Faculty Bibliography

PURPOSE: To retrospectively determine whether relative cerebral blood volume (CBV) measurements can be used to predict clinical outcome in patients with high-grade gliomas (HGGs) and low-grade gliomas (LGGs) and specifically whether patients who have gliomas with a high initial relative CBV have more rapid progression than those who have gliomas with a low relative CBV. MATERIALS AND METHODS: Approval for this retrospective HIPAA-compliant study was obtained from the Institutional Board of Research Associates, with waiver of informed consent. One hundred eighty-nine patients (122 male and 67 female patients; median age, 43 years; range, 4-80 years) were examined with dynamic susceptibility-weighted contrast material-enhanced perfusion magnetic resonance (MR) imaging and were followed up clinically with MR imaging (median follow-up, 334 days). Log-rank tests were used to evaluate the association between relative CBV and time to progression by using Kaplan-Meier curves. Binary logistic regression was used to determine whether age, sex, and relative CBV were associated with an adverse event (progressive disease or death). RESULTS: Values for the mean relative CBV for patients according to each clinical response were as follows: 1.41 +/- 0.13 (standard deviation) for complete response (n = 4), 2.36 +/- 1.78 for stable disease (n = 41), 4.84 +/- 3.32 for progressive disease (n = 130), and 3.82 +/- 1.93 for death (n = 14). Kaplan-Meier estimates of median time to progression in days indicated that patients with a relative CBV of less than 1.75 had a median time to progression of 3585 days, whereas patients with a relative CBV of more than 1.75 had a time to progression of 265 days. Age and relative CBV were also independent predictors for clinical outcome. CONCLUSION: Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can be used to predict median time to progression in patients with gliomas, independent of pathologic findings. Patients who have HGGs and LGGs with a high relative CBV (>1.75) have a significantly more rapid time to progression than do patients who have gliomas with a low relative CBV

BACKGROUND AND PURPOSE: MR imaging can measure tissue perfusion and the integrity of the blood-brain barrier. We hypothesize that a combined measure of cerebral blood volume and vascular permeability using vascular-space occupancy (VASO) MR imaging, a recently developed imaging technique, is of diagnostic value for predicting tumor grade. MATERIALS AND METHODS: Thirty-nine patients (9 World Health Organization [WHO] grade II, 20 grade III, and 10 grade IV as determined by histopathologic assessment) were examined using VASO MR imaging, and regions-of-interest analysis was performed in tumoral regions, as well as in regions contralateral to the tumor. A Mann-Whitney test was conducted on the resulting VASO indices for a pairwise comparison across tumor grades. Nominal logistic regression was used to evaluate the use of VASO parameters for predicting group membership (by the percentage of correct classifications). RESULTS: The ratio between tumor side and contralateral side, VASO(Ratio), showed significant differences in all 3 of the pairwise comparisons (P < .01). VASO values in the tumoral regions, VASO(Tumor), showed significant difference between grade II and III and between II and IV but not between III and IV. Both VASO(Tumor) and VASO(Ratio) were found to be significant predictors of tumor grade, giving diagnostic accuracies of 66.7% and 71.8%, respectively. When testing to discriminate grade II tumors from higher grade tumors, the areas under the receiver operating characteristic curve were found to be 0.974 and 0.985 for VASO(Tumor) and VASO(Ratio), respectively. CONCLUSION: VASO MR imaging can be used for noninvasive tumor grade prediction based on cerebral blood volume and vascular permeability. VASO is more effective in separating WHO grade II from higher grades than in separating grade III from grade IV

OBJECTIVE: Diffusion tensor imaging (DTI) allows in vivo delineation of brainstem white matter tracts. The purpose of this study was to determine whether or not abnormalities of DTI metrics and fiber tractography correlate with neurological deficits and clinical status in patients with primary posterior fossa tumors. METHODS: A review of patients with primary posterior fossa tumors who underwent magnetic resonance imaging with DTI was performed. Patients were stratified by tumor type (well-circumscribed or infiltrating lesions). Fractional anisotropy (FA) color maps were used to localize the corticospinal tracts within the brainstem. FA, mean diffusivity, and eigenvalues were measured. Tractography was performed. Correlations between DTI metrics and clinical status and between DTI metrics and neurological examination findings were assessed within each patient group using Bonferroni correction for multiple comparisons. Comparisons of DTI metrics were also made between patient groups (infiltrating lesions versus well-circumscribed lesions). RESULTS: Thirty patients were studied (mean age, 14.1 yr; 16 male, 14 female). Eighteen patients had infiltrating lesions and 12 had well-circumscribed lesions. Twelve patients (four well-circumscribed and eight infiltrating) demonstrated motor weakness on physical examination (four right, three left, five bilateral). Patients with well-circumscribed lesions and weakness had higher mean diffusivity and lower FA in the contralateral corticospinal tract (P < 0.05). No such association was seen in patients with infiltrating tumors. In 102 total patient-years of follow-up (average follow-up period, 4.2 yr), 17 patients (six well-circumscribed and 11 infiltrating lesions) demonstrated complete response or stable disease and six patients (three well-circumscribed and three infiltrating lesions) demonstrated progressive disease or death. No differences were seen in terms of DTI metrics between patients with infiltrating lesions and those with well-circumscribed lesions. Patients with well-circumscribed tumors and a bad outcome had significantly lower transverse eigenvalue measures in the corticospinal tracts compared with those with a more favorable clinical status (P < 0.05). CONCLUSION: In patients with well-circumscribed primary posterior fossa masses, higher mean diffusivity and lower FA in the brainstem corticospinal tract are associated with contralateral motor deficits; lower transverse eigenvalue may be observed with an unfavorable clinical outcome

Geldanamycin is a naturally occurring benzoquinone ansamycin product of Streptomyces geldanus that binds the protein chaperone heat shock protein 90. As geldanamycin binds to heat shock protein 90 interfering with its function and heat shock protein 90 is overexpressed in many cancers, heat shock protein 90 has become a target for cancer therapy. As the geldanamycin analogue 17-allylamino-17-demethoxygeldanamycin has a favorable toxicity profile, it is being tested extensively in clinical trials in patients with advanced cancer. In this study, GL261 glioma cells from C57BL/6 mice were used to investigate the anti-tumor effect of 17-allylamino-17-demethoxygeldanamycin both in vitro and in vivo. Heat shock protein 90 inhibitors possess potent anti-proliferative activity, usually at low nanomolar ranges, owing to their pharmacological characteristics of binding tightly to heat shock protein 90, coupled with a slow dissociation rate. We found that 17-allylamino-17-demethoxygeldanamycin at doses as low as 200 nmol/l showed anti-tumor activity within 24 h of treatment. Treatment with 17-allylamino-17-demethoxygeldanamycin arrested GL261 cells in the G2 phase of the cell cycle associated with the downregulation of cyclin B1. Low doses of 17-allylamino-17-demethoxygeldanamycin significantly inhibited migration of GL261 cells within 16 h of treatment, concomitant with the downregulation of phosphorylated focal adhesion kinase and matrix metalloproteinase 2 secretion. Using an orthotopic glioma model with well-established intracranial tumors, 3 weekly cycles of 17-allylamino-17-demethoxygeldanamycin significantly reduced tumor volumes of treated animals compared with untreated controls (P=0.002). Given these promising results, clinical testing of 17-allylamino-17-demethoxygeldanamycin or other novel heat shock protein 90 inhibitors being developed should be considered for glioma patients whose tumors remain refractory to most current treatment regimens

PURPOSE: Rhabdoid tumors are rare but aggressive pediatric malignancies characterized by biallelic loss of INI1/hSNF5. Reintroduction of INI1 causes cell arrest and senescence in rhabdoid cells. Our purpose was to identify INI1-downstream genes and to determine their functional and therapeutic significance for rhabdoid tumors. EXPERIMENTAL DESIGN: INI1 downstream targets in rhabdoid cells were identified using a cDNA microarray analysis and the expression of selected INI1 targets was confirmed by quantitative reverse transcription-PCR, Western analysis, and/or immunohistochemical analysis of rhabdoid cells and primary rhabdoid tumors. To determine the functional significance of downstream targets, activated targets of INI1 were induced and repressed targets of INI1 were knocked down (by using RNA interference) in rhabdoid cells, in the absence of INI1. Consequence of altered expression of INI1 downstream targets for rhabdoid cell survival, cell cycle, and apoptosis was assessed. RESULTS: Microarray studies indicated that INI1 activated IFN-stimulated genes at early time points and senescence markers at late time points and repressed mitotic genes such as Polo like kinase 1 (PLK1), selectively in rhabdoid cells. Treatment of rhabdoid cells with recombinant IFNs resulted in induction of IFN-stimulated genes, G1 arrest, and flat cell formation. PLK1 was overexpressed in primary human and mouse rhabdoid tumors. RNA interference-mediated knock down of PLK1 in rhabdoid cells resulted in mitotic arrest, aberrant nuclear division, decreased survival, and induction of apoptosis. CONCLUSIONS: Targeting downstream effectors of INI1 such as IFN pathway and mitotic genes leads to antiproliferative effects in rhabdoid cells. IFN treatment and down-modulation of PLK1 constitute potential novel therapeutic strategies for rhabdoid tumors

PURPOSE: To determine if increased perfusion using dynamic susceptibility contrast perfusion MRI (DSC MRI) in gliomas may be predictive of 1p19q deletions. Loss of heterozygosity of chromosomes 1p and 19q confers responsiveness to chemotherapy improving survival in gliomas. MATERIALS AND METHODS: We retrospectively reviewed 16 patients who had DSC MRI and molecular studies of their excised gliomas for 1p19q deletions. Allelic status was assessed by loss of heterozygosity using polymerase chain reaction (PCR). DNA was extracted from paraffin curls of brain tumor sections and nail clippings. Relative cerebral blood volume (rCBV) measurements were then statistically compared with the presence of 1p and 19q deletions. RESULTS: Patients with 1p19q deletions (N = 7) demonstrated rCBV values of 10.54 +/- 2.93. Patients without 1p deletions (N = 9) had rCBV values of 4.84 +/- 2.4 (P = 0.012). Logistic regression demonstrated that rCBV was able to predict the presence of a 1p deletion to significance levels of 0.038 and 0.044, adjusted and not adjusted for age and sex, respectively. The kappa coefficient for the agreement between predicted deletion status using rCBV and the truedeletion status was 0.746 (P = 0.0028). Deletions of 19q alone, or together with 1p deletions, were not associated with high rCBV. CONCLUSION: Histopathologic, molecular, and imaging evidence supports increased neovascularity in gliomas with 1p deletions in this preliminary study. We propose a diagnostic algorithm to obtain molecular studies in gliomas demonstrating high rCBV.

Cell cycle progression requires precise expression and activation of several cyclins and cyclin-dependent kinases. Geldanamycin (GA) affects cell cycle progression in various kinds of cells. We analyzed GA-induced cell cycle regulation in glioblastoma cells. GA-induced G2 or M arrest in glioblastoma cells in a cell line-dependent manner. GA decreased the expression of Cdc2 and cyclin B1 in U87MG cells. And phosphorylated Cdc2 decreased along with Cdc2 in the GA-treated cells. This cell line showed G2 arrest after GA treatment. In contrast, GA failed to down-regulate these cell cycle regulators in U251MG cells. In U251MG cells, the cell cycle was arrested at M phase in addition to G2 by GA. Next, we analyzed the mechanism of the GA-induced regulation of Cdc2 and cyclin B1 in U87MG cells. Cdc2 and cyclin B1 were ubiquitinated by GA. MG132 abrogated the GA-induced decrease of Cdc2 and cyclin B1 indicating that these proteins were degraded by proteasomes. In conclusion, GA controls the stability of Cdc2 and cyclin B1 in glioblastomas cell species-dependently. Cdc2 and cyclin B1 might be responsible for the different responses of glioblastoma cell lines to GA