John C. Waterton

Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field.

At high and medium magnetic field, the transverse NMR relaxation rate (T-1(2)) of water proteins in blood is determined predominantly by the oxygenation state of haemoglobin. T-1(2) depends quadratically on the field strength and on the proportion of haemoglobin that is deoxygenated. Deoxygenation increases the volume magnetic susceptibility within the erythrocytes and thus creates local field gradients around these cells. From volume susceptibility measurements and the dependence of T-1(2) on the pulse rate in the Carr-Purcell-Meiboom-Gill experiment, we show that the increase in T-1(2) with increasing blood deoxygenation arises from diffusion of water through these field gradients.

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial.

BACKGROUND Magnetic resonance imaging (MRI) can noninvasively assess changes in atherosclerotic plaque morphology and composition. The ORION trial assessed the effects of rosuvastatin on carotid plaque volume and composition. METHODS The randomized, double-blind ORION trial used 1.5-T MRI to image carotid atherosclerotic plaques at baseline and after 24 months of treatment. Forty-three patients with fasting low-density lipoprotein cholesterol > or = 100 and < 250 mg/dL and 16% to 79% carotid stenosis by duplex ultrasound were randomized to receive either a low (5 mg) or high (40/80 mg) dose of rosuvastatin. RESULTS After 24 months, 33 patients had matched serial MRI scans to compare by reviewers blinded to clinical data, dosage, and temporal sequence of scans. Low-density lipoprotein cholesterol was significantly reduced from baseline in both the low- and high-dose groups (38.2% and 59.9%, respectively, both P < .001). At 24 months, there were no significant changes in carotid plaque volume for either dosage group. In all patients with a lipid-rich necrotic core (LRNC) at baseline, the mean proportion of the vessel wall composed of LRNC (%LRNC) decreased by 41.4% (P = .005). CONCLUSIONS In patients with moderate hypercholesterolemia, both low- and high-dose rosuvastatin were effective in reducing low-density lipoprotein cholesterol. Furthermore, rosuvastatin was associated with a reduction in %LRNC, whereas the overall plaque burden remained unchanged over the course of 2 years of treatment. These findings provide evidence that statin therapy may have a beneficial effect on plaque volume and composition, as assessed by noninvasive MRI.

Magnetic Resonance Imaging Measurements of the Response of Murine and Human Tumors to the Vascular-Targeting Agent ZD6126

Purpose: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors. Experimental Design: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space. Results: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6–48% at 50 mg/kg (n = 3)], 58–91% at 100 mg/kg (n = 4), and 11–93% at 200 mg/kg (n = 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n = 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P = 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m2 and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36–72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter- and intratumor coefficients of variation were 64 and 18%. Conclusions: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.

Improved 3D Quantitative Mapping of Blood Volume and Endothelial Permeability in Brain Tumors

We describe a new method to allow simultaneous mapping of endothelial permeability and blood volume in intracranial lesions. The technique is based on a tumor leakage profile during the first pass (fp) of contrast bolus calculated from the time‐dependent plasma‐contrast concentration function (PCCF) in three‐dimensional (3D) T1‐weighted dynamic studies. The performance of the method has been evaluated by comparing results with those obtained from more conventional methods in patients with primary brain neoplasms. The new permeability maps (kfp) are visually compatible with those calculated using a conventional multicompartment model (ktran). Quantitatively, the new maps are free from overestimation of ktran due to first‐pass effects. The new blood volume maps, which segment out the contamination of contrast leakage, agree closely with maps derived from susceptibility studies. The new method is fast, robust, and easy to perform. The method is suitable for use in clinical environments and is likely to be of benefit where longitudinal assessment of treatment response is required. J. Magn. Reson. Imaging 2000;12:347–357.

Imaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and Clinical Outcome

Tumors exhibit genomic and phenotypic heterogeneity, which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as CT density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death, and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks using PET, MRI, and other emerging molecular imaging techniques. These methods can establish whether one tumor is more or less heterogeneous than another and can identify subregions with differing biology. In this article, we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. Clin Cancer Res; 21(2); 249–57. ©2014 AACR.

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.

Comparative study into the robustness of compartmental modeling and model-free analysis in DCE-MRI studies

To evaluate and compare the reproducibility of the preferred phenomenological parameter IAUC60 (initial area under the time‐concentration curve [IAUC] defined over the first 60 seconds postenhancement) with the preferred modeling parameter (Ktrans), as derived using two simple models, in abdominal and cerebral data collected in typical Phase I clinical trial conditions.

Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), using gadopentetate dimeglumine, was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor-A (VEGF-A) signal transduction. Mice bearing PC-3 human prostate adenocarcinoma xenografts were treated with ZD6474, a VEGF receptor-2 (KDR) tyrosine kinase inhibitor. The pharmacokinetic parameter Ktrans was obtained, which reflects vascular permeability and perfusion. Mice were imaged immediately before, and following, acute treatment with ZD6474 (12.5–100 mg kg−1 orally). Whole tumours were analysed to obtain mean Ktrans values, and a histogram approach was used to examine intratumour heterogeneity. Reproducibility of Ktrans measurements gave inter- and intra-animal coefficients of variation of 40 and 18%, respectively. Dose-related reductions in Ktrans were evident following acute ZD6474 treatment. A Ktrans reduction of approximately 30% (P<0.001) was evident with 50 and 100 mg kg−1 ZD6474, a reduction of 12.5% (P<0.05) at 25 mg kg−1, and a reduction that did not reach statistical significance at 12.5 mg kg−1. A correlation between this dose response and the growth inhibitory effect of ZD6474 following chronic treatment was also observed. The histogram analysis of the data indicated that ZD6474-induced a Ktrans reduction in both the most enhancing rim and the core of PC-3 tumours. Dynamic contrast-enhanced magnetic resonance imaging may have a role in assessing the acute effects of VEGF signalling inhibition, in clinical dose-ranging studies.

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.