concordance (OR = 4.9, 95%CI = 1.8-13.5, p = 0.002) were associated with a good postoperative seizure outcome. Small retrospective cohort studies are inherently prone to bias, some of which are overcome using individual participant data. The best available evidence suggests four preoperative factors predictive of good seizure outcomes following resective epilepsy surgery. Large long-term prospective multicenter observational studies are required to further evaluate the risk factors identified in this review.
  PLoS ONE 01/2013; 8(2):e53565. · 4.09 Impact Factor
• Article: Altered rolandic gamma-band activation associated with motor impairment and ictal network desynchronization in childhood epilepsy.

  Sam M Doesburg, George M Ibrahim, Mary Lou Smith, Rohit Sharma, Amrita Viljoen, Bill Chu, James T Rutka, O Carter Snead, Elizabeth W Pang
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  ABSTRACT: Epilepsy is associated with an abnormal expression of neural oscillations and their synchronization across brain regions. Oscillatory brain activation and synchronization also play an important role in cognition, perception and motor control. Childhood epilepsy is associated with a variety of cognitive and motor deficits, but the relationship between altered functional brain responses in various frequency ranges and functional impairment in these children remains poorly understood. We investigated functional magnetoencephalographic (MEG) responses from motor cortex in multiple functionally relevant frequency bands following median nerve stimulation in twelve children with epilepsy, including four children with motor impairments. We demonstrated that children with motor impairments exhibit an excessive gamma-band response from Rolandic cortex, and that the magnitude of this Rolandic gamma response is negatively associated with motor function. Abnormal responses from motor cortex were also associated with ictal desynchronization of oscillations within Rolandic cortex measured using intracranial EEG (iEEG). These results provide the evidence that ictal disruption of motor networks is associated with an altered functional response from motor cortex, which is in turn associated with motor impairment.
  PLoS ONE 01/2013; 8(1):e54943. · 4.09 Impact Factor
• Article: Glioblastoma, a Brief Review of History, Molecular Genetics, Animal Models and Novel Therapeutic Strategies.

  Sameer Agnihotri, Kelly E Burrell, Amparo Wolf, Sharzhad Jalali, Cynthia Hawkins, James T Rutka, Gelareh Zadeh
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  ABSTRACT: Glioblastoma (GBM) is the most common and lethal primary brain tumor. Over the past few years tremendous genomic and proteomic characterization along with robust animal models of GBM have provided invaluable data that show that "GBM", although histologically indistinguishable from one another, are comprised of molecularly heterogenous diseases. In addition, robust pre-clinical models and a better understanding of the core pathways disrupted in GBM are providing a renewed optimism for novel strategies targeting these devastating tumors. Here, we summarize a brief history of the disease, our current molecular knowledge, lessons from animal models and emerging concepts of angiogenesis, invasion, and metabolism in GBM that may lend themselves to therapeutic targeting.
  Archivum Immunologiae et Therapiae Experimentalis 12/2012; · 2.54 Impact Factor
• Article: The role of drebrin in glioma migration and invasion.

  Yuzo Terakawa, Sameer Agnihotri, Brian Golbourn, Mustafa Nadi, Nesrin Sabha, Christian A Smith, Sidney E Croul, James T Rutka
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  ABSTRACT: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite current advances in therapy consisting of surgery followed by chemotherapy and radiation, the overall survival rate still remains poor. Therapeutic failures are partly attributable to the highly infiltrative nature of tumor adjacent to normal brain parenchyma. Recently, evidence is mounting to suggest that actin cytoskeleton dynamics are critical components of the cell invasion process. Drebrin is an actin-binding protein involved in the regulation of actin filament organization, and plays a significant role in cell motility; however, the role of drebrin in glioma cell invasiveness has not yet been fully elucidated. Therefore, this study was aimed to clarify the role of drebrin in glioma cell morphology and cell motility. Here we show that drebrin is expressed in glioma cell lines and in operative specimens of GBM. We demonstrate that stable overexpression of drebrin in U87 cells leads to alterations in cell morphology, and induces increased invasiveness in vitro while knockdown of drebrin in U87 cells by small interfering RNA (siRNA) decreases invasion and migration. In addition, we show that depletion of drebrin by siRNA alters glioma cell morphology in A172GBM cell line. Our results suggest that drebrin contributes to the maintenance of cell shape, and may play an important role in glioma cell motility.
  Experimental Cell Research 11/2012; · 3.58 Impact Factor
• Article: Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma.

  Adrian M Dubuc, Marc Remke, Andrey Korshunov, Paul A Northcott, Shing H Zhan, Maria Mendez-Lago, Marcel Kool, David T W Jones, Alexander Unterberger, A Sorana Morrissy, [......], Cynthia Hawkins, Rajeev Vibhakar, Sidney Croul, James T Rutka, William A Weiss, Steven J M Jones, Charles G Eberhart, Marco A Marra, Stefan M Pfister, Michael D Taylor
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  ABSTRACT: Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.
  Acta Neuropathologica 11/2012; · 9.32 Impact Factor
• Article: High-resolution Whole-Genome Analysis of Skull Base Chordomas Implicates FHIT Loss in Chordoma Pathogenesis.

  Roberto Jose Diaz, Mustafa Guduk, Rocco Romagnuolo, Christian A Smith, Paul Northcott, David Shih, Fitim Berisha, Adrienne Flanagan, David G Munoz, Michael D Cusimano, M Necmettin Pamir, James T Rutka
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  ABSTRACT: Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemotherapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22%) than previously reported for sacral chordoma. At a similar frequency (21%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98% of sacral chordomas and 67%of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm.
  Neoplasia (New York, N.Y.) 09/2012; 14(9):788-98. · 5.48 Impact Factor
• Article: Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells.

  Ho Jun Seol, Jong Hee Chang, Junkoh Yamamoto, Rocco Romagnuolo, Youngchul Suh, Adrienne Weeks, Sameer Agnihotri, Christian A Smith, James T Rutka
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  ABSTRACT: The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas.
  Genes & cancer 09/2012; 3(9-10):535-49.
• Article: The use of high frequency oscillations to guide neocortical resections in children with medically-intractable epilepsy: How do we ethically apply surgical innovations to patient care?

  George M Ibrahim, Aria Fallah, O Carter Snead, James M Drake, James T Rutka, Mark Bernstein
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  ABSTRACT: PURPOSE: Resective surgical strategies are increasingly applied to treat medically-intractable epilepsy in children as uncontrolled seizures are associated with poor cognitive, developmental and behavioral outcomes. Innovative surgical strategies are, however, needed to improve outcomes and minimize the morbidity of such procedures. METHOD: The current article utilizes an axiological approach to explore and highlight ethical issues in the use of high frequency oscillations (HFOs) to guide surgical resections in children with medically-intractable epilepsy. We frame our discussion in the context of the broader challenges in the application of surgical innovation to patient care. RESULTS: Despite a paucity of knowledge regarding their pathogenesis, limited evidence suggests the use of HFOs as biomarkers of epileptogenicity in resective procedures can improve seizure outcome. Clinicians must therefore weigh deficiencies in knowledge against the limited evidence supporting the utility of HFOs and make ethical decisions for the treatment of individual patients. Important ethical considerations for clinicians include the extent of deviation from established practice, the extent of evidence required to establish clinical validity, and the impact of technique implementation on equitable distribution of healthcare. CONCLUSION: The use of HFO signatures to guide neocortical resections represents a novel approach for the treatment of epilepsy. It is hoped that the issues discussed herein will contribute to and advance meaningful dialog on the ethical application of this surgical innovation to the treatment of a very vulnerable patient population.
  Seizure 08/2012; · 1.80 Impact Factor
• Article: Neurosurgical management of frontal lobe epilepsy in children.

  Shobhan Vachhrajani, Sandrine de Ribaupierre, Hiroshi Otsubo, Ayako Ochi, Shelly K Weiss, Elizabeth J Donner, Elysa Widjaja, Elizabeth Kerr, Mary Lou Smith, James Drake, James T Rutka
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  ABSTRACT: Pediatric frontal lobe epilepsy (FLE) remains a challenging condition for neurosurgeons and epileptologists to manage. Postoperative seizure outcomes remain far inferior to those observed in temporal lobe epilepsies, possibly due to inherent difficulties in delineating and subsequently completely resecting responsible epileptogenic regions. In this study, the authors review their institutional experience with the surgical management of FLE and attempt to find predictors that may help to improve seizure outcome in this population. All surgically treated cases of intractable FLE from 1990 to 2008 were reviewed. Demographic information, preoperative and intraoperative imaging and electrophysiological investigations, and follow-up seizure outcome were assessed. Inferential statistics were performed to look for potential predictors of seizure outcome. Forty patients (20 male, 20 female) underwent surgical management of FLE during the study period. Patients were an average of 5.6 years old at the time of FLE onset and 11.7 years at the time of surgery; patients were followed for a mean of 40.25 months. Most patients displayed typical FLE semiology. Twenty-eight patients had discrete lesions identified on MRI. Eight patients underwent 2 operations. Cortical dysplasia was the most common pathological diagnosis. Engel Class I outcome was obtained in 25 patients (62.5%), while Engel Class II outcome was observed in 5 patients (12.5%). No statistically significant predictors of outcome were found. Control of FLE remains a challenging problem. Favorable seizure outcome, obtained in 62% of patients in this series, is still not as easily obtained in FLE as it is in temporal lobe epilepsy. While no statistically significant predictors of seizure outcome were revealed in this study, patients with FLE continue to require extensive workup and investigation to arrive at a logical and comprehensive neurosurgical treatment plan. Future studies with improved neuroimaging and advanced invasive monitoring strategies may well help define factors for success in this form of epilepsy that is difficult to control.
  Journal of Neurosurgery Pediatrics 07/2012; 10(3):206-16. · 1.53 Impact Factor
• Source

  Available from: Giuseppe Cinalli

  Article: Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

  Paul A Northcott, David J H Shih, John Peacock, Livia Garzia, A Sorana Morrissy, Thomas Zichner, Adrian M Stütz, Andrey Korshunov, Jüri Reimand, Steven E Schumacher, [......], Eric Bouffet, Stephen W Scherer, James T Rutka, David Malkin, Steven C Clifford, Steven J M Jones, Jan O Korbel, Stefan M Pfister, Marco A Marra, Michael D Taylor
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  ABSTRACT: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
  Nature 07/2012; 488(7409):49-56. · 36.28 Impact Factor
• Article: Pediatric neurosurgery at the Hospital for Sick Children, The University of Toronto.

  James T Rutka, James Drake, Peter Dirks, Abhaya Kulkarni, Michael Taylor, Robin P Humphreys
  Child s Nervous System 07/2012; 28(8):1127-8. · 1.54 Impact Factor
• Article: ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells.

  Adrienne Weeks, Nadia Okolowsky, Brian Golbourn, Stacey Ivanchuk, Christian Smith, James T Rutka
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  ABSTRACT: Malignant astrocytomas are highly invasive brain tumors. The Rho family of cytoskeletal GTPases are key regulators of astrocytoma migration and invasion; expression of the guanine nucleotide exchange factor ECT2 is elevated in primary astrocytomas and predicts both survival and malignancy. Mice bearing orthotopically implanted astrocytoma cells with diminished ECT2 levels following ECT2 knockdown exhibit longer survival. Although ECT2 is normally expressed in the nucleus, we show that ECT2 is aberrantly localized to the cytoplasm in both astrocytoma cell lines and primary human astrocytomas, and colocalizes with RAC1 and CDC42 at the leading edge of migrating astrocytoma cells. Inhibition of ECT2 expression by RNA interference resulted in decreased RAC1 and CDC42 activity, but no change in RHO activity, suggesting that ECT2 is capable of activating these pro-migratory Rho family members. ECT2 overexpression in astrocytoma cells resulted in a transition to an amoeboid phenotype that was abolished with the ROCK inhibitor, Y-27632. Cytoplasmic fractionation of astrocytoma cells followed by ECT2 immunoprecipitation and mass spectrometry were used to identify protein-binding partners that modulate the activity of ECT2 toward RAC1 and RHO/ROCK. We identified RASAL2 as an ECT2-interacting protein that regulates RHO activity in astrocytoma cells. RASAL2 knockdown leads to a conversion to an amoeboid phenotype. Our studies reveal that ECT2 has a novel role in mesenchymal-amoeboid transition in human astrocytoma cells.
  American Journal Of Pathology 06/2012; 181(2):662-74. · 4.89 Impact Factor
• Article: Corticospinal tract mapping in children with ruptured arteriovenous malformations using functionally guided diffusion-tensor imaging.

  Michael J Ellis, James T Rutka, Abhaya V Kulkarni, Peter B Dirks, Elysa Widjaja
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  ABSTRACT: Arteriovenous malformations (AVMs) can lead to distortion or reorganization of functional brain anatomy, making localization of eloquent white matter tracts challenging. To improve the accuracy of corticospinal tract (CST) mapping, recent studies have examined the use of functional imaging techniques to help localize cortical motor activations and use these as seed points to reconstruct CSTs using diffusion-tensor imaging (DTI). The authors examined the role of pretreatment functionally guided DTI CST mapping in 3 children with ruptured AVMs. In 2 patients, magnetoencephalography motor activations were adjacent to the nidus and/or hemorrhagic cavity. However, in 1 child, functional MRI motor activations were detected in both hemispheres, suggestive of partial transfer of cortical motor function. In all children, quantitative analysis showed that fractional anisotropy values and fiber density indices were reduced in the CSTs of the hemisphere harboring the AVM compared with the unaffected side. In 2 children, CST caliber was slightly diminished, corresponding to no motor deficit in 1 patient and a temporary motor deficit in the other. In contrast, 1 child demonstrated marked reduction and displacement of the CSTs, correlating with severe motor deficit. Preoperative motor tractography data were loaded onto the intraoperative neuronavigation platform to guide complete resection of the AVM in 2 cases without permanent neurological deficits. These preliminary results confirm the feasibility of CST mapping in children with ruptured AVMs using functionally guided DTI tractography. Prospective studies are needed to assess the full value of this technique in the risk stratification, prognosis, and multimodality management of pediatric AVMs.
  Journal of Neurosurgery Pediatrics 05/2012; 9(5):505-10. · 1.53 Impact Factor
• Article: Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor.

  Meihua Li, Will Lockwood, Maria Zielenska, Paul Northcott, Young Shing Ra, Eric Bouffet, Maisa Yoshimoto, James T Rutka, Hai Yan, Michael D Taylor, Charles Eberhart, Cynthia E Hawkins, Wan Lam, Jeremy A Squire, Annie Huang
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  ABSTRACT: Embryonal brain tumors, which include medulloblastoma and the more aggressive supratentorial primitive neuroectodermal tumor (sPNET), comprise one of the largest group of malignant pediatric brain tumors. We observed in high resolution array comparative genomic hybridization and polymerase chain reaction analyses that several different components of the CDK/CYCLIND/pRB regulatory complex, including the CDK4/6 and CCND1/2 loci, are targets of gene amplification in medulloblastoma and sPNET. CDK6 and CCND1 gene amplification were respectively most common and robust, and overall CDK/CYCLIND gene amplification was more commonly observed in sPNET (25%) than medulloblastoma (1-5%). CDK6 overexpression enhanced in vitro and in vivo oncogenicity and endogenous CDK6 or CCND1 knockdown decreased pRB phosphorylation and impaired cell cycle progression in both medulloblastoma and sPNET cell lines. Although animal models implicate the pRB tumor suppressor pathway in medulloblastoma and sPNET, mutations of RB1 or the related INK4 tumor suppressor loci are rare in primary human tumors. Our data suggest that CDK/CYCLIND gene amplification may represent important mechanisms for functional inactivation of pRB in medulloblastoma and sPNET.
  Cancer Genetics 05/2012; 205(5):220-31.
• Article: Alterations of the p53 and pRB pathways in human astrocytoma

  James T. Rutka, Yasuhiko Akiyama, Sang Pyung Lee, Stacey Ivanchuk, Atsushi Tsugu, Paul A. Hamel
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  ABSTRACT: Human astrocytomas are characterized by a number of molecular changes affecting two critical tumor suppressor pathways: the pRB and the p53 pathways. Genetic alterations functionally eliminate pRB and p53 themselves or upstream and/or downstream molecules such as products of theInk4a/ARF locus, p16Ink4a and p14ARF. As a result, malignant cells are defective in critical cell cycle and apoptosis regulatory elements contributing to unrelenting tumour growth and invasion. Current research aims to discover effective means of reconstituting p53 and pRB pathway components in an effort to attenuate the aggressive phenotype of astrocytoma.
  Brain Tumor Pathology 04/2012; 17(2):65-70. · 1.19 Impact Factor
• Article: The most cited works in epilepsy: Trends in the "Citation Classics".

  George M Ibrahim, O Carter Snead, James T Rutka, Andres M Lozano
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  ABSTRACT: The number of times that a published article is cited is one indicator of its scientific impact. An article is termed a "Citation Classic" once it has accumulated more than 400 citations. Trends in these highly cited works allow projection of future directions of high-impact research within a field. Herein, we identified 89 articles in the field of epilepsy published in 35 different journals that have been cited more than 400 times (citation range 401-3,749). The journal that published the greatest number of Citation Classics was Epilepsia (9 articles with 656 mean citations per article). Laboratory studies constituted the fastest growing area of highly cited epilepsy research, whereas clinical studies showed a bimodal distribution in representation among Citation Classics. There were also considerably fewer epilepsy-specific Citation Classics compared to other disciplines. In this study, we find that the Citation Classics of epilepsy comprise a heterogeneous group of articles and that changes in the trends of these highly cited works represent the evolution of epilepsy research over time. The results of this study should inform the academic community and provide a guide of essential literature for scientists who are engaged in epilepsy research.
  Epilepsia 03/2012; 53(5):765-70. · 3.96 Impact Factor
• Article: Inequities in access to pediatric epilepsy surgery: a bioethical framework.

  George M Ibrahim, Benjamin W Barry, Aria Fallah, O Carter Snead, James M Drake, James T Rutka, Mark Bernstein
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  ABSTRACT: Epilepsy is a common childhood condition associated with a considerable medical and psychosocial burden. Children in whom medical treatment fails to reduce seizure burden represent an especially vulnerable patient population because prolonged, uncontrolled seizures are associated with poor developmental and neurocognitive outcomes. Surgical treatment in the form of cortical resection, functional disconnection, or neuromodulation may alleviate or significantly reduce the disease burden for a subset of these patients. However, there remains a dichotomy between the perceived benefits of surgery and the implementation of surgical strategies in the management of medically intractable epilepsy. The current paper presents an analysis of the bioethical implications of existing inequities in access to pediatric epilepsy surgery that result from inconsistent referral practices and discrepant evaluation techniques. The authors provide a basic bioethical framework composed of 5 primary expectations to inform public, institutional, and personal policies toward the provision of epilepsy surgery to afflicted children.
  Neurosurgical FOCUS 03/2012; 32(3):E2. · 2.87 Impact Factor