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Background and Purpose: Currently it is difficult to predict tumor response to anti-angiogenic therapy in individual patients. Our aim was to determine if ADC histogram analysis can stratify progression-free and overall survival in patients with newly diagnosed GBM treated "up-front" (ie, before tumor recurrence) with bevacizumab., Materials and Methods: Up-front bevacizumab-treated and control patients (n = 59 and 62, respectively) with newly diagnosed GBM were analyzed by using an ADC histogram approach based on enhancing tumor. Progression-free and overall survival was determined by using Cox proportional HRs and the Kaplan-Meier method with logrank and Wilcoxon tests., Results: For up-front bevacizumab-treated patients, lower ADC(L) was associated with significantly longer progression-free survival (median, 459 days for ADC(L) < 1200 versus 315 days for ADC(L) ≥ 1200 10(-6)mm(2)/s; P = .008, logrank test) and trended with longer overall survival (581 versus 429 days, P = .055). ADC values did not stratify progression-free or overall survival for patients in the control group (P = .92 and P = .22, respectively). Tumors with MGMT promoter methylation had lower ADC(L) values than unmethylated tumors (mean, 1071 versus 1183 10(-6)mm(2)/s; P = .01, 2-group t test)., Conclusions: Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with newly diagnosed GBM. Lower ADC is associated with tumor MGMT promoter methylation, which may, in part, account for the favorable outcome associated with low ADC(L) tumors.

Although the effects of bevacizumab on magnetic resonance images (MRIs) of recurrent glioblastoma multiforme (GBM) are well documented, to our knowledge, no studies have explicitly quantified the volumetric changes resulting from initial treatment, nor have there been studies examining the ability for volumetric changes in conventional MRI to predict progression-free survival (PFS) and overall survival (OS). In the current study, we retrospectively examined volumetric changes on conventional MRI scans in 84 patients with recurrent GBM. MRIs were obtained before (mean, 11 days) and after (mean, 42 days) treatment with bevacizumab. The volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal intensity, the volume of contrast enhancement, and the ratio of the 2 were quantified for each patient before and after initial treatment. Results demonstrated that initial treatment with bevacizumab resulted in a significant decrease in both the volume of abnormal FLAIR signal and the volume of contrast enhancement. Initial, residual, and change in FLAIR volume were not predictive of PFS or OS. Initial contrast-enhancing volume was predictive of PFS but not OS. The pretreatment relative nonenhancing tumor ratio, defined as the ratio of FLAIR to contrast-enhancing volume, was found to be predictive of both PFS and OS.

Purpose: This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity., Patients and Methods: Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison., Results: The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials., Conclusion: Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

The contribution of radiology to brain tumor research is unknown. We sought to determine how the proportion of neuro-oncologic publications generated by radiology departments has changed and if there is an association with NIH funding levels. Therefore we searched The National Library of Medicine's PubMed database for all articles published on brain neoplasms from 1996 to 2007. Country and department of origin and NIH grant support were noted for each article. Approximately 10% of brain tumor publications originated from radiology departments, ranking third among medical specialties. NIH funding for this research grew from less than 20% in 1996 to more than 50% in 2007. Overall NIH funding levels rose approximately 2.5 fold during this time. The U.S. was the dominant producer of brain tumor publications, and the gap between the U.S. and the rest of the world grew over the study period. Thus a substantial proportion of brain tumor publications originate from radiology departments, and the percentage of this research that is funded by the NIH has grown significantly during a period of increasing NIH budgets.

Current therapies for glioblastoma (GBM) target bulk tumor through measures such as resection and radiotherapy. However, recent evidence suggests that targeting a subset of tumor cells, so-called cancer stem cells, may be critical for inhibiting tumor growth and relapse. The subventricular zone (SVZ), which lines the ventricles of the brain, is thought to be the origin for the majority of neural stem cells and potentially cancer stem cells. Therefore, we assessed the relationship between tumor contact with the SVZ as determined by MRI, cancer stem cell gene expression and survival in 47 patients with GBM. Using DNA microarrays, we found that genes associated with cancer stem cells were not over-expressed in tumors contacting the SVZ. Contact with the SVZ trended with shorter survival (median 358 versus 644, P = 0.066). Over-expression of CD133 (prominin-1) and maternal embryonic leucine zipper kinase (MELK) was associated with shorter survival, whereas mitogen activated protein kinase 8 (MAPK8) was associated with longer survival (P values 0.008, 0.005 and 0.002 respectively). Thus we found no evidence of a stem-cell derived genetic signature specific for GBM in contact with the SVZ, but there was a relationship between stem cell gene expression and survival. More research is required to clarify the relationship between the SVZ, cancer stem cells and survival.

The human visual pathways that are specialized for object recognition stretch from lateral occipital cortex (LO) to the ventral surface of the temporal lobe, including the fusiform gyrus. Plasticity in these pathways supports the acquisition of visual expertise, but precisely how training affects the different regions remains unclear. We used functional magnetic resonance imaging to measure neural activity in both LO and the fusiform gyrus in radiologists as they detected abnormalities in chest radiographs. Activity in the right fusiform face area (FFA) correlated with visual expertise, measured as behavioral performance during scanning. In contrast, activity in left LO correlated negatively with expertise, and the amount of LO that responded to radiographs was smaller in experts than in novices. Activity in the FFA and LO correlated negatively in experts, whereas in novices, the 2 regions showed no stable relationship. Together, these results suggest that the FFA becomes more engaged and left LO less engaged in interpreting radiographic images over the course of training. Achieving expert visual performance may involve suppressing existing neural representations while simultaneously developing others.

We report a case of a 5-year-old boy with intractable epilepsy who underwent therapeutic corticectomy. Histopathologic findings within the resection specimen included severe cortical dysplasia associated with abundant subpial and intraparenchymal Rosenthal fibers in a large right frontal lesion that merged into the basal ganglia. Rosenthal fiber proliferation may represent a reactive process, are frequent in pilocytic astrocytomas, and are a defining feature of Alexander disease. There was no evidence of neoplasm or leukodystrophy in this case. Genetic analysis of the specimen showed a few previously reported polymorphisms but no mutation in the GFAP gene. This case is unique among several hundred cortical resection specimens that we have studied, including numerous cases of severe cortical dysplasia.

Purpose: To determine if apparent diffusion coefficient (ADC) histogram analysis can stratify progression-free survival in patients with recurrent glioblastoma multiforme (GBM) prior to bevacizumab treatment., Materials and Methods: The study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. Bevacizumab-treated and control patients (41 per cohort) diagnosed with recurrent GBM were analyzed by using whole enhancing tumor ADC histograms with a two normal distribution mixture fitting curve on baseline (pretreatment) magnetic resonance (MR) images to generate ADC classifiers, including the overall mean ADC as well as the mean ADC from the lower curve (ADC(L)). Overall and 6-month progression-free survival (as defined by the Macdonald criteria) was determined by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test., Results: For bevacizumab-treated patients, the hazard ratio for progression by 6 months in patients with less than versus greater than mean ADC(L) was 4.1 (95% confidence interval: 1.6, 10.4), and there was a 2.75-fold reduction in the median time to progression. For the control patients, there was no significant difference in median time to progression for the patients with low versus high ADC(L) (hazard ratio, 1.8; 95% confidence interval: 0.9, 3.7). For bevacizumab-treated patients, pretreatment ADC more accurately stratified 6-month progression-free survival than did change in enhancing tumor volume at first follow-up (73% vs 58% accuracy, P = .034)., Conclusion: Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with recurrent GBM., ((c) RSNA, 2009.)

Purpose: To determine the difference in gene expression between completely versus incompletely enhancing glioblastoma multiforme (GBM)., Materials and Methods: Gene expression was determined for 52 newly diagnosed GBMs by using DNA microarrays, and the relationship to enhancement pattern and survival was analyzed. This study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained., Results: Thirty-eight percent (20 of 52) of GBMs were incompletely enhancing (IE). The expression of eight genes was increased more than twofold in IE GBM when compared with completely enhancing (CE) GBM. Among these were tight junction protein-2 (2.2-fold increase, P = .019), and the oligodendroglioma markers oligodendrocyte lineage transcription factor 2 (2.4-fold increase, P = .029) and Achaete-scute complex-like 1 (ASCL1; 2.7-fold increase, P = .023). The expression of 71 genes showed relative overexpression in CE when compared with IE GBM. These included several proangiogenic and edema-related genes, including vascular endothelial growth factor (2.1-fold, P = .005) and neuronal pentraxin-2 (3.0-fold, P = .029). Several genes associated with primary GBM were overexpressed in CE tumors, whereas ASCL1, which is associated with secondary GBM, was overexpressed in IE tumors. Many genes overexpressed in IE GBM were associated with longer survival, whereas several genes overexpressed in CE GBM correlated with shortened survival., Conclusion: The enhancement pattern divides GBM in two groups with differing prognoses. By comparing gene expression between IE and CE GBMs, it was possible to identify genes that may affect magnetic resonance imaging features of edema and enhancement, and genes whose expression levels are predictive of both improved and shortened survival., ((c) RSNA, 2008.)

Glioblastoma multiforme (GBM) are morphologically heterogeneous tumors, with varying amounts of necrosis, and edema. Previous studies have shown that treatments incorporating the VEGF antibody bevacizumab can reduce edema and tumor burden in GBM. Additionally it has been suggested that bevacizumab regimen treatment reduces the percent of tumoral necrosis. Therefore we sought to (1) determine the time course of change in necrosis, tumor, and edema volume in patients who respond to bevacizumab regimen treatment and (2) determine if GBM that progress following a response to bevacizumab regimen treatment are morphologically different from their appearance at prior tumor progression. Therefore, we retrospectively assessed tumor, necrosis, and edema volumes on MRI scans from 15 patients with recurrent GBM who responded to bevacizumab regimen treatment, and had extended (>7 month) follow-up. We found that the median time to best tumor response was 158 days (range, 16-261, SD = 63). The median best response was 72.1% reduction in tumor volume and 72.8% reduction in peritumoral edema. Most tumors (77.8%) showed resolution of necrotic areas. The relative reduction of edema and necrosis was sustained, even in patients (n = 7) who developed tumor progression. Thus the mean ratio of edema-to-tumor volume at progression on bevacizumab regimen treatment was 38.4% lower than that for the same tumors seen on progression scans following prior chemotherapy. The percentage of necrotic tumor also was diminished following progression on bevacizumab regimen treatment. These findings illustrate the time course of changes in edema and tumor volume with prolonged bevacizumab regimen treatment, and support the conclusion that the morphology of recurrent GBM following bevacizumab regimen therapy is distinct from that on other chemotherapy.

Bevacizumab in combination with chemotherapy is now being studied for the treatment of malignant gliomas. However, the risk of intracranial hemorrhage has limited its use in patients requiring full anticoagulation for venous thrombosis. To assess the safety of using anticoagulation with bevacizumab, we conducted a retrospective review of our patients who were treated with bevacizumab while receiving anticoagulation. We reviewed their medical records and imaging for signs of hemorrhage. In total, we had 21 patients who received anticoagulation and bevacizumab concurrently for a median time of 72 days. Eighteen patients had adequate anticoagulation for venous thrombosis. There were no frank lobar hemorrhages in any patient. Three patients had small, intraparenchymal hemorrhages on MRI, but only one patient actually developed symptoms due to the hemorrhage. None of these patients had residual neurological deficits from the hemorrhages. Two more patients had evidence of a minor increase in signal on noncontrast T1-weighted sequence, presumed to be petechial hemorrhages, without any clinical sequelae or progression. In contrast, seven patients who had symptomatic hemorrhages from bevacizumab were not on any anticoagulation. In this retrospective review, anticoagulation did not lead to any major hemorrhages and does not appear to be a contraindication for starting bevacizumab therapy.

Purpose: Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability. VEGF inhibition reduces edema and tumor burden in some patients with malignant glioma, whereas others show no response. The role of VEGF expression in edema production and the relationship to survival is not well understood., Experimental Design: Using DNA microarray analysis, we examined VEGF and related gene expression in 71 newly diagnosed malignant gliomas and analyzed the relationship to edema and survival., Results and Conclusions: VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P<0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P<0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P=0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P<0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.

Purpose: To prospectively use 3.0-T breath-hold high-spatial-resolution contrast material-enhanced magnetic resonance (MR) angiography with highly accelerated parallel acquisition to image the supraaortic arteries of patients suspected of having arterial occlusive disease., Materials and Methods: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant study. Eighty patients (44 men, 36 women; age range, 44-90 years) underwent contrast-enhanced MR angiography of the head and neck at 3.0 T with an eight-channel neurovascular array coil. By applying a generalized autocalibrating partially parallel acquisition algorithm with an acceleration factor of four, high-spatial-resolution (0.7 x 0.7 x 0.9 mm = 0.44-mm(3) voxels) three-dimensional contrast-enhanced MR angiography was performed during a 20-second breath hold. Two neuroradiologists evaluated vascular image quality and arterial stenoses. Interobserver variability was tested with the kappa coefficient. Quantitation of stenosis at MR angiography was compared with that at digital subtraction angiography (DSA) (n = 13) and computed tomographic (CT) angiography (n = 12) with Spearman rank correlation coefficient (R(s))., Results: Arterial stenoses were detected with contrast-enhanced MR angiography in 208 (reader 1) and 218 (reader 2) segments, with excellent interobserver agreement (kappa = 0.80). There was a significant correlation between contrast-enhanced MR angiography and CT angiography (R(s) = 0.95, reader 1; R(s) = 0.87, reader 2) and between contrast-enhanced MR angiography and DSA (R(s) = 0.94, reader 1; R(s) = 0.92, reader 2) for the degree of stenosis. Sensitivity and specificity of contrast-enhanced MR angiography for detection of arterial stenoses greater than 50% were 94% and 98% for reader 1 and 100% and 98% for reader 2, with DSA as the standard of reference. Vascular image quality was sufficient for diagnosis or excellent for 97% of arterial segments evaluated., Conclusion: By using highly accelerated parallel acquisition, the described 3.0-T contrast-enhanced MR angiographic protocol enabled visualization and characterization of the majority of supraaortic arteries, with diagnostic or excellent image quality (97% of arterial segments) and diagnostic values comparable with those obtained by using CT angiography and DSA for detection of arterial stenoses., ((c) RSNA, 2007.)

Background and Purpose: For patients with malignant gliomas, clinical data-including age, perioperative Karnofsky Performance Status (KPS), and tumor resection-and tumor imaging features-including necrosis and edema-have been found to correlate with survival. The purpose of this study was to assess the validity of these results and determine whether other imaging features are useful in predicting survival., Methods: We analyzed the relationship between 15 imaging variables obtained from contrast-enhanced MR imaging scans and survival in patients with grade III (n = 43) and grade IV (n = 110) glioblastoma multiforme (GBM) gliomas. Image analysis was performed by 2 neuroradiologists who were blinded to clinical data. The Kaplan-Meier method was used to estimate survival probabilities. Univariable Cox models were used to assess the impact of imaging features on survival. A recursive partitioning analysis also was performed., Results: As expected, age and KPS scores had significant prognostic value for both tumor grades. The extent of resection was not a statistically meaningful predictor of survival. For GBM, univariable analysis revealed the following imaging features to be significant, (hazard ratios in parentheses): noncontrast-enhancing tumor (nCET, 0.55), edema (1.62), satellites (1.74), and multifocality (4.34). For grade III tumors, the Cox hazard ratio for necrosis was 4.43 (P = .014) and correlated with a poor outcome and survival rates comparable to GBM patients. Lack of nCET, multifocality, and satellite lesions also were correlated with shortened survival., Conclusion: Of 15 tumor imaging features in GBM patients, only nCET, edema, and multifocality/satellites are statistically significant prognostic indicators. The survival advantage of nCET is a novel finding.

A phosphorylated tau epitope specific for paired helical filaments in Alzheimer's disease is recognized by monoclonal antibody PHF-1. Healthy adult brains lack the PHF-1 epitope (PHF-1 tau), but it is transiently expressed by immature neurons during development. We have found that proliferating SH-SY5Y human neuroblastoma cells also express PHF-1 tau. Consistent with the recent finding that cell-cycle-dependent kinases can phosphorylate tau in vitro, flow cytometry showed that mitotic SH-SY5Y cells were up to 18-fold more PHF-1 immunoreactive than nonmitotic cells. On immunoblots, PHF-1 tau in mitotic and nonmitotic cells also was strikingly different. First, mitosis induced a prominent PHF-1 reactive band at 120 kDa, which likely accounted for the large increase in PHF-1 signal seen at mitosis. Although the size of the 120-kDa band is consistent with it being the high-molecular-weight form of tau, other antibodies to tau did not recognize it. Second, mitosis caused a hyperphosphorylation of the PHF-1 immunoreactive tau band normally seen at 50 kDa. In mitotic cells this band had an increased intensity and molecular weight. Alkaline phosphatase treatment abolished tau M(r) heterogeneity, verifying that the variations in mobility were due to phosphorylation. These data show that cell-cycle-dependent hyperphosphorylation of tau occurs in intact cells, and they support the hypothesis that aberrant activity of cell-cycle-dependent kinases may contribute to tau phosphorylation and PHF formation in Alzheimer's disease.

Neuritogenesis and synapse formation are transient phenomena mediated in part by filopodial attachments (Tsui, Lankford, and Klein, Proc. Natl. Acad. Sci. 82:8256-8260 1985). The attachments can be labeled by antisera against adherons, adhesive microparticles isolated from cell culture media (Tsui, Schubert, and Klein, J. Cell Biol. 106:2095-2108 1988). Here, two monoclonal antibodies raised against adherons have been found to recognize transiently expressed membrane antigens of developing avian retina. Early in development, monoclonal antibody (mAb) AD1 stained antigens that spanned the entire tissue. With time, immunoreactivity became restricted to optic fiber, ganglion cell, and inner plexiform layers. Immunoblots of embryonic day (E) 13 retina showed a broad band at 66-72 kD for particulate fractions and a fine band at 70 kD for soluble fractions. The particulate forms disappeared as retinas matured, but the soluble form did not. mAb AD2 initially labeled retina antigens of optic fiber, ganglion cell, and inner plexiform layers (IPL). Labeling in the plexiform layer showed discrete lamina. Immunoreactivity first appeared at E9, peaked at E15, and then disappeared shortly after hatching. In isolated cells, AD2 labeled small cell surface aggregates. Cytoarchitectural studies, using whole-mount transmission electron microscopy, showed AD2 antigen in cell surface microfilaments, including some that joined filopodia together. The adheron antigens recognized by mAbs AD1 and AD2 thus were (1) topographically restricted; (2) associated with cell surfaces; and (3) developmentally down-regulated. This pattern suggests a role in developmentally transient cell surface phenomena, such as neurite extension or junction biogenesis.