Faculty Bibliography

An adenovirus, AdCDTK, expressing both bacterial cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSVTK) was constructed and introduced into glioma cells. AdCDTK selectively rendered glioma cells sensitive to both 5-fluorocytosine (5-FCyt) and ganciclovir (GCV) (termed AdCDTK/5-FCyt-GCV). AdCDTK/5-FCyt-GCV not only potently mediated apoptosis and the arrest of glioma cell growth in vitro, but also significantly increased the survival time of glioma-bearing rats as compared with controls. The 90-day survival time was observed in 50% of rats. Interferon-alpha (IFN-alpha) further enhanced the tumor cell killing of AdCDTK/5-FCyt-GCV. In the group of AdCDTK/5-FCyt-GCV/IFN-alpha, the average survival time was significantly increased, and the average tumor size was smaller than that in the group of AdCDTK/5-FCyt-GCV. Ninety-day survival increased from 50% in the group of AdCDTK/5-FCyt-GCV to 75% in the group of AdCDTK/5-FCyt-GCV/IFN-alpha. Complete tumor regression was observed in 50% of rats in the group of AdCDTK/5-FCyt-GCV/IFN-alpha. The data indicate that AdCDTK/5-FCyt-GCV induces glioma cell killing greater than that induced by either CD/5-FCyt or HSVTK/GCV alone. IFN-alpha synergistically enhances this effect by increasing apoptosis

In contrast with the prevailing view that most tumors and metastases begin as avascular masses, evidence is presented here that a subset of tumors instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumor but instead regresses, leading to a secondarily avascular tumor and massive tumor cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin. The expression patterns of the angiogenic antagonist angiopoietin-2 and of pro-angiogenic vascular endothelial growth factor (VEGF) suggest that these proteins may be critical regulators of this balance between vascular regression and growth

PURPOSE: To evaluate the role of T2*-weighted echo-planar perfusion imaging by using a first-pass gadopentetate dimeglumine technique to determine the association of magnetic resonance (MR) imaging-derived cerebral blood volume (CBV) maps with histopathologic grading of astrocytomas and to improve the accuracy of targeting of stereotactic biopsy. MATERIALS AND METHODS: MR imaging was performed in 29 patients by using a first-pass gadopentetate dimeglumine T2*-weighted echo-planar perfusion sequence followed by conventional imaging. The perfusion data were processed to obtain a color map of relative regional CBV. This information formed the basis for targeting the stereotactic biopsy. Relative CBV values were computed with a nondiffusible tracer model. The relative CBV of lesions was expressed as a percentage of the relative CBV of normal white matter. The maximum relative CBV of each lesion was correlated with the histopathologic grading of astrocytomas obtained from samples from stereotactic biopsy or volumetric resection. RESULTS: The maximum relative CBV in high-grade astrocytomas (n = 26) varied from 1.73 to 13.7, with a mean of 5.07 +/- 2.79 (+/- SD), and in the low-grade cohort (n = 3) varied from 0.92 to 2.19, with a mean of 1.44 +/- 0.68. This difference in relative CBV was statistically significant (P < .001; Student t test). CONCLUSION: Echo-planar perfusion imaging is useful in the preoperative assessment of tumor grade and in providing diagnostic information not available with conventional MR imaging. The areas of perfusion abnormality are invaluable in the precise targeting of the stereotactic biopsy

Angiogenesis is a crucial process in inflammatory reactions as well as in tumor implantation and growth. Tumors with high rates of invasion and recurrence such as gliomas, are specially dependent on neovascularization. This suggests that inhibition of angiogenesis might reduce the growth of these tumors. Thalidomide has been previously shown to inhibit angiogenesis induced by basic fibroblast growth factor in vivo, using the rabbit corneal micropocket assay. Therefore, the effect of thalidomide and a thalidomide analogue (cc-1069) on the proliferation in vitro of endothelial and glioma cells was tested. We observed a decrease in endothelial cell proliferation in cultures treated with thalidomide or the thalidomide analogue cc-1069. The analogue inhibited endothelial cell proliferation more efficiently than thalidomide. The inhibition occurred in association with a marked decrease in the activity of the nuclear factor SP1 and a moderate inhibition of NF-kappaB activation in nuclear extracts of endothelial cells. The drugs did not impair cell viability. There was no effect of thalidomide or the thalidomide analogue on the proliferation of the glioma cell line (U251) in vitro

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) is typically occult at angiography and fails to enhance on MR images. After observing angiographic abnormalities characterized by arteriovenous shunting and pathologic parenchymal blush in patients with AIDS-related PML, often in the absence of contrast enhancement on MR images, we hypothesized that there might be distinct changes in the cerebral microvasculature that account for the reduction in vascular transit time (arteriovenous shunting) in the absence of blood-brain barrier dysfunction. METHODS: The imaging studies and neuropathologic specimens of six patients with biopsy-proved PML were reviewed retrospectively. In all patients contrast-enhanced MR imaging and CT, followed by cerebral angiography, were performed before stereotactically directed biopsy. The angiograms were evaluated for the presence of vascular displacement, pathologic parenchymal blush, arteriovenous shunting, and neovascularity. The CT and MR studies were reviewed for the presence of enhancement of the PML lesions. Biopsy specimens were examined for the presence of necrosis, perivascular inflammation, and neovascularity. RESULTS: All patients had oligodendrocytic intranuclear inclusions diagnostic of PML, together with perivascular inflammation and neovascularity to a varying extent; no other neuropathologic processes were identified. Angiographic abnormalities, characterized by a pathologic parenchymal blush and arteriovenous shunting, were identified in four of the six patients. In only one of these cases, however, was abnormal enhancement identified on cross-sectional imaging studies (MR and CT), and this patient had florid perivascular inflammatory infiltrates histologically. CONCLUSION: The pathologic parenchymal blush and arteriovenous shunting seen angiographically in some patients with PML reflect small-vessel proliferation and perivascular inflammatory changes incited by the presence of the JC virus in infected oligodendrocytes

We present the case of a young man with a diagnosis of a childhood-onset pervasive developmental disorder who developed a progressive neurologic deterioration with persistent catatonia and right hemiparesis. On his initial evaluation approximately three years after the onset of mutism, he manifested right hemiparesis and catalepsy. Two years later, although catalepsy had subsided, motor function had deteriorated so that he could not use his hands to feed or dress himself. Oral-facialbuccal dyskinesia manifested by blepharospasm and grimacing were present constantly during waking hours. Quantitative electroencephalography demonstrated markedly decreased amplitude, a finding associated with catatonia. Left sural nerve biopsy indicated large axon cylinder degeneration. Left deltoid biopsy demonstrated perimysial fibrosis and type II fiber predominance. Although magnetic resonance imaging of the head without contrast was normal, positron emission tomography indicated hypometabolism of the right cerebral and the right cerebellar hemispheres. The patient continues to deteriorate despite a course of 25 electroconvulsive treatments. He continues to manifest criteria for catatonia including motoric immobility, mutism, and peculiarities of voluntary movement such as prominent grimacing. We suspect an inherited neurodegenerative disorder. Since catatonia is a treatable condition frequently associated with medical and neurological diseases, examination for the features of catatonia must be included in the assessment of patients with progressive brain degeneration. This report is an attempt to clarify the traits of a serious variant of progressive brain degeneration