The effects of cryoablation on renal cell carcinoma perfusion and glomerular filtration rate measured using dynamic contrast-enhanced MRI: a feasibility study.

AIM: To assess the effect of cryoablation on renal cell carcinoma (RCC) perfusion and single kidney (SK) glomerular filtration rate (GFR) using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Eighteen patients undergoing percutaneous cryoablation of a solitary RCC between August 2010 and November 2011 were evaluated with DCE-MRI immediately before and 1 month post-cryoablation. DCE-MRI data were acquired with 2 s temporal resolution in a coronal plane during the first pass of a 0.1 mmol/kg bolus dose of Gd-DOTA. Perfusion of the RCC (in ml/min/100 ml tissue) was estimated using a maximum slope technique. An index of SK GFR (SK-GFRi) was assessed using data acquired every 30 s for the following 3 min in the axial plane and analysed using Rutland-Patlak plots. This was compared to the GFR estimated by creatinine clearance (eGFR). RESULTS: Perfusion in the zone of ablation decreased significantly (p<0.001) from a mean of 98.0 ± 37.5 ml/min/100 ml pre-cryoablation to 11.6 ± 4.1 ml/min/100 ml post-cryoablation; a mean decrease of 88.2%. Functional analysis was performed in seventeen patients. eGFR was underestimated by SK-GFRi which decreased significantly in tumour-bearing (-31.7%, p = 0.011), but not in contralateral kidneys (-4.4%, p = 0.14). CONCLUSION: It is feasible to measure RCC perfusion pre- and post-cryoablation using DCE-MRI. The significant decrease within the zone of ablation suggests that this technique may be useful for assessment of treatment response. Further work is required to address the underestimation of eGFR by SK-GFRi and to validate the perfusion findings.

Overcoming the low relaxivity of gadofosveset at high field with spin locking.

The contrast agent gadofosveset, which binds reversibly to serum albumin, has a high longitudinal relaxivity at lower magnetic fields (≤3.0 T) but a much lower relaxivity at high fields. Spin locking is sensitive to macromolecular content; it is hypothesized that combining this technique with the albumin-binding properties of gadofosveset may enable increased relaxivity at high fields. In vitro measurements at 4.7 T found significantly higher spin-lock relaxation rates, R1ρ (1/T1ρ), when gadofosveset was serum albumin-bound than when unbound. R1ρ values for a nonbinding contrast agent (gadopentetate dimeglumine) in serum albumin were similar to those for unbound gadofosveset. R2 (1/T2) values were also significantly higher at 4.7 T for serum albumin-bound gadofosveset than for unbound. Spin locking at high field generates significantly higher relaxation rates for gadofosveset than conventional contrast agents and may provide a method for differentiating free and bound molecules at these field strengths.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Comparison of dynamic contrast-enhanced MRI and dynamic contrast-enhanced CT biomarkers in bladder cancer.

Dynamic contrast-enhanced MRI (DCE-MRI) is frequently used to provide response biomarkers in clinical trials of novel cancer therapeutics but assessment of their physiological accuracy is difficult. DCE-CT provides an independent probe of similar pharmacokinetic processes and may be modeled in the same way as DCE-MRI to provide purportedly equivalent physiological parameters. In this study, DCE-MRI and DCE-CT were directly compared in subjects with primary bladder cancer to assess the degree to which the model parameters report modeled physiology rather than artefacts of the measurement technique and to determine the interchangeability of the techniques in a clinical trial setting. The biomarker K(trans) obtained by fitting an extended version of the Kety model voxelwise to both DCE-MRI and DCE-CT data was in excellent agreement (mean across subjects was 0.085 ± 0.030 min(-1) for DCE-MRI and 0.087 ± 0.033 min(-1) for DCE-CT, intermodality coefficient of variation 9%). The parameter v(p) derived from DCE-CT was significantly greater than that derived from DCE-MRI (0.018 ± 0.006 compared to 0.009 ± 0.008, P = 0.0007) and v(e) was in reasonable agreement only for low values. The study provides evidence that the biomarker K(trans) is a robust parameter indicative of the underlying physiology and relatively independent of the method of measurement.

Enhancing fraction measured using dynamic contrast-enhanced MRI predicts disease-free survival in patients with carcinoma of the cervix.

BACKGROUND: There is a need for simple imaging parameters capable of predicting therapeutic outcome. METHODS: This retrospective study analysed 50 patients with locally advanced carcinoma of the cervix who underwent dynamic contrast-enhanced MRI before receiving potentially curative radiotherapy. The proportion of enhancing pixels (E(F)) in the whole-tumour volume post-contrast agent injection was calculated and assessed in relation to disease-free survival (DFS). RESULTS: Tumours with high E(F) had a significantly poorer probability of DFS than those with low E(F) (P=0.011). INTERPRETATION: E(F) is a simple imaging biomarker that should be studied further in a multi-centre setting.

Magnetic resonance imaging: advances in the investigation of atheromatous renovascular disease.

Prediction of renal functional outcome following revascularization procedures in atheromatous renovascular disease (ARVD) has remained a challenge. In considering the etiology of renal impairment, researchers have shifted their focus now from the influence of degree of renal artery stenosis (RAS) to the importance of intrinsic parenchymal damage caused by hypertension, atheroemboli, downstream cytokine and/or cholesterol crystal release, as well as indicators of tissue viability. Magnetic resonance (MR) imaging techniques and MR-based indices are able to provide a detailed assessment of the morphologic and functional aspects of the ARVD kidney. These indices look beyond "lumenology" and enable a better understanding of the parenchyma's physiology which may provide insight into predictors of outcome. This review summarizes the multipurpose benefits of MR in the assessment of ARVD.

Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.

PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

Estrogens decrease reperfusion-associated cortical ischemic damage: an MRI analysis in a transient focal ischemia model.

BACKGROUND AND PURPOSE: Early identification of irreversible cerebral ischemia is critical in defining strategies that influence neuronal survival after stroke. We used MRI to investigate the effects of 17beta-estradiol (E2) on the temporal evolution of focal ischemia. METHODS: Female rats were ovariectomized and divided into 1 of 2 groups: ovariectomy alone (OVX; n=4) or ovariectomy with estrogen replacement (OVX+E2; n=3). Both groups were then subjected to 1-hour middle cerebral artery occlusion (MCAO), with the use of a standardized endovascular monofilament model, followed by reperfusion. Sequential diffusion-weighted (DWI) and T2-weighted (T2WI) MRI were obtained during and after the MCAO. In separate groups of animals (n=5 for OVX and OVX+E2), cerebral blood flow (CBF) was measured by laser-Doppler methods before, during, and after occlusion. RESULTS: DWI detected similar lesion characteristics during MCAO in both groups. In the OVX group, lesion size did not change during reperfusion, but the signal intensity ratio increased early and stabilized during the latter stages. In contrast, DWI lesion size decreased during reperfusion in OVX+E2 rats by 50% to 60% (P<0.05), a size reduction almost exclusively limited to cortical regions. During MCAO, the signal intensity ratio in OVX+E2 rats was reduced compared with OVX rats. Reperfusion further attenuated the signal intensity ratio in cortical but not subcortical regions (P<0.05 versus OVX). T2WI revealed no lesions in either group during MCAO, but it detected lesion sizes similar to that of DWI during reperfusion. Furthermore, similar patterns and magnitudes of estrogen treatment-related decrease in lesion size were noted after reperfusion. T2WI demonstrated less intense signal intensity ratio changes in both groups compared with DWI. There were no differences in CBF between groups either during occlusion, early reperfusion, or 1 day after reperfusion. CONCLUSIONS: This study strongly suggests that estrogens selectively protect cortical tissue from ischemic damage during MCAO and that this protection is exerted during both the occlusion and reperfusion phases of ischemia and does not involve an estrogen-related change in CBF.

Nuclear magnetic resonance imaging measurements of water diffusion in the perfused hippocampal slice during N-methyl-D-aspartate-induced excitotoxicity.

Significant changes in the apparent diffusion coefficient of water are observed in nuclear magnetic resonance images of patients with acute ischemic stroke. However, the underlying mechanisms of these apparent diffusion coefficient changes are still unresolved. To analyse possible mechanisms, this study applies nuclear magnetic resonance imaging on a 14.1 Tesla narrow-bore magnet to quantitatively study water diffusion in individually perfused brain slices following exposure to N-methyl-D-aspartate excitotoxicity. The results indicate that brain slices have at least two distinct diffusing water compartments with apparent diffusion coefficients of 0.96+/-0.10x10(-3) mm2/s and 0.06+/-0.01x10(-3) mm2/s. When excitotoxicity was induced with N-methyl-D-aspartate, there was a significant decrease in the fraction of the fast diffusing water component in the slices (P<0.001). However, neither apparent diffusion coefficient changed significantly. Prior treatment with dizocilpine maleate (MK-801) depressed the effects of N-methyl-D-aspartate (P<0.01, ANOVA). The results demonstrate brain slice compartmental changes resulting from direct receptor stimulation and provide evidence for tissue water redistribution as an important mechanism for changes in apparent diffusion coefficient seen in clinical magnetic resonance imaging. The brain slice preparation affords a well-controlled method to study the mechanisms of tissue nuclear magnetic resonance contrast, bridging the gap between basic nuclear magnetic resonance studies and clinical magnetic resonance imaging. The brain slice model also offers a new way to test the utility of potential anti-stroke drugs using high field nuclear magnetic resonance imaging.

In vivo dynamics and distribution of intracerebroventricularly administered gadodiamide, visualized by magnetic resonance imaging.

Direct injections into the cerebroventricles have been extensively utilized in neurophysiological studies. Mapping the distribution of injectate after intracerebroventricular injection has been made only by post mortem analysis, and the dynamic distribution of injectate within the brain has not been well characterized. In this report, we apply contrast-enhanced magnetic resonance imaging to study the pharmacokinetics and extent of non-ionic gadodiamide transport into brain tissue in vivo after intracerebroventricular administration. The results indicate that intracerebroventricular injectate travels quickly throughout the ventricular system from the lateral ventricular site of injection to the fourth ventricle and foramina of Luschka and Magendie within 2 min. After this, the signal intensity begins to increase in the periventricular and paraventricular brain parenchyma. Contrast enhancement is visible 2 mm into the brain tissue from the ventricles. Quantitative analysis of the data shows that the transport of gadodiamide across the ependymal layer that lines the cerebrospinal fluid space characterized a rate constant of 0.066+/-0.017 min(-1). These results provide a better understanding of chemical transport and diffusion following direct injection into the cerebroventricles. They provide information on the in vivo dynamics of injectate after intracerebroventricular administration, and show that contrast enhanced magnetic resonance imaging may be used to more precisely define the target sites of chemicals after intracerebroventricular administration into the brain.

Dynamic contrast-enhanced magnetic resonance imaging of the breast combined with pharmacokinetic analysis of gadolinium-DTPA uptake in the diagnosis of local recurrence of early stage breast carcinoma.

RATIONALE AND OBJECTIVES: This study was designed to assess the efficacy of dynamic contrast-enhanced magnetic resonance imaging (MRI) of the breast combined with pharmacokinetic analysis of gadolinium (Gd)-DTPA uptake in the diagnosis of local recurrence of early stage breast carcinoma. METHODS: Fifty women treated with breast-conserving surgery and radiotherapy underwent breast MRI. Dynamic magnetic resonance data obtained at four preselected slice locations were analyzed to examine Gd-DTPA uptake based on a pharmacokinetic model using three parameters: wash-in rate, wash-out rate, and amplitude of uptake. Synthetic images were produced from the above parameters and their derivatives--maximum uptake and reciprocal of half the time to maximum. For each region of interest (ROI), median parameter values were calculated. The mean pixel signal intensity of each ROI was plotted against time, and an enhancement index was determined. RESULTS: Sixty ROIs were selected: 49 lesions were benign, and 11, malignant. Significant differences between benign and malignant lesions were found for the enhancement index (P < 0.0001), maximum uptake (P < 0.0001), amplitude of uptake (P < 0.0001), wash-in rate (P = 0.03), wash-out rate (P = 0.01), and the reciprocal of half the time to maximum (P = 0.0005). The respective sensitivities and specificities were as follows: for the enhancement index, 1.00 and 0.96; for maximum uptake, 1.00 and 0.96; for amplitude of uptake, 0.91 and 0.94; for wash-in rate 0.82 and 0.47; for wash-out rate 0.91 and 0.59; and for the reciprocal of half the time to maximum, 1.00 and 0.51. CONCLUSIONS: Dynamic scanning proved essential for the detection and differential diagnosis of local tumor recurrence. Pharmacokinetic analysis of Gd-DTPA uptake can be used to produce parametric images that retain the spatial resolution of the original images while providing additional information about lesion permeability and vascularity, and helping to avoid the observer variability associated with ROI analysis.

Tumour volume determination from MR images by morphological segmentation.

Accurate tumour volume measurement from MR images requires some form of objective image segmentation, and therefore a certain degree of automation. Manual methods of separating data according to the various tissue types which they are thought to represent are inherently prone to operator subjectivity and can be very time consuming. A segmentation procedure based on morphological edge detection and region growing has been implemented and tested on a phantom of known adjustable volume. Comparisons have been made with a traditional data thresholding procedure for the determination of tumour volumes on a set of patients with intracerebral glioma. The two methods are shown to give similar results, with the morphological segmentation procedure having the advantages of being automated and faster.

Dynamic MR imaging of invasive breast cancer: correlation with tumour grade and other histological factors.

The purpose of this study was to explore the association between dynamic MR enhancement characteristics and histopathological prognostic factors of invasive breast cancer. 53 women with primary invasive breast cancer underwent dynamic contrast enhanced breast MRI. Region of interest (ROI) analysis was performed on synthetic images obtained by kinetic modelling of the dynamic data. Operator-defined, large ROIs and computer-defined, 9-pixel ROIs were selected for each tumour. The relative increase in mean ROI pixel intensity was expressed in the form of enhancement ratios. Univariate and multivariate analyses were performed to explore the association of these ratios with standard histological factors, including tumour size, histopathological classification, histological grade, the presence of extensive in situ component and lymphovascular invasion, multifocal disease, and axillary lymph node status. All enhancement ratios showed significant differences between node-positive and node-negative tumours (max. p = 0.002). However, automated ROI ratios showed less overlap between node-positive and node-negative carcinomas than did large ROI ratios. A strongly significant association was observed between all automated ROI enhancement ratios and histological tumour grade (max. p = 0.001). Based on stepwise multiple regression analysis, node status and histological grade were the only histopathological factors with a significant independent effect on the enhancement characteristics. In summary, there is a strong association between dynamic MR characteristics and two important prognostic markers of invasive breast cancer, namely axillary node status and histological grade. This may allow MRI to be used in pre-operative predictions of tumour behaviour and biological activity.

Observer variability in the interpretation of contrast enhanced MRI of the breast.

The purpose of this study was to determine observer variability in the interpretation of contrast enhanced breast MRI and to evaluate its effect on the detection and differentiation of breast cancer. 57 women underwent breast MRI using spin echo and dynamic spoiled gradient-recalled sequences. Images were independently reviewed by three radiologists, two experienced and one newly trained in breast MRI interpretation. One of the experienced readers reviewed all examinations twice. Interpretation was based on lesion conspicuity, signal intensity, contour and enhancement pattern. Contrast uptake was assessed using region of interest (ROI) analysis of the dynamic images and calculation of a maximum enhancement index. Sensitivity and specificity in the diagnosis of malignancy irrespective of disease extent, and in the diagnosis of multifocal malignancy were estimated. 113 lesions were reported. Kappa coefficient estimations showed only a moderate agreement between the two experienced readers in rating morphological characteristics; the agreement between the newly trained reader and the experienced readers was even worse. Moreover, there was significant interobserver and intraobserver variation in the enhancement index measurements. Weighted kappa values indicated good agreement between the experienced readers in lesion and overall interpretation, excellent intraobserver agreement, but substantial disagreement between the newly trained reader and both experienced readers. All readers showed good sensitivity in cancer detection, but specificity was substantially lower. There is significant observer variability and a substantial learning curve in the interpretation of breast MRI, and variability in the ROI analysis of dynamic data. Further efforts to improve the reliability of ROI analysis and image interpretation are needed to help MRI realise its full potential in the clinical management of breast cancer.

Tracer kinetic modelling in MRI: estimating perfusion and capillary permeability.

The tracer-kinetic models developed in the early 1990s for dynamic contrast-enhanced MRI (DCE-MRI) have since become a standard in numerous applications. At the same time, the development of MRI hardware has led to increases in image quality and temporal resolution that reveal the limitations of the early models. This in turn has stimulated an interest in the development and application of a second generation of modelling approaches. They are designed to overcome these limitations and produce additional and more accurate information on tissue status. In particular, models of the second generation enable separate estimates of perfusion and capillary permeability rather than a single parameter K(trans) that represents a combination of the two. A variety of such models has been proposed in the literature, and development in the field has been constrained by a lack of transparency regarding terminology, notations and physiological assumptions. In this review, we provide an overview of these models in a manner that is both physically intuitive and mathematically rigourous. All are derived from common first principles, using concepts and notations from general tracer-kinetic theory. Explicit links to their historical origins are included to allow for a transfer of experience obtained in other fields (PET, SPECT, CT). A classification is presented that reveals the links between all models, and with the models of the first generation. Detailed formulae for all solutions are provided to facilitate implementation. Our aim is to encourage the application of these tools to DCE-MRI by offering researchers a clearer understanding of their assumptions and requirements.

MR-derived renal morphology and renal function in patients with atherosclerotic renovascular disease.

Appropriate selection of patients with atherosclerotic renovascular disease (ARVD) for revascularization might be improved if accurate non-invasive investigations were used to assess severity of pre-existing parenchymal damage. The purpose of this study was to evaluate the associations between magnetic resonance imaging (MRI)-measured renal morphological parameters and single-kidney glomerular filtration rate (GFR) in ARVD. Three-dimensional (3D)-MRI was performed on 35 ARVD patients. Renal bipolar length (BL), parenchymal volume, parenchymal (PT), and cortical thicknesses (CT) were measured in 65 kidneys. Thirteen kidneys were supplied by normal vessels, 13 had insignificant (<50%) renal artery stenosis (RAS), 33 significant (>or=50%) RAS, and six complete vessel occlusion. All patients underwent radioisotopic measurement of single-kidney GFR (isoSK-GFR). Overall, 3D parameters such as parenchymal volume were better correlates of isoSK-GFR (r=0.86, P<0.001) than BL (r=0.78, P<0.001), PT (r=0.63, P<0.001) or CT (r=0.60, P<0.001). Kidneys with >or=50% RAS did show significant reduction in mean CT compared to those supplied by normal vessel (5.67+/-1.63 vs 7.28+/-1.80 mm, P=0.002; 22.1% reduction) and an even greater loss of parenchymal volume (120.65+/-47.15 vs 179.24+/-86.90 ml, P<0.001; 32.7% reduction) with no significant reduction in BL. In a proportion of >or=50% RAS kidneys, a disproportionately high parenchymal volume to isoSK-GFR was observed supporting a concept of 'hibernating parenchyma'. 3D parameters of parenchymal volume are stronger correlates of isoSK-GFR than two-dimensional measures of BL, PT or CT. 3D morphological evaluation together with isoSK-GFR might be useful in aiding patient selection for renal revascularization. Kidneys with increased parenchymal volume to SK-GFR might represent a subgroup with the potential to respond beneficially to angioplasty.

Effect of temporal resolution on the diagnostic efficacy of contrast-enhanced MRI in the conservatively treated breast.

PURPOSE: Our goal was to assess the effect of image acquisition rate on the diagnostic efficacy of contrast-enhanced MRI in the conservatively treated breast. METHOD: Sixty-seven women, treated with breast-conserving surgery and radiotherapy for early-stage breast cancer, were imaged at 1.5 T using a dynamic contrast-enhanced sequence with a temporal resolution of 12 s. Enhancement was recorded over time for the dominant lesion in each patient. Data were subsequently removed to simulate various acquisition rates and the enhancement indexes of benign and malignant lesions were compared. RESULTS: Seventeen patients had confirmed local recurrence and 50 remained disease-free. There were significant differences in the enhancement indexes of benign and malignant lesions 24-264 s after contrast agent administration. Acquisition rate had a negligible effect upon diagnostic efficacy. CONCLUSION: Two image data sets collected before contrast agent administration and between 1.5 and 3.5 min afterward may be sufficient to differentiate recurrent and benign disease.