Stuart A Grossman

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (172)965.73 Total impact

  • Roy E Strowd, Matthias Holdhoff, Stuart A Grossman
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    ABSTRACT: Gliomas classified as grade II by the World Health Organization (WHO) include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. This heterogeneous group of conditions is associated with a more favorable prognosis and longer-term survival than high-grade gliomas (HGGs). Neurosurgical resection and radiation therapy improve survival in symptomatic, progressive, or high-risk grade II gliomas. Until recently, the role of chemotherapy has been less clear. This review draws on insights from the management of HGGs and emerging data on the addition of PCV (procarbazine, lomustine [CCNU], and vincristine) to radiation for these neoplasms. Specifically, this review focuses on the current status of chemotherapeutic management of grade II gliomas, including optimal timing of treatment, and management of 1p19q codeleted and non-codeleted tumors.
    Oncology (Williston Park, N.Y.) 12/2014; 28(12). · 3.19 Impact Factor
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    ABSTRACT: Eight brain-derived proteins were evaluated regarding their potential for further development as a blood-based biomarker for malignant gliomas. Plasma levels for glial fibrillary acidic protein, neurogranin, brain-derived neurotrophic factor, intracellular adhesion molecule 5, metallothionein-3, beta-synuclein, S100 and neuron specific enolase were tested in plasma of 23 patients with high-grade gliomas (WHO grade IV), 11 low-grade gliomas (WHO grade II), and 15 healthy subjects. Compared to the healthy controls, none of the proteins appeared to be specific for glioblastomas. However, the data are suggestive of higher protein levels in gliosarcomas (n = 2), which may deserve further exploration.
    Cancer Investigation 07/2014; · 2.24 Impact Factor
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    ABSTRACT: To evaluate the efficacy of rituximab (R) when added to high-dose methotrexate (HD-MTX) in patients with newly diagnosed immunocompetent primary CNS lymphomas (PCNSLs).METHODS: Immunocompetent adults with newly diagnosed PCNSL treated at The Johns Hopkins Hospital between 1995 and 2012 were investigated. From 1995 to 2008, patients received HD-MTX monotherapy (8 g/m(2) initially every 2 weeks and after complete response [CR] monthly to complete 12 months of therapy). From 2008 to 2012, patients received the same HD-MTX with rituximab (375 mg/m(2)) with each HD-MTX treatment. CR rates and median overall and progression-free survival were analyzed for each patient cohort in this single-institution, retrospective study.RESULTS: A total of 81 patients were identified: 54 received HD-MTX (median age 66 years) while 27 received HD-MTX/R (median age 65 years). CR rates were 36% in the HD-MTX cohort and 73% in the HD-MTX/R cohort (p = 0.0145). Median progression-free survival was 4.5 months in the HD-MTX cohort and 26.7 months in the HD-MTX/R cohort (p = 0.003). Median overall survival was 16.3 months in the HD-MTX cohort and has not yet been reached in the HD-MTX/R cohort (p = 0.01).CONCLUSIONS: The addition of rituximab to HD-MTX appears to improve CR rates as well as overall and progression-free survival in patients with newly diagnosed PCNSL. Comparisons of long-term survival in the 2 cohorts await further maturation of the data.CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in immunocompetent patients with PCNSL, HD-MTX plus rituximab compared with HD-MTX alone improves CR and overall survival rates.
    Neurology 06/2014; · 8.30 Impact Factor
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    ABSTRACT: Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3+3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.
    Autophagy 05/2014; 10(8). · 12.04 Impact Factor
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    ABSTRACT: Prolonged lymphopenia correlating with decreased survival commonly occurs among glioma patients undergoing radiation therapy (RT) and temozolomide (TMZ) treatment. To better understand the pathophysiology of this phenomenon, we prospectively monitored serum cytokine levels and lymphocyte subsets in 15 high-grade glioma patients undergoing combined radiation and TMZ (referred to as RT/TMZ) treatment. Sufficient data for analysis were acquired from 11 of the patients initially enrolled. Lymphocyte phenotyping data were obtained using cytofluorometric analysis and serum cytokine levels were measured using the a multiplex bead-based assays. Total lymphocyte counts (TLCs) were > 1000 cells per μL peripheral blood in 10/11 patients at baseline, but dropped significantly after treatment. Specifically, after RT/TMZ therapy, the TLCs were found to be < 500 cells/μL in 2/11 patients, 500-1000 cells/μL in 7/11 patients, and > 1000 cells/μL in the remaining 2 patients. Among residual mononuclear blood cells, we observed a proportional drop in B and CD4(+) T cells but not in CD8(+) T lymphocytes. Natural killer cells remained to near-to-baseline levels and there was a transient and slight (insignificant) increase in regulatory T cells (Tregs). The circulating levels of IL-7 and IL-15 remained low despite marked drops in both the total and CD4(+) T lymphocyte counts. Thus, patients with malignant glioma undergoing RT/TMZ treatment exhibit a marked decline in TLCs, affecting both CD4(+) T cells and B lymphocytes, in the absence of a compensatory increase in interleukin-7 levels. The failure to mount an appropriate homeostatic cytokine response may be responsible for the prolonged lymphopenia frequently observed in these patients.
    Oncoimmunology. 01/2014; 3(1):e27357.
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    ABSTRACT: Background Severe treatment-related lymphopenia (TRL) occurs commonly in many cancers and is associated with early tumor progression. Data is lacking as to whether this occurs in squamous cell head/neck cancer. Methods Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes. Results The median baseline TLC in 56 patients was 1660 cells/mm(3) which fell by 73% to 445 cells/mm(3) two months after initiating chemoradiation (p<0.0001). HPV- patients with TLC<500 cells/mm(3) at two months had significantly earlier disease progression than those with higher TLCs (HR 5.75, p=0.045). Conclusions: Baseline TLCs were normal but at two months ~60% of patients had severe TRL regardless of HPV status. Severe TRL in HPV- patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings which suggest that immune preservation is important in this cancer. Head Neck, 2013.
    Head & Neck 10/2013; · 2.83 Impact Factor
  • International journal of radiation oncology, biology, physics 08/2013; 86(5):809-810. · 4.59 Impact Factor
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    ABSTRACT: Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression. The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood-brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, blood-based biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific. This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors. This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.
    Journal of Neuro-Oncology 05/2013; · 3.12 Impact Factor
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    ABSTRACT: OBJECTIVES:: Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes. METHODS:: A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival. RESULTS:: A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P<0.00001), and 46% had TLC<500 cells/mm. Patients with TLC<500 cells/mm 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3 mo, P=0.03) and PFS (4.9 vs. 9.0 mo, P=0.15). Multivariate analysis revealed TLC<500 cells/mm to be an independent predictor of inferior survival (HR=2.879, P=0.001) along with baseline serum albumin (HR=3.584, P=0.0002), BUN (HR=1.060, P=0.02), platelet count (HR=1.004, P=0.005), and radiation planning target volume (HR=1.003, P=0.0006). CONCLUSIONS:: Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival.
    American journal of clinical oncology 05/2013; · 2.21 Impact Factor
  • Journal of Neuro-Oncology 03/2013; · 3.12 Impact Factor
  • Jian L Campian, Xiaobu Ye, Malcolm Brock, Stuart A Grossman
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    ABSTRACT: Background: This study sought to estimate the severity, etiology, and clinical importance of treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Methods: Serial lymphocyte counts and survival were analyzed retrospectively in 47 patients accounting for known prognostic factors. Results: Total lymphocyte counts (TLCs) were normal before therapy and did not change following neoadjuvant chemotherapy. Following radiation, TLC fell by 67% (median 500 cells/mm(3), p <.00001). Multivariate analysis revealed an association between severe TLC and survival (HR 1.70, 95% CI: 0.8-3.6). Conclusions: Rapid and severe lymphopenia occurred in 50% of patients following radiation which was associated with reduced survival.
    Cancer Investigation 02/2013; · 2.24 Impact Factor
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    ABSTRACT: Purpose: Severe treatment-related lymphopenia (TRL) occurs in 40% of patients with high grade gliomas (HGG) receiving glucocorticoids, temozolomide, and radiation. This occurs following radiation, persists for months, and is associated with reduced survival. As all three treatment modalities are lymphotoxic, this study was conducted to estimate the radiation dose that lymphocytes receive passing through the radiation field and if this could explain the observed TRL. Materials and Methods: A typical glioblastoma plan (8-cm tumor, 60 Gy/30 fractions) was constructed using the Pinnacle™ radiation planning system. Radiation doses to circulating cells (DCC) were analyzed using MatLab™. The primary endpoints were mean DCC and percent of circulating cells receiving ≥0.5 Gy. The model was also used to study how changes in target volumes (PTV), dose rates, and delivery techniques affect DCC. Results: The modeling determined that while a single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received ≥0.5 Gy. The mean DCC was 2.2 Gy and was similar for IMRT, 3D-conformal techniques, and different dose rates. Major changes in PTV size affected mean DCC and percent of circulating cells receiving ≥0.5 Gy. Conclusions: Standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Novel approaches are needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with HGG.
    Cancer Investigation 02/2013; 31(2):140-4. · 2.24 Impact Factor
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    ABSTRACT: Background The signal transduction pathways of epidermal growth factor receptor and Ras are both important in the growth of glioblastoma multiforme (GBM). We hypothesized that inhibition of both pathways would improve the survival time of patients with recurrent GBM.Methods Patients with recurrent/progressive GBM with 0-2 prior chemotherapy regimens received erlotinib 150 mg once daily and sorafenib 400 mg twice daily until progression. The primary endpoint was overall survival. Pharmacokinetic sampling was performed during cycle 1.ResultsThe median overall survival was 5.7 months. Progression-free survival at 6 months was 14%. Toxicity was manageable. Clearance of erlotinib was markedly enhanced by sorafenib.Conclusion The study did not meet its objective of a 30% increase in overall survival time compared with historical controls. Erlotinib and sorafenib have significant pharmacokinetic interactions that may negatively impact the efficacy of the combination regimen.
    Neuro-Oncology 01/2013; · 6.18 Impact Factor
  • Neuro-Oncology. 01/2013; 15(suppl 3):iii98-iii135.
  • Susannah Yovino, Stuart A Grossman
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    ABSTRACT: Lymphopenia is a common consequence of therapy for malignant glioma. Current standard therapy includes corticosteroids, temozolomide and radiation therapy, all of which are toxic to lymphocytes. The resulting immunosuppression has serious clinical consequences. Decreased lymphocyte counts can result in opportunistic infections, decreased efficacy of immunotherapy and reduced overall survival. The exact mechanisms underlying the association between decreased survival and lymphopenia in malignant glioma patients are unclear. However, as lymphocytes are key effector cells in the immune response to cancer, it is likely that depleting their numbers renders the immune system less effective at eliminating malignant cells. Currently, no strategies exist for the prevention or reversal of treatment-related immunosuppression in malignant glioma patients, although there are several promising theoretical approaches. This article reviews the current state of knowledge regarding the severity, etiology and possible consequences of treatment-related lymphopenia in patients with malignant glioma.
    CNS oncology. 11/2012; 1(2):149-154.
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    ABSTRACT: This study was conducted to assess the current pattern of use and the impact of available molecular predictive and prognostic biomarkers on clinical care in patients with glioblastoma (GBM). An online questionnaire consisting of 15 questions about the frequency of use and clinical utility of tissue-based molecular tests was distributed to 1,053 members of the Neuro-Oncology Community in the United States. A total of 320 responses (30.4 %) were collected. 73 respondents who did not see GBM patients were excluded from analysis. MGMT promoter methylation testing (MGMT-meth) was the most commonly requested (37.2; 95 % CI, 31-44), followed by EGFR amplification (22.7; 95 % CI, 18-28), co-deletion of 1p/19q (22.3 %), EGFR expression (21.5 %), P53 mutation (19.8 %), PTEN mutation or deletion (17.4 %), EGFRvIII mutation (12.1 %), IDH1/2 mutation (12.1 %), PDGFR (4.5 %), and PIK3CA (0.8 %). The perceived utility of these studies was variable between participants. A small percentage of respondents felt that any of the studies were "always" or "almost always" helpful in clinical decision making (MGMT-meth 10.9 %; range, 0-13.8 %), but more frequently "never" or "almost never" helpful (MGMT-meth 25.9 %; range, 25-54.7 %). 26.7 % reported not to routinely order any of these studies. Although molecular markers are frequently ordered for patients with GBM, only a minority of clinicians ordering these tests report that the results influence clinical decision-making. Molecular markers that are likely to affect patient care should be ordered with the goal to maximize benefit for patients and to avoid non-actionable results and additional costs.
    Journal of Neuro-Oncology 08/2012; 110(2):279-85. · 3.12 Impact Factor
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    ABSTRACT: Fifty-three patients with resected pancreatic adenocarcinoma were studied to determine if adjuvant chemo-radiation causes severe lymphopenia and if this is associated with adverse outcomes. Total lymphocyte counts (TLC) were normal in 91% before adjuvant chemo-radiation. Two months later, TLC fell by 63% (p < .0001) with 45% of patients having TLC < 500 cells/mm(3). Median survival in patients with low TLC was 14 versus 20 months (p = .048). Multivariate analysis revealed a significant association between treatment related lymphopenia and survival (HR 2.2, p = .014). Adjuvant chemo-radiation induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma.
    Cancer Investigation 07/2012; 30(8):571-6. · 2.24 Impact Factor
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    ABSTRACT: The poor prognosis for patients with glioblastoma (GB) heightens the importance of maintaining function throughout treatment. Hyperglycemia has been linked to poor neurological outcomes following stroke, traumatic brain and spinal cord injury. We hypothesized this may also be true following the resection of GB. We assessed associations with post-operative function with the goal of identifying modifiable factors in the peri-operative period with a particular focus on blood glucose levels. Independent associations with worse post-operative function included: patient age, pre-operative motor deficit, deep tumor location, post-operative motor deficit, and elevated mean peri-operative glucose. Interestingly, controlling for associated factors including dexamethasone dosing, patients with elevated peri-operative glucose levels were nearly twice as likely to have new post-operative neurological deficits. These results suggest, together with the broad literature supporting a role for hyperglycemia in neurological injury, that this may represent a modifiable factor in the peri-operative care of these patients.
    Journal of Clinical Neuroscience 05/2012; 19(7):996-1000. · 1.25 Impact Factor
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    ABSTRACT: BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. Cancer 2012. © 2012 American Cancer Society.
    Cancer 04/2012; · 5.20 Impact Factor
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    ABSTRACT: Therapies that disrupt or repair blood-brain barrier integrity can result in major changes in MRI images even when the tumor volume remains constant. Thus, a reliable blood-based tumor biomarker could significantly improve clinical care and research studies in these patients. This study was performed to assess plasma concentrations of glial fibrillary acidic protein (GFAP) in patients with high- and low-grade gliomas before and after debulking surgery. Pre-operative plasma was collected from 33 patients with radiation- and chemotherapy-naïve gliomas. Additional plasma was collected 24-48 h post-operatively from 23 of these patients. Plasma GFAP (pGFAP) concentrations were determined using an electrochemiluminescent immunoassay and were analyzed as a function of tumor grade, tumor GFAP expression, the integrity of the blood-brain barrier, and post-operative status. Detectable pGFAP levels (≥ 0.04 ng/mL) were found pre-operatively in 52 % of patients and post-operatively in 96 %. Detectable pGFAP was more common in patients with WHO grade IV (100 %) than WHO grade III (56 %) or WHO grade II gliomas (20 %). No patient with undetectable GFAP had WHO grade IV glioma. Higher pGFAP concentrations were also associated with contrast enhancement but not related to tumor GFAP expression. GFAP is commonly detected in the plasma of patients with high-grade gliomas. pGFAP levels rise rather than fall following debulking surgery which is probably a result of surgical trauma. GFAP remains a potentially informative plasma biomarker for gliomas. Longitudinal studies are required to correlate pGFAP levels with patient outcomes.
    Journal of Neuro-Oncology 04/2012; 109(1):123-7. · 3.12 Impact Factor

Publication Stats

4k Citations
965.73 Total Impact Points


  • 1988–2014
    • Johns Hopkins University
      • • Department of Radiology
      • • Department of Radiation Oncology and Molecular Radiation Sciences
      • • Department of Biomedical Engineering
      Baltimore, Maryland, United States
  • 2013
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
  • 2012
    • University of California, Irvine
      • Division of Hematology/Oncology
      Irvine, CA, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2011–2012
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
    • University of Texas Southwestern Medical Center
      • Division of Hematology/Oncology
      Dallas, TX, United States
  • 1987–2012
    • Johns Hopkins Medicine
      • • Sidney Kimmel Comprehensive Cancer Center
      • • Department of Neurology
      Baltimore, Maryland, United States
  • 2010
    • University of Pennsylvania
      • Department of Neurology
      Philadelphia, PA, United States
  • 2009
    • University of Washington Seattle
      • Division of General Internal Medicine
      Seattle, WA, United States
  • 2008
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
  • 2006
    • Vanderbilt University
      • Department of Neurological Surgery
      Nashville, MI, United States
  • 2003–2006
    • Regional Cancer Centre
      Tiruvananantapuram, Kerala, India
    • City of Hope National Medical Center
      Duarte, California, United States
    • Emory University
      Atlanta, Georgia, United States
    • Wake Forest University
      • Department of Neurosurgery
      Winston-Salem, North Carolina, United States
  • 2005
    • Moffitt Cancer Center
      Tampa, Florida, United States
  • 2004
    • Royal North Shore Hospital
      Sydney, New South Wales, Australia
  • 2000
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1997
    • Columbia University
      • Department of Neurology
      New York City, NY, United States