James T Rutka

University of Toronto, Toronto, Ontario, Canada

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Publications (438)1679.07 Total impact

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    ABSTRACT: Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10−8). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
    Acta Neuropathologica 10/2015; · 9.73 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; · 1.63 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; · 8.65 Impact Factor
  • James T Rutka
    Journal of neurosurgery. 10/2014;
  • James T Rutka
    Journal of neurosurgery. 10/2014;
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    ABSTRACT: The indications for operating on lesions in or near areas of cortical eloquence balance the benefit of resection with the risk of permanent neurological deficit. In adults, awake craniotomy has become a versatile tool in tumor, epilepsy and functional neurosurgery, permitting intra-operative stimulation mapping particularly for language, sensory and motor cortical pathways. This allows for maximal tumor resection with considerable reduction in the risk of post-operative speech and motor deficits. We report our experience of awake craniotomy and cortical stimulation for epilepsy and supratentorial tumors located in and around eloquent areas in a pediatric population (n=10, five females). The presenting symptom was mainly seizures and all children had normal neurological examinations. Neuroimaging showed lesions in the left opercular (n=4) and precentral or peri-sylvian regions (n=6). Three right-sided and seven left-sided awake craniotomies were performed. Two patients had a history of prior craniotomy. All patients had intra-operative mapping for either speech or motor or both using cortical stimulation. The surgical goal for tumor patients was gross total resection, while for all epilepsy procedures, focal cortical resections were completed without any difficulty. None of the patients had permanent post-operative neurologic deficits. The patient with an epileptic focus over the speech area in the left frontal lobe had a mild word finding difficulty post-operatively but this improved progressively. Follow-up ranged from 6 to 27months. Pediatric awake craniotomy with intra-operative mapping is a precise, safe and reliable method allowing for resection of lesions in eloquent areas. Further validations on larger number of patients will be needed to verify the utility of this technique in the pediatric population.
    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 10/2014;
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    ABSTRACT: Object Resective surgery is increasingly used in the management of pediatric epilepsy. Frequently, invasive monitoring with subdural electrodes is required to adequately map the epileptogenic focus. The risks of invasive monitoring include the need for 2 operations, infection, and CSF leak. The aim of this study was to evaluate the feasibility and outcomes of resective epilepsy surgery guided by magnetoencephalography (MEG) in children who would have otherwise been candidates for electrode implantation. Methods The authors reviewed the records of patients undergoing resective epilepsy surgery at the Hospital for Sick Children between 2001 and 2010. They identified cases in which resections were based on MEG data and no intracranial recordings were performed. Each patient's chart was reviewed for presentation, MRI findings, MEG findings, surgical procedure, pathology, and surgical outcome. Results Sixteen patients qualified for the study. All patients had localized spike clusters on MEG and most had abnormal findings on MRI. Resection was carried out in each case based on the MEG data linked to neuronavigation and supplemented with intraoperative neuromonitoring. Overall, 62.5% of patients were seizure free following surgery, and 20% of patients experienced an improvement in seizures without attaining seizure freedom. In 2 cases, additional surgery was performed subsequently with intracranial monitoring in attempts to obtain seizure control. Conclusions MEG is a viable alternative to invasive monitoring with intracranial electrodes for planning of resective surgery in carefully selected pediatric patients with localization-related epilepsy. Good candidates for this approach include patients who have a well-delineated, localized spike cluster on MEG that is concordant with findings of other preoperative evaluations and patients with prior brain pathologies that make the implantation of subdural and depth electrodes somewhat problematic.
    Journal of Neurosurgery Pediatrics 09/2014; · 1.63 Impact Factor
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    ABSTRACT: Advances in surgical procedures and improvements in patient outcomes have resulted from applications of new technologies in the operating room over the past three decades. All surgeons would be excited about the possibilities of improving their resections of tumors for patients with cancer if a new technology were introduced to facilitate this. In this issue of ACS Nano, Karabeber et al. use a hand-held Raman scanner to probe the completeness of resection of glioblastoma multiforme (GBM), the most malignant brain cancer, in a genetically engineered mouse model. They show that the hand-held scanner could accurately detect gold-silica surface-enhanced Raman scattering nanoparticles embedded within the GBM, resulting in a complete tumor resection. In this Perspective, we review potential applications of nanotechnologies to neurosurgery and describe how new systems, such as the one described in this issue, may be brought closer to the operating room through modifications in nanoparticle size, overcoming the obstacles presented by the blood-brain barrier, and functionalizing nanoparticle conjugates so that they reach their target at highest concentrations possible. Finally, with adaptations of the actual hand-held Raman scanner device itself, one can envision the day when "nanosurgical" procedures will be a part of the surgeon's armamentarium.
    ACS Nano 09/2014; · 12.03 Impact Factor
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    ABSTRACT: Cerebellar tubers have been recognized as a feature of tuberous sclerosis complex (TSC), but the evolution of cerebellar tubers with brain maturation remains unclear. The aim of this study was to assess the evolution of MRI characteristics of cerebellar tubers in children with TSC longitudinally.
    Child s Nervous System 09/2014; · 1.24 Impact Factor
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    ABSTRACT: Objective Multiple tubers in patients with tuberous sclerosis complex (TSC) often are responsible for drug-resistant epilepsy. The complexity of the epileptic network formed by multiple tubers complicates localization of the epileptogenic zone that is needed to design a surgical treatment strategy. High frequency oscillations (HFOs) on intracranial video-electroencephalography (IVEEG) may be a valuable surrogate marker for the localization of the epileptogenic zone. The purpose of this study was to test the hypothesis that high occurrence rate (OR) of interictal HFOs can guide the localization of the epileptogenic zone.Methods We analyzed the OR of interictal HFOs at 80–200 Hz (ripples) and >200 Hz (fast ripples, FRs). We divided OR of interictal HFOs between high and low rates by thresholding. We analyzed the correlation between seizure outcomes using Engel classification and the resection ratio of the seizure onset zone (SOZ), and high-OR HFOs using ordinal logistic regression analysis.ResultsWe collected 10 patients. The seizure outcomes resulted in Engel classification I in three patients, II in four, III in one, and IV in two. High-OR ripples (5–57 [mean 29] channels, 1–4 [2.8] lobes) and high-OR FRs (9–66 [mean 27] channels, 1–4 [2.6] lobes) were widely distributed. The resection ratio of SOZ did not show statistically significant correlation with the seizure outcome. The resection ratio of high-OR ripples showed statistically significant correlation with the seizure outcome (p = 0.038). The resection ratio of high-OR FRs showed statistically significant correlation with the seizure outcome (p = 0.048).SignificanceThe multiple extensive zones with high-OR HFOs suggest a complex and widespread epileptic network in patients with TSC. In a subset of TSC patients with drug-resistant epilepsy, resection of cortex with both interictal high-OR FRs and ripples on IVEEG correlated with a good seizure outcome.
    Epilepsia 09/2014; · 3.96 Impact Factor
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    ABSTRACT: Astrocytic inclusions (AIs) have been identified on histologic specimens of patients with early onset seizures, and the proteomic contents have been described. The aim of this study was to compare the clinical, electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance imaging (MRI), and surgical outcomes of AIs relative to focal cortical dysplasia (FCD).
    Epilepsia 08/2014; · 3.96 Impact Factor
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    ABSTRACT: The effects of interictal epileptiform discharges on neurocognitive development in children with medically-intractable epilepsy are poorly understood. Such discharges may have a deleterious effect on the brain's intrinsic connectivity networks, which reflect the organization of functional networks at rest, and in turn on neurocognitive development. Using a combined functional magnetic resonance imaging-magnetoencephalography approach, we examine the effects of interictal epileptiform discharges on intrinsic connectivity networks and neurocognitive outcome. Functional magnetic resonance imaging was used to determine the location of regions comprising various intrinsic connectivity networks in 26 children (7-17 years), and magnetoencephalography data were reconstructed from these locations. Inter-regional phase synchronization was then calculated across interictal epileptiform discharges and graph theoretical analysis was applied to measure event-related changes in network topology in the peri-discharge period. The magnitude of change in network topology (network resilience/vulnerability) to interictal epileptiform discharges was associated with neurocognitive outcomes and functional magnetic resonance imaging networks using dual regression. Three main findings are reported: (i) large-scale network changes precede and follow interictal epileptiform discharges; (ii) the resilience of network topologies to interictal discharges is associated with stronger resting-state network connectivity; and (iii) vulnerability to interictal discharges is associated with worse neurocognitive outcomes. By combining the spatial resolution of functional magnetic resonance imaging with the temporal resolution of magnetoencephalography, we describe the effects of interictal epileptiform discharges on neurophysiological synchrony in intrinsic connectivity networks and establish the impact of interictal disruption of functional networks on cognitive outcome in children with epilepsy. The association between interictal discharges, network changes and neurocognitive outcomes suggests that it is of clinical importance to suppress discharges to foster more typical brain network development in children with focal epilepsy.
    Brain : a journal of neurology. 08/2014;
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    ABSTRACT: Alkylating agents are a frontline therapy for the treatment of several aggressive cancers including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed; increasing therapeutic response while minimizing toxicity. Using a siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM) were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors.
    Cancer Discovery 08/2014; · 15.93 Impact Factor
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    ABSTRACT: Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.
    Acta Neuropathologica 08/2014; · 9.73 Impact Factor
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    ABSTRACT: Object Porencephalic cyst/encephalomalacia (PC/E) is a brain lesion caused by ischemic insult or hemorrhage. The authors evaluated magnetoencephalography (MEG) spike sources (MEGSS) to localize the epileptogenic zone in children with intractable epilepsy secondary to PC/E. Methods The authors retrospectively studied 13 children with intractable epilepsy secondary to PC/E (5 girls and 8 boys, age range 1.8-15 years), who underwent prolonged scalp video-electroencephalography (EEG), MRI, and MEG. Interictal MEGSS locations were compared with the ictal and interictal zones as determined from scalp video-EEG. Results Magnetic resonance imaging showed PC/E in extratemporal lobes in 3 patients, within the temporal lobe in 2 patients, and in both temporal and extratemporal lobes in 8 patients. Magnetoencephalographic spike sources were asymmetrically clustered at the margin of PC/E in all 13 patients. One cluster of MEGSS was observed in 11 patients, 2 clusters in 1 patient, and 3 clusters in 1 patient. Ictal EEG discharges were lateralized and concordant with MEGSS in 8 patients (62%). Interictal EEG discharges were lateralized and concordant with MEGSS hemisphere in 9 patients (69%). Seven patients underwent lesionectomy in addition to MEGSS clusterectomy with (2 patients) and without (5 patients) intracranial video-EEG. Temporal lobectomy was performed in 1 patient and hemispherectomy in another. Eight of 9 patients achieved seizure freedom following surgery. Conclusions Magnetoencephalography delineated the extent of the epileptogenic zone adjacent to PC/E in patients with intractable epilepsy. Complete resection of the MEGSS cluster along with PC/E can provide favorable seizure outcomes.
    Journal of Neurosurgery Pediatrics 07/2014; · 1.63 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.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii35. · 6.18 Impact Factor
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    ABSTRACT: The malignant astrocytoma is a highly proliferative and invasive neoplasm that infiltrates diffusely into regions of normal brain rendering total surgical resection impossible and effective local radiation therapy difficult. For truly significant advances to be made in the treatment of patients with malignant astrocytoma, we must develop a greater understanding of the molecular machinery driving invasion and identify novel treatment targets.
    Neuro-oncology. 07/2014; 16 Suppl 3:iii34.
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    ABSTRACT: Typical childhood development is characterized by the emergence of intrinsic connectivity networks (ICNs) by way of internetwork segregation and intranetwork integration. The impact of childhood epilepsy on the maturation of ICNs is, however, poorly understood. The developmental trajectory of ICNs in 26 children (8-17 years) with localization-related epilepsy and 28 propensity-score matched controls was evaluated using graph theoretical analysis of whole brain connectomes from resting-state functional magnetic resonance imaging (fMRI) data. Children with epilepsy demonstrated impaired development of regional hubs in nodes of the salience and default mode networks (DMN). Seed-based connectivity and hierarchical clustering analysis revealed significantly decreased intranetwork connections, and greater internetwork connectivity in children with epilepsy compared to controls. Significant interactions were identified between epilepsy duration and the expected developmental trajectory of ICNs, indicating that prolonged epilepsy may cause progressive alternations in large-scale networks throughout childhood. DMN integration was also associated with better working memory, whereas internetwork segregation was associated with higher full-scale intelligence quotient scores. Furthermore, subgroup analyses revealed the thalamus, hippocampus, and caudate were weaker hubs in children with secondarily generalized seizures, relative to other patient subgroups. Our findings underscore that epilepsy interferes with the developmental trajectory of brain networks underlying cognition, providing evidence supporting the early treatment of affected children. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 06/2014; · 6.88 Impact Factor
  • 06/2014;
  • Society for Neuro-Oncology; 06/2014

Publication Stats

9k Citations
1,679.07 Total Impact Points

Institutions

  • 1992–2014
    • University of Toronto
      • • Division of Neurosurgery
      • • Hospital for Sick Children
      • • Faculty of Medicine
      • • Department of Paediatrics
      Toronto, Ontario, Canada
  • 1990–2014
    • SickKids
      • • Division of Neurosurgery
      • • Division of Neurology
      • • Division of Pathology
      • • Department of Paediatric Laboratory Medicine (DPLM)
      Toronto, Ontario, Canada
  • 2013
    • University of Florida Health Science Center-Jacksonville
      Jacksonville, Florida, United States
    • McMaster University
      • Department of Clinical Epidemiology and Biostatistics
      Hamilton, Ontario, Canada
  • 2011
    • Nationwide Children's Hospital
      Columbus, Ohio, United States
    • University of Toyama
      • Department of Neurosurgery
      Тояма, Toyama, Japan
  • 2010
    • National Neuroscience Institute
      • Department of Neurosurgery
      Tumasik, Singapore
  • 2009
    • Shinshu University
      • Department of Neurosurgery
      Shonai, Nagano, Japan
  • 2008
    • University of North Carolina at Chapel Hill
      • Department of Neurosurgery
      Chapel Hill, NC, United States
    • University of São Paulo
      San Paulo, São Paulo, Brazil
    • Baylor College of Medicine
      • Department of Neurosurgery
      Houston, TX, United States
    • Kyungpook National University
      • Department of Neurosurgery
      Daikyū, Daegu, South Korea
    • Taipei Veterans General Hospital
      • General Neurosurgery Division
      T’ai-pei, Taipei, Taiwan
    • University of Tehran
      Teheran, Tehrān, Iran
  • 2006
    • Universitätsklinikum Freiburg
      • Department of Neurosurgery
      Freiburg, Lower Saxony, Germany
  • 1987–2006
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 2004
    • University of Bonn
      • Department of Neurobiology
      Bonn, North Rhine-Westphalia, Germany
  • 2003
    • University of Manitoba
      Winnipeg, Manitoba, Canada
    • The Royal Marsden NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2002
    • St. Michael's Hospital
      Toronto, Ontario, Canada
  • 2001
    • Kumamoto University
      • Department of Neurosurgery
      Kumamoto, Kumamoto Prefecture, Japan
  • 1987–1990
    • University of California, San Francisco
      • • Department of Neurological Surgery
      • • Division of Hospital Medicine
      San Francisco, CA, United States