Faculty Bibliography

Dynamic contrast agent-enhanced perfusion magnetic resonance (MR) imaging provides physiologic information that complements the anatomic information available with conventional MR imaging. Analysis of dynamic data from perfusion MR imaging, based on tracer kinetic theory, yields quantitative estimates of cerebral blood volume that reflect the underlying microvasculature and angiogenesis. Perfusion MR imaging is a fast and robust imaging technique that is increasingly used as a research tool to help evaluate and understand intracranial disease processes and as a clinical tool to help diagnose, manage, and understand intracranial mass lesions. With the increasing number of applications of perfusion MR imaging, it is important to understand the principles underlying the technique. In this review, the essential underlying physics and methods of dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging are described. The clinical applications of cerebral blood volume maps obtained with perfusion MR imaging in the differential diagnosis of intracranial mass lesions, as well as the pitfalls and limitations of the technique, are discussed. Emphasis is on the clinical role of perfusion MR imaging in providing insight into the underlying pathophysiology of cerebral microcirculation

BACKGROUND AND PURPOSE: MR imaging characteristics of gliomatosis cerebri reiterate the diffuse nature of this tumor but are nonspecific and thus may pose a diagnostic challenge. Because perfusion MR imaging can provide a physiologic map of the microcirculation, we compared the measured relative cerebral blood volume (rCBV) at perfusion imaging with histopathologic findings in gliomatosis cerebri. MR spectroscopic findings were also reviewed. METHODS: Retrospective analysis was performed of conventional and perfusion MR images from seven patients with proved gliomatosis cerebri. The conventional MR images were evaluated for the presence or absence of contrast enhancement, necrosis, and extent of T2-weighted signal intensity abnormality. Dynamic contrast-enhanced T2*-weighted gradient-echo echo-planar images were acquired during the first pass of a bolus injection of gadopentetate dimeglumine. The rCBV was calculated by using nondiffusible tracer kinetics and expressed relative to normal-appearing white matter. Pathologic findings were reviewed in all patients and compared with the MR perfusion data. Multivoxel 2D chemical shift imaging proton MR spectroscopic data were available for three patients and single-voxel data for one patient. RESULTS: Conventional MR images showed diffuse abnormality in all cases and absence of contrast enhancement in all but one case. Average rCBV range was 0.75-1.26 (mean, 1.02 +/- 0.42 [SD]). MR spectroscopic data revealed spectra consistent with presence of tumoral disease. Histopathologic review showed absence of vascular hyperplasia in all specimens. CONCLUSION: The low MR rCBV measurements of gliomatosis cerebri are in concordance with the lack of vascular hyperplasia found at histopathologic examination; thus, perfusion MR imaging provides useful adjunctive information that is not available from conventional MR imaging techniques

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis

Human pathological conditions of the central nervous system (CNS) associated with angiogenesis (i.e. neovascularization) include neoplastic, as well as infectious, ischemic, and traumatic processes. Upregulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and tenascin-C (TN-C) is spatially and temporally related to neovascularization. Spatially, VEGF/VPF and TN-C are both found at the site of neovascularization, but they are not detected in areas of normal brain or in areas without neovascularization. Temporally, VEGF/VPF and TN-C are found at the peak of angiogenesis and are not detected when angiogenesis had ceased

Cap43 is a protein whose RNA is induced under conditions of severe hypoxia or prolonged elevations of intracellular calcium. Cap43 protein is expressed at low levels in normal tissues; however, in a variety of cancers, including lung, brain, melanoma, liver, prostate, breast, and renal cancers, Cap43 protein is overexpressed in cancer cells. The low level of expression of Cap43 in some normal tissues compared to their cancerous counterparts combined with the high stability of Cap43 protein and mRNA makes the Cap43 gene a new, important cancer marker. We hypothesize that the mechanism of Cap43 overexpression in cancer cells involves a state of hypoxia characteristic of cancer cells where the Cap43 protein becomes a signature for this hypoxic state

PURPOSE: Dynamic contrast-enhanced T2*-weighted MR imaging has been helpful in characterizing intracranial mass lesions by providing information on vascularity. Tumefactive demyelinating lesions (TDLs) can mimic intracranial neoplasms on conventional MR images, can be difficult to diagnose, and often result in surgical biopsy for suspected tumor. The purpose of this study was to determine whether dynamic contrast-enhanced T2*-weighted MR imaging can be used to distinguish between TDLs and intracranial neoplasms that share common features on conventional MR images. METHODS: We retrospectively reviewed the conventional and dynamic contrast-enhanced T2*-weighted MR images and medical records of 10 patients with tumefactive demyelinating disease that was diagnosed by either biopsy or strong clinical suspicion supported by laboratory evaluation that included CSF analysis and evoked potential tests. Twelve TDLs in 10 patients and 11 brain tumors that appeared similar on conventional MR images were studied. Relative cerebral blood volume (rCBV) was calculated from dynamic MR data and was expressed as a ratio to contralateral normal white matter. rCBV values from 11 patients with intracranial neoplasms with very similar conventional MR imaging features were used for comparison. RESULTS: The rCBV values of TDLs ranged from 0.22 to 1.79 (n = 12), with a mean of 0.88 +/- 0.46 (SD). The rCBV values of intracranial neoplasms ranged from 1.55 to 19.20 (n = 11), with a mean of 6.47 +/- 6.52. The difference in rCBV values between the two groups was statistically significant (P =.009). The difference in rCBV values between TDLs and primary cerebral lymphomas (n = 4) was less pronounced but was statistically significant (P =.005). CONCLUSION: Dynamic contrast-enhanced T2*-weighted MR imaging is a useful diagnostic tool in differentiating TDLs from intracranial neoplasms and may therefore obviate unnecessary surgical biopsy

OBJECT: A variant of C6 glioma cells, C6R-G/H cells express hygromycin phosphotransferase (HPT) and appear to have reduced tumorigenicity in the embryonic brain. The goal of this study was to investigate their reduced capacity to generate tumors in the adult rat brain. METHODS: Cell lines were implanted into rat brains and tumorigenesis was evaluated. After 3 weeks, all rats with C6 cells showed signs of neurological disease, whereas rats with C6R-G/H cells did not and were either killed then or allowed to survive until later. Histological studies were performed to analyze tumor size, malignancy, angiogenesis, and cell proliferation. Cells isolated from rat brain tumors were analyzed for mutation to HPT by testing their sensitivity to hygromycin. CONCLUSIONS: The results indicate that HPT suppresses tumor formation. Three weeks after implantation, only 44% of animals implanted with C6R-G/H cells developed tumors, whereas all animals that received C6 glioma cells developed high-grade gliomas. The C6R-G/H cells filled a 20-fold smaller maximal cross-sectional area than the C6 cells, and exhibited less malignant characteristics, including reduced angiogenesis, mitosis, and cell proliferation. Similar results were obtained in the brain of nude rats, indicating that the immune system did not play a significant role in suppressing tumor growth. The combination of green fluorescent protein (GFP) and HPT was more effective in suppressing tumorigenesis than either plasmid by itself, indicating that the GFP may protect against inactivation of the HPT. Interestingly. hygromycin resistance was lost in tumor cells that were recovered from a group of animals in which C6R-G/H cells formed tumors, confirming the correlation of HPT with reduced tumorigenicity