Faculty Bibliography

The mechanism of action of many chemotherapeutic agents targets the cell cycle. Recently, we demonstrated cytotoxic and other anti-tumor effects of flavopiridol, the first synthetic cyclin dependent kinase (CDK) inhibitor to enter clinical trials, on the murine GL261 glioma cell line in vitro (Newcomb et al., Cell Cycle 2003; 2:243). Given that flavopiridol has demonstrated anti-tumor activity in several human xenograft models, we wanted to evaluate it for anti-glioma activity in vivo in our established subcutaneous and intracranial GL261 experimental tumor models. In particular, the intracranial animal model recapitulates many of the histopathological and biological features of human high-grade glioma including both necrosis with pseudopalisading and invasion of the brain adjacent to tumor. Here we tested the activity of flavopiridol against tumors formed by GL261 cells, first as subcutaneous implants, and then in the intracranial model. We demonstrate efficacy of flavopiridol as a single modality treatment in delaying tumor growth in both animal models. We hypothesize that flavopiridol treatment induced tumor growth delay by two possible mechanisms involving growth arrest combined with recruitment of tumor cells to S-phase. Based on our findings, flavopiridol should be considered as a treatment approach for patients with high-grade glioma

BACKGROUND AND PURPOSE: Sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of conventional MR imaging in predicting glioma grade are not high. Relative cerebral blood volume (rCBV) measurements derived from perfusion MR imaging and metabolite ratios from proton MR spectroscopy are useful in predicting glioma grade. We evaluated the sensitivity, specificity, PPV, and NPV of perfusion MR imaging and MR spectroscopy compared with conventional MR imaging in grading primary gliomas. METHODS: One hundred sixty patients with a primary cerebral glioma underwent conventional MR imaging, dynamic contrast-enhanced T2*-weighted perfusion MR imaging, and proton MR spectroscopy. Gliomas were graded as low or high based on conventional MR imaging findings. The rCBV measurements were obtained from regions of maximum perfusion. Metabolite ratios (choline [Cho]/creatine [Cr], Cho/N-acetylaspartate [NAA], and NAA/Cr) were measured at a TE of 144 ms. Tumor grade determined with the three methods was then compared with that from histopathologic grading. Logistic regression and receiver operating characteristic analyses were performed to determine optimum thresholds for tumor grading. Sensitivity, specificity, PPV, and NPV for identifying high-grade gliomas were also calculated. RESULTS: Sensitivity, specificity, PPV, and NPV for determining a high-grade glioma with conventional MR imaging were 72.5%, 65.0%, 86.1%, and 44.1%, respectively. Statistical analysis demonstrated a threshold value of 1.75 for rCBV to provide sensitivity, specificity, PPV, and NPV of 95.0%, 57.5%, 87.0%, and 79.3%, respectively. Threshold values of 1.08 and 1.56 for Cho/Cr and 0.75 and 1.60 for Cho/NAA provided the minimum C2 and C1 errors, respectively, for determining a high-grade glioma. The combination of rCBV, Cho/Cr, and Cho/NAA resulted in sensitivity, specificity, PPV, and NPV of 93.3%, 60.0%, 87.5%, and 75.0%, respectively. Significant differences were noted in the rCBV and Cho/Cr, Cho/NAA, and NAA/Cr ratios between low- and high-grade gliomas (P <.0001,.0121,.001, and.0038, respectively). CONCLUSION: The rCBV measurements and metabolite ratios both individually and in combination can increase the sensitivity and PPV when compared with conventional MR imaging alone in determining glioma grade. The rCBV measurements had the most superior diagnostic performance (either with or without metabolite ratios) in predicting glioma grade. Threshold values can be used in a clinical setting to evaluate tumors preoperatively for histologic grade and provide a means for guiding treatment and predicting postoperative patient outcome

BACKGROUND AND PURPOSE: The measurement of relative cerebral blood volume (rCBV) and the volume transfer constant (K(trans)) by means of dynamic contrast-enhanced (DCE) perfusion MR imaging (pMRI) can be useful in characterizing brain tumors. The purpose of our study was to evaluate the utility of these measurements in differentiating typical meningiomas and atypical meningiomas. METHODS: Fifteen patients with pathologically confirmed typical meningiomas and seven with atypical meningiomas underwent conventional imaging and DCE pMRI before resection. rCBV measurements were calculated by using standard intravascular indicator dilution algorithms. K(trans) was calculated from the same DCE pMRI data by using a new pharmacokinetic modeling (PM) algorithm. Results were compared with pathologic findings. RESULTS: Mean rCBV was 8.02 +/- 4.74 in the 15 typical meningiomas and 10.50 +/- 2.1 in the seven atypical meningiomas. K(trans) was 0.0016 seconds(-1) +/- 0.0012 in the typical group and 0.0066 seconds(-1) +/- 0.0026 in the atypical group. The difference in K(trans) was statistically significant (P <.01, Student t test). Other parameters generated with the PM algorithm (plasma volume, volume of the extravascular extracellular space, and flux rate constant) were not significantly different between the two tumor types. CONCLUSION: DCE pMRI may have a role in the prospective characterization of meningiomas. Specifically, the measurement of K(trans) is of use in distinguishing atypical meningiomas from typical meningiomas

OBJECTIVE: To describe the pathological features of three very similar and unusual primary central nervous system tumors that are not readily recognized as conventional ependymomas but which, by ultrastructural examination, have an ependymomatous character. METHODS: Three distinctive tumors were found in a review of our files for cases of ependymoma. In each case, hematoxylin and eosin-stained sections were reviewed, and immunostains for epithelial membrane antigen, cytokeratin, vimentin, and glial fibrillary acidic protein were performed on formalin-fixed, paraffin-embedded sections. Electron microscopy was performed in each case. RESULTS: The tumors had a diffuse myxoid background, often containing tightly clustered cells that mimicked multinucleated giant cells, but lacking perivascular pseudorosettes or central lumen rosettes. Glial fibrillary acidic protein and vimentin immunostains did not reveal perivascular processes. Epithelial membrane antigen immunostains showed a dot-like cytoplasmic immunoreactivity in some cell clusters in two of the three cases. Cytokeratin was negative in all three cases. However, ultrastructurally, the cells of each tumor had extensive surface microvilli; the giant cell-like clusters had cells with extensive close appositions, some junctions, and, in two cases, lumina with microvilli. Two of the patients were adults (both with temporal lobe tumors), and one patient was 13 years old and had a cervical spinal cord intramedullary tumor. Each tumor was sharply circumscribed from adjacent central nervous system tissue but was not encapsulated. One of the cases in an adult was mitotically highly active; this tumor recurred locally 4 years after initial gross total excision. CONCLUSION: These tumors are unusual variants of ependymoma. This pattern of ependymoma is sufficiently distinctive to be recognized in hematoxylin and eosin stains once the architecture of the epithelioid clusters is appreciated

Mycosis fungoides is a malignant, cutaneous lymphoma of T-helper (TH or CD4+) cells. At presentation, the disease is usually limited to the skin, with lesions that resemble eczema or psoriasis. Neurologic involvement is uncommon. This case demonstrates the conventional MRI and dynamic contrast enhanced perfusion MRI findings in intracerebral mycosis fungoides. T1-weighted spin echo imaging demonstrated a lesion with slightly decreased signal within the body of the corpus callosum. The lesion was isointense with grey matter on axial T2-weighted imaging. Following administration of contrast, there was patchy heterogeneous enhancement. Multiple relative cerebral blood volume (rCBV) measurements were made and the minimum rCBV was 0.30 with the maximum rCBV being 1.61. The mean rCBV was 0.81 +/- 0.49 (average of 10 measurements and standard deviation)

Despite clear indications of their importance in lower organisms, the contributions of protein tyrosine phosphatases (PTPs) to development or function of the mammalian nervous system have been poorly explored. In vitro studies have indicated that receptor protein tyrosine phosphatase alpha (RPTPalpha) regulates SRC family kinases, potassium channels and NMDA receptors. Here, we report that absence of RPTPalpha compromises correct positioning of pyramidal neurons during development of mouse hippocampus. Thus, RPTPalpha is a novel member of the functional class of genes that control radial neuronal migration. The migratory abnormality likely results from a radial glial dysfunction rather than from a neuron-autonomous defect. In spite of this aberrant development, basic synaptic transmission from the Schaffer collateral pathway to CA1 pyramidal neurons remains intact in Ptpra(-/-) mice. However, these synapses are unable to undergo long-term potentiation. Mice lacking RPTPalpha also underperform in the radial-arm water-maze test. These studies identify RPTPalpha as a key mediator of neuronal migration and synaptic plasticity

Focal adhesion kinase (FAK) and hypoxia-inducible factor (HIF-1alpha) are both up-regulated in glioblastoma multiforme (GBMs), particularly in invasive zones. Because FAK may play an important role in the invasion of glioma cells into the surrounding brain, we sought an agent that causes down-regulation of FAK phosphorylation as a potential inhibitor of brain tumor invasion and growth. Geldanamycin (GA), a benzoquinone ansamycin antibiotic, binds to heat shock protein 90 (Hsp90) and interferes with its function. GA inhibits the proliferation of various non-glial cells and has anti-tumor activity. Moreover, GA blocks HIF-regulated transcription of VEGF and inhibits the VEGF-induced phosphorylation of FAK and migration of endothelial cells. Here, we tested the effect of GA on glioma cell migration in vitro and its potential to down-regulate HIF-1alpha induction. Our results demonstrate that GA (i) decreases U87MG, LN229, and U251MG glioma cell migration; (ii) reduces cell migration independent of p53 and PTEN status; (iii) prevents migration at non-toxic concentrations; (iv) reduces phosphorylation of FAK; and (v) inhibits cobalt chloride (CoCl(2))-mediated induction of HIF-1alpha in glioma cells. To the best of our knowledge, this is the first report showing that GA can inhibit phosphorylation of FAK concomitant with a decrease in cellular migration. One of the most clinically relevant aspects of this study is that GA interferes with the induction of HIF-1alpha that has been linked with glioma cell migration and angiogenesis. Given the fact that GA is a small lipophilic molecule capable of penetrating the blood brain barrier together with the data presented here provide a strong rationale for its use or its analogues in the treatment of highly invasive GBMs