David R. Checkley

Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined T1 and T2* contrast‐enhanced dynamic MR imaging

This study describes a method for imaging brain tumors that combines T1‐weighted (T1W) and T2*‐weighted (T2*W) dynamic contrast‐enhanced acquisitions. Several technical improvements have been made to produce high‐quality three‐dimensional mapping of endothelial permeability surface area product (k) and leakage space (vl), based on T1W data. Tumor blood volume maps are obtained from T2*W images with a complete removal of residual relaxivity effects. The method was employed in 15 patients with brain tumors (5 gliomas, 5 meningioma, and 5 acoustic schwannoma). Mean values of vl were significantly greater in acoustic schwannomas (53% ± 9%) than in meningiomas (34% ± 7%) or gliomas (22% ± 4%). Mean values of vl in meningioma were significantly greater than those of gliomas. Mean values of rCBV correlated closely with k. There was also a positive correlation between k and vl for pixels with low k values. This relationship was weaker in areas of high k. The highest mean ratios of k to vl (kep) were seen in two patients with glioblastoma, one patient with transitional cell meningioma, and one patient with angioblastic meningioma. Pixel‐by‐pixel comparison showed a strong correlation between rCBV and k in 11 of 15 patients. However, decoupling between pixel‐wise rCBV and k was found in four patients who had lesions with moderate k and vl elevation but no increase of rCBV. Results from this study suggest that in assessing the angiogenic activities in brain tumors it is advisable to monitor simultaneously changes in tumor blood volume, vessel permeability, and leakage space of tumor neovasculature. J. Magn. Reson. Imaging 2000;11:575–585.

Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging

ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time–concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T2*, which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R2* (=1/T2*) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.

Dynamic contrast-enhanced MRI of vascular changes induced by the VEGF-signalling inhibitor ZD4190 in human tumour xenografts

Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) was used to examine the acute effects of treatment with an inhibitor of vascular endothelial growth factor (VEGF) signaling. ZD4190 is an orally bioavailable inhibitor of VEGF receptor-2 (KDR) tyrosine kinase activity, which elicits broad-spectrum antitumour activity in preclinical models following chronic once-daily dosing. Nude mice, bearing established (0.5-1.0 mL volume) human prostate (PC-3), lung (Calu-6) and breast (MDA-MB-231) tumor xenografts, were dosed with ZD4190 (p.o.) using a 1 day (0 and 22 h) or 7 day (0, 24, 48, 72, 96,120,144, and 166 h) treatment regimen. DCEMRI was employed 2 h after the last dose of ZD4190, using the contrast agent gadopentetate dimeglumine. Dynamic data were fit to a compartmental model to obtain voxelwise K(trans), the transfer constant for gadopentetate into the tumor. K(trans) was averaged over the entire tumor, and a multi-threshold histogram analysis was also employed to account for tumor heterogeneity. Reductions in K(trans) reflect reductions in flow, in endothelial surface area, and/or in vascular permeability. A vascular input function was obtained for each mouse simultaneously with the tumor DCEMRI data. ZD4190 treatment produced a dose-dependent (12.5-100 mg x kg(-1) per dose) reduction in K(trans) in PC-3 prostate tumors. At 100 mg x kg(-1), the largest concentration examined, ZD4190 reduced K(trans) in PC-3 tumors by 31% following 2 doses (1 day treatment regimen; p < 0.001) and by 53% following 8 doses (7 day regimen; p < 0.001). Comparative studies in the three models using a showed similar reductions in K(trans) for the lung and breast tumors using the histogram analysis, although the statistical significance was lost when K(trans) was averaged over the entire tumor. Collectively these studies suggest that DCEMRI using gadopentetate may have potential clinically, for monitoring inhibition of VEGF signaling in solid tumors.

Effective blood signal suppression using double inversion-recovery and slice reordering for multislice fast spin-echo MRI and its application in simultaneous proton density and T2 weighted imaging†

To design a multislice double inversion‐recovery fast spin‐echo (FSE) sequence, with k‐space reordered by inversion time at slice position (KRISP) technique, to produce black‐blood vessel wall magnetic resonance imaging (MRI).

MRI studies of the neurotoxic effects of l-2-chloropropionic acid on rat brain

L-2-Chloropropionic acid (L-CPA) is selectively toxic to rat cerebellar granule cells; necrosis is first observed about 36 hours after administration of L-CPA (750 mg/kg p.o.) becoming more marked by 48 h. Parallel to the onset of cell death an increase in cerebellar water content and sodium concentration has been reported suggesting an oedematous reaction. In this study T(2)-weighted (T(2)WI) and diffusion weighted (DWI) imaging were used to detect the development of neuronal damage in the cerebellum of rats as a result of exposure to L-CPA. T(2)WI and DWI were not able to detect cerebellar abnormalities at 37 h post-dosing except for a slight swelling of the cerebellum. However, at 48 h post-dosing when cerebellar swelling and granule cell necrosis were marked, T(2)WI and DWI hyperintensities were observed in the cerebellum. Therefore, under the conditions of this study, MRI was not able to detect abnormalities in the cerebellum prior to the onset of the clinical signs of neurotoxicity or at the time of early histological changes. T(2)WI also suggested a marked increase in the amount of fluid in the ventricular system of rats 37 and 48 h after dosing; fluid accumulation was observed in all animals studied whether or not necrosis was detected. The occurrence of T(2)WI hyperintensity in the forebrain lead us to discover a new lesion in the habenular nucleus.

Misregistration artifacts in image-derived arterial input function in non-echo-planar imaging-based dynamic contrast-enhanced MRI.

To characterize misregistration artifact in arterial input function (AIF) pixels in dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) using a two‐dimensional non‐echo‐planar imaging (EPI)‐based gradient‐recalled echo (GRE) sequence.