Faculty Bibliography

BACKGROUND:Invasion of tumor cells into adjacent brain parenchyma is a major cause of treatment failure in glioblastoma. Furthermore, invasive tumors are shown to have a different genomic composition and metabolic abnormalities that allow for a more aggressive GBM phenotype and resistance to therapy. We thus seek to identify those genomic abnormalities associated with a highly aggressive and invasive GBM imaging-phenotype. METHODS:We retrospectively identified 104 treatment-naïve glioblastoma patients from The Cancer Genome Atlas (TCGA) whom had gene expression profiles and corresponding MR imaging available in The Cancer Imaging Archive (TCIA). The standardized VASARI feature-set criteria were used for the qualitative visual assessments of invasion. Patients were assigned to classes based on the presence (Class A) or absence (Class B) of statistically significant invasion parameters to create an invasive imaging signature; imaging genomic analysis was subsequently performed using GenePattern Comparative Marker Selection module (Broad Institute). RESULTS:Our results show that patients with a combination of deep white matter tracts and ependymal invasion (Class A) on imaging had a significant decrease in overall survival as compared to patients with absence of such invasive imaging features (Class B) (8.7 versus 18.6 months, p < 0.001). Mitochondrial dysfunction was the top canonical pathway associated with Class A gene expression signature. The MYC oncogene was predicted to be the top activation regulator in Class A. CONCLUSION/CONCLUSIONS:We demonstrate that MRI biomarker signatures can identify distinct GBM phenotypes associated with highly significant survival differences and specific molecular pathways. This study identifies mitochondrial dysfunction as the top canonical pathway in a very aggressive GBM phenotype. Thus, imaging-genomic analyses may prove invaluable in detecting novel targetable genomic pathways.

OBJECTIVE: Glioblastoma (GBM) is a heterogeneous neoplasm with a small percentage of long-term survivors. Despite aggressive surgical resection and advances in radiotherapy and chemotherapy, the median survival for patients with GBM is 12-14 months. Factors associated with a favorable prognosis include young age, high performance status, gross resection >98%, non-eloquent tumor location and O6-methylguanine methyltransferase (MGMT) promoter methylation. We retrospectively analyzed the relationship of clinical, epidemiologic, genetic and molecular characteristics with survival in patients with GBM. METHODS: This retrospective analysis of overall survival looked at the outcomes of 480 patients diagnosed with GBM over 14 years at a single institution. Multivariate analysis was performed examining multiple patient characteristics. RESULTS: Median survival time improved from 11.8 months in patients diagnosed from 1995 to 1999 to 15.9 months in those diagnosed from 2005 to 2008. Factors associated with survivor groups were age, KPS, tumor resection, treatment received and early progression. 18 cancer-related genes were upregulated in short-term survivors and five genes were downregulated in short-term survivors. CONCLUSIONS: Epidemiologic, clinical, and molecular characteristics all contribute to GBM prognosis. Identifying factors associated with survival is important for treatment strategies as well as research for novel therapeutics and technologies. This study demonstrated improved survival for patients over time as well as significant differences among survivor groups.

OBJECTIVE: The purposes of this article are to review the American Board of Radiology requirements for practice quality improvement and to describe our approach to improving imaging utilization while offering a guide to implementing similar projects at other institutions, emphasizing the plan-do-study-act approach. CONCLUSION: There is increased emphasis on improving quality in health care. Our institution has undertaken a multiphase practice quality improvement project addressing the appropriate utilization of screening cervical spinal CT in an emergency department.

PURPOSE: The aim of this study was to determine the effect of a clinical education initiative on the appropriate utilization of screening cervical spine CT in the emergency department. The purpose was to assess if clinical education can produce stricter adherence to the ACR Appropriateness Criteria and improve the utilization of screening CT examinations in the emergency department. METHODS: Institutional review board approval was obtained for this HIPAA-compliant study. All adult patients presenting to a level 1 trauma center with blunt trauma prompting screening cervical spine CT were eligible. For each study, the requesting clinician completed a survey selecting all clinical indications. CT examinations were evaluated by a board-certified radiologist blinded to survey data. Results were compared with retrospective and prospective studies performed before the institution of the education initiative. RESULTS: Of the 388 cervical spine CT examinations performed, 12 (3.1%) were positive for acute cervical spine injury, compared to only 1.0% before the clinical education program (phase 2). Of the 376 examinations without injury, 13% met all 5 National Emergency X-Radiography Utilization Study criteria for nonimaging (down from 16.1% in phase 2), and 15 (4%) required no imaging when both National Emergency X-Radiography Utilization Study and abbreviated Canadian cervical spine rule criteria were applied. CONCLUSIONS: Implementation of a clinical education initiative resulted in improved adherence to ACR Appropriateness Criteria and improved clinical effectiveness of the studies by increasing fracture detection rate. Initiatives such as these could potentially influence imaging overutilization without burdening emergency department clinicians with excessive roadblocks to image ordering.

The aim of the study was to determine the antiangiogenic efficacy of vatalanib, sunitinib, and AMD3100 in an animal model of human glioblastoma (GBM) by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumor protein expression analysis. Orthotopic GBM-bearing animals were randomly assigned either to control group or vatalanib, sunitinib, and AMD3100 treatment groups. Following 2 weeks of drug treatment, tumor growth and vascular parameters were measured using DCE-MRI. Expression of different angiogenic factors in tumor extracts was measured using a membrane-based human antibody array kit. Tumor angiogenesis and invasion were determined by immunohistochemistry. DCE-MRI showed a significant increase in tumor size after vatalanib treatment. AMD3100-treated group showed a significant decrease in a number of vascular parameters determined by DCE-MRI. AMD3100 significantly decreased the expression of different angiogenic factors compared to sunitinib or vatalanib; however, there were no significant changes in vascular density among the groups. Sunitinib-treated animals showed significantly higher migration of the invasive cells, whereas in both vatalanib- and AMD3100-treated animals the invasive cell migration distance was significantly lower compared to that of control. Vatalanib and sunitinib resulted in suboptimal therapeutic effect, but AMD3100 treatment resulted in a significant reduction in tumor growth, permeability, interstitial space volume, and invasion of tumor cells in an animal model of GBM.

Various imaging techniques have been employed to evaluate blood-brain-barrier leakiness in brain tumors, as higher tumor vascular leakiness is known to be associated with higher grade and malignant potential of the tumor, and hence can help provide additional diagnostic and prognostic information. These imaging techniques range from routine post-contrast T1 -weighted images that highlight degree of contrast enhancement to absolute measurement of quantitative metrics of vascular leakiness employing complex pharmacokinetic modeling. The purpose of this article is to discuss the clinical applications of available imaging techniques, and in particular dynamic contrast-enhanced T1 -weighted MR imaging (DCE-MRI), to evaluate tumor vascular leakiness.