Implementing diffusion-weighted MRI for body imaging in prospective multicentre trials: current considerations and future perspectives.

For body imaging, diffusion-weighted MRI may be used for tumour detection, staging, prognostic information, assessing response and follow-up. Disease detection and staging involve qualitative, subjective assessment of images, whereas for prognosis, progression or response, quantitative evaluation of the apparent diffusion coefficient (ADC) is required. Validation and qualification of ADC in multicentre trials involves examination of i) technical performance to determine biomarker bias and reproducibility and ii) biological performance to interrogate a specific aspect of biology or to forecast outcome. Unfortunately, the variety of acquisition and analysis methodologies employed at different centres make ADC values non-comparable between them. This invalidates implementation in multicentre trials and limits utility of ADC as a biomarker. This article reviews the factors contributing to ADC variability in terms of data acquisition and analysis. Hardware and software considerations are discussed when implementing standardised protocols across multi-vendor platforms together with methods for quality assurance and quality control. Processes of data collection, archiving, curation, analysis, central reading and handling incidental findings are considered in the conduct of multicentre trials. Data protection and good clinical practice are essential prerequisites. Developing international consensus of procedures is critical to successful validation if ADC is to become a useful biomarker in oncology. KEY POINTS: • Standardised acquisition/analysis allows quantification of imaging biomarkers in multicentre trials. • Establishing "precision" of the measurement in the multicentre context is essential. • A repository with traceable data of known provenance promotes further research.

Imaging atherosclerosis in rheumatoid arthritis: evidence for increased prevalence, altered phenotype and a link between systemic and localised plaque inflammation.

In rheumatoid arthritis (RA), chronic inflammation is thought to drive increased cardiovascular risk through accelerated atherosclerosis. It may also lead to a more high-risk plaque phenotype. We sought to investigate carotid plaque phenotype in RA patients using Dynamic Contrast-Enhanced MRI (DCE-MRI) and Fludeoxyglucose Positron Emission Tomography(FDG-PET). In this pilot study, RA patients and age/sex-matched controls were evaluated for cardiovascular risk factors and carotid plaque on ultrasound. Subjects with plaque >2 mm thick underwent DCE-MRI, and a subgroup of patients had FDG-PET. Comparison of MRI findings between groups and correlation between clinical, serological markers and imaging findings was undertaken. 130 patients and 62 controls were recruited. Plaque was more prevalent in the RA group (53.1% vs 37.0%, p = 0.038) and was independently associated with IL6 levels (HR[95%CI]: 2.03 [1.26, 3.26] per quartile). DCE-MRI data were available in 15 patients and 5 controls. Higher prevalence of plaque calcification was noted in RA, despite similar plaque size (73.3% vs 20%, p = 0.04). FDG-PET detected plaque inflammation in 12/13 patients scanned and degree of inflammation correlated with hs-CRP (r = 0.58, p = 0.04). This study confirms increased prevalence of atherosclerosis in RA and provides data to support the hypothesis that patients have a high-risk plaque phenotype.

Tumour biomechanical response to the vascular disrupting agent ZD6126 in vivo assessed by magnetic resonance elastography.

BACKGROUND: Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo. METHODS: In this study, MRE was used to quantify (kPa) the absolute value of the complex shear modulus |G*|, elasticity Gd and viscosity Gl of SW620 human colorectal cancer xenografts before and 24 h after treatment with either 200 mg kg(-1) of the vascular disrupting agent ZD6126 (N-acetylcolchinol-O-phosphate) or vehicle control, and the data were compared with changes in water diffusivity measured by diffusion-weighted magnetic resonance imaging. RESULTS: A heterogeneous distribution of |G*|, Gd and Gl was observed pre-treatment with an intertumoral coefficient of variation of 13% for |G*|. There were no significant changes in the vehicle-treated cohort. In contrast, ZD6126 induced a significant decrease in the tumour-averaged |G*| (P<0.01), Gd (P<0.01) and Gl (P<0.05), and this was associated with histologically confirmed central necrosis. This reduction in tumour viscoelasticity occurred at a time when no significant change in tumour apparent diffusion coefficient (ADC) was observed. CONCLUSIONS: These data demonstrate that MRE can provide early imaging biomarkers for treatment-induced tumour necrosis.

Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI.

BACKGROUND: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. METHODS: Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. RESULTS: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls. CONCLUSION: Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies.

False-negative MRI biomarkers of tumour response to targeted cancer therapeutics.

BACKGROUND: Non-invasive quantitative imaging biomarkers are essential for the evaluation of novel targeted therapeutics. Before deployment in clinical trials, such imaging biomarkers require qualification, typically through pre-clinical identification of imaging-pathology correlates. METHODS: First, in investigating imaging biomarkers of invasion, the response of orthotopic murine PC3 prostate xenografts to the Src inhibitor saracatinib was assessed using susceptibility contrast MRI. Second, the longitudinal response of chemically induced rat mammary adenocarcinomas to the VEGFR2 inhibitor vandetanib was monitored by intrinsic susceptibility MRI, to identify the time window of transient vascular normalisation. RESULTS: No significant differences in fractional blood volume (%), vessel calibre (µm), native T(1) (ms) or apparent water diffusion coefficient were determined, despite reduced expression of activated Fak and paxillin in the saracatinib cohort. Treatment with vandetanib elicited a 60% antitumour response (P<0.01), 80% inhibition in vessel density (P<0.05) and reduction in hypoxia (P<0.05). There was, however, no significant change in tumour baseline R(2)* (s(-1)) or carbogen-induced ΔR(2)* with treatment. CONCLUSION: Reporting negative imaging biomarker responses is important, to avoid the risk of clinical trials using the same biomarkers being undertaken with a false expectation of success, and the abandonment of promising new therapeutics based on a false-negative imaging biomarker response being mistaken for a true-negative.

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.

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.

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.

Multiple-bolus dynamic contrast-enhanced MRI in the pancreas during a glucose challenge.

PURPOSE: To assess the feasibility of multiple-bolus dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in the pancreas; to optimize the analysis; and to investigate application of the method to a glucose challenge in type 2 diabetes. MATERIALS AND METHODS: A 4-bolus DCE-MRI protocol was performed on five patients with type 2 diabetes and 11 healthy volunteers during free-breathing. Motion during the dynamic time series was corrected for using a model-driven nonlinear registration. A glucose challenge was administered intravenously between the first and second DCE-MRI acquisition in all patients and in seven of the healthy controls. RESULTS: Image registration improved the reproducibility of the DCE-MRI model parameters across the repeated bolus-acquisitions in the healthy controls with no glucose challenge (eg, coefficient of variation for K(trans) improved from 38% to 28%). Native tissue T(1) was significantly lower in patients (374 +/- 68 msec) compared with volunteers (519 +/- 41 msec) but there was no significant difference in any of the baseline DCE-MRI parameters. No effect of glucose challenge was observed in either the patients or healthy volunteers. CONCLUSION: Multiple bolus DCE-MRI is feasible in the pancreas and is improved by nonlinear image registration but is not sensitive to the effects of an intravenous glucose challenge.

Measurement and visualisation of focal cartilage thickness change by MRI in a study of knee osteoarthritis using a novel image analysis tool.

We describe the application of a novel analysis method that provides detailed maps of changes in cartilage thickness measured from MRI scans for individuals and cohorts of patients together with regional measures. A cohort of osteoarthritis patients was imaged using a 1.0 T MR scanner over a 36-month period. Hyaline cartilage was manually segmented from a three-dimensional (3D) spoiled gradient-echo sequence with fat suppression. Representative outlines of the bone surfaces of the distal femur and proximal tibia were automatically generated from T2 weighted images using statistical models of the shape and appearance of the bones. Cartilage thickness was measured from a dense set of points representing the bony surface. The models of the bones provided a common frame of reference, relative to which change maps were generated and aggregated across the cohort and anatomically corresponding subregions of the joint to be identified. In the reproducibility arm involving six patients, the thickness of cartilage had coefficients of variation of 2.66% within the tibiofemoral joint and 2.94% within the medial femoral condyle region. In the 9 patients (6 female, 3 male) who completed the 36-month study, the most striking observation was that lack of change in global measures of cartilage thickness concealed substantial focal changes. Specifically, the cartilage thickness within the tibiofemoral joint decreased by 0.85% per annum (95% CI -2.13% to 0.45%) with the medial femoral condyle as the region with the most significant change, decreasing by 2.43% per annum (uncorrected 95% CI -4.31% to 0.51%).

Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3-6 months' observation using advanced image analysis of 3T MRI?

PURPOSE: Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1-2 years duration. We hypothesized that smaller, shorter duration, "Proof of Concept" (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur. METHODS: Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)> or =25 kg/m(2), symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m(2), with eight index knees graded as Kellgren-Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF x ThCtAB), with changes in other regions considered as secondary endpoints. RESULTS: Anatomical mal-alignment ranged from -1.9 degrees to 6.3 degrees , with mean 0.9 degrees . With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF x ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was -2.1% [95% confidence interval (CI) (-4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (-2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT x ThCtAB) at 6 month follow-up (-1.5%, 95% CI [-2.9, -0.2]), but was not significant at the 5% level after correction for multiple comparisons. CONCLUSIONS: The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed.

Effects of AZD2171 and vandetanib (ZD6474, Zactima) on haemodynamic variables in an SW620 human colon tumour model: an investigation using dynamic contrast-enhanced MRI and the rapid clearance blood pool contrast agent, P792 (gadomelitol).

The effect of two novel therapeutic agents on tumour haemodynamics was investigated using a fast dynamic contrast-enhanced (DCE)-MRI protocol (0.5 s/image) sensitive to signal changes in both the vascular input function and tumour during the administration of the macromolecular rapid clearance blood pool agent (MM-RCBPA), gadomelitol (P792, Vistarem). This enabled simultaneous measurement of the tumour blood flow per unit volume of tissue (F/V(T), mL/s/mL), the fractional plasma volume (V(p), %), and the permeability surface area product per unit volume of tissue (PSrho, s(-1)) in subcutaneous SW620 human colorectal tumour xenografts grown in nude rats before and after (at 0 and 22 h; imaging at 24 h) acute treatment with AZD2171 (3 mg/kg) and vandetanib (ZD6474, Zactima; 50 mg/kg), which have inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase. MRI was performed at 4.7 T using a single-slice, modified, T(1)-weighted, spoiled gradient-echo technique. Both compounds reduced gadomelitol uptake into the tumour. AZD2171 and vandetanib, respectively, (a) greatly reduced PSrho to 19.7 +/- 9.5% and 28.9 +/- 14.1% of baseline (P = 0.007 and P = 0.02), (b) markedly reduced V(p) to 31.2 +/- 19.1% and 54.8 +/- 21.2% of baseline (P = 0.015 and P = 0.09), and (c) had no significant effect on F/V(T). There was no significant difference between groups treated with AZD2171 and vandetanib when each variable was compared. The reductions in PSrho and V(p) are consistent with inhibition of VEGF signalling. AZD2171 (3 mg/kg) and vandetanib (50 mg/kg) were also found to produce a comparable chronic inhibition of SW620 tumour growth (89% for both). This study shows that DCE-MRI using an MM-RCPBA can be used to distinguish tumour vascular flow, volume, and permeability surface area product in a tumour model, and enables the acute effects of VEGF signalling inhibition to be examined in detail.

MR measurement of articular cartilage thickness distribution in the hip.

OBJECTIVE: To develop a method to determine the distribution of articular cartilage in the hip and to evaluate the potential of the method in a study of normal weight-bearing effects in asymptomatic young volunteers. DESIGN: Six volunteers were scanned after periods of standing and lying supine, using 3D gradient-echo magnetic resonance imaging (MRI). The protocol was repeated for two successive weeks to determine reproducibility. The femoral and acetabular cartilage layers were segmented as a single unit and thickness distribution maps were calculated using a spherical bone model as a frame of reference. Thickness maps were combined over the population using the bone model and post-weight-bearing and post-resting maps were compared. RESULTS: Mean thickness values were compared using an analysis of variance and a significant increase in cartilage thickness of 0.05 mm (P=0.02) was observed. The reproducibility of the method, assessed using test-retest coefficient of variation was 2.5%. CONCLUSIONS: The technique is reproducible, sensitive to sub-millimetre changes in thickness and may be useful in monitoring changes due to disease progression in patients with arthritis of the hip.

Magnetic resonance imaging (MRI) of articular cartilage in knee osteoarthritis (OA): morphological assessment.

OBJECTIVE: Magnetic resonance imaging (MRI) is a three-dimensional imaging technique with unparalleled ability to evaluate articular cartilage. This report reviews the current status of morphological assessment of cartilage with quantitative MRI (qMRI), and its relevance for identifying disease status, and monitoring progression and treatment response in knee osteoarthritis (OA). METHOD: An international panel of experts in MRI of knee OA, with direct experience in the analysis of cartilage morphology with qMRI, reviewed the existing published and unpublished data on the subject, and debated the findings at the OMERACT-OARSI Workshop on Imaging technologies (December 2002, Bethesda, MA) with scientists and clinicians from academia, the pharmaceutical industry and the regulatory agencies. This report reviews (1) MRI pulse sequence considerations for morphological analysis of articular cartilage; (2) techniques for segmenting cartilage; (3) semi-quantitative scoring of cartilage status; and (4) technical validity (accuracy), precision (reproducibility) and sensitivity to change of quantitative measures of cartilage morphology. RESULTS: Semi-quantitative scores of cartilage status have been shown to display adequate reliability, specificity and sensitivity, and to detect lesion progression at reasonable observation periods (1-2 years). Quantitative assessment of cartilage morphology (qMRI), with fat-suppressed gradient echo sequences, and appropriate image analysis techniques, displays high accuracy and adequate precision (e.g., root-mean-square standard deviation medial tibia=61 microl) for cross-sectional and longitudinal studies in OA patients. Longitudinal studies suggest that changes of cartilage volume of the order of -4% to -6% occur per annum in OA in most knee compartments (e.g., -90 microl in medial tibia). Annual changes in cartilage volume exceed the precision errors and appear to be associated with clinical symptoms as well as with time to knee arthroplasty. CONCLUSIONS: MRI provides reliable and quantitative data on cartilage status throughout most compartments of the knee, with robust acquisition protocols for multi-center trials now being available. MRI of cartilage has tremendous potential for large scale epidemiological studies of OA progression, and for clinical trials of treatment response to structure modifying OA drugs.

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.

Measurement of cartilage volumes in rheumatoid arthritis using MRI.

MRI is a valuable imaging modality for assessment of the articular cartilage in rheumatoid arthritis (RA) and is potentially of use in monitoring disease progression and response to therapy. In this study, we investigated the sources of error in volume measurements obtained by segmentation of MR images of knee cartilage in patients with RA and followed cartilage volume in a group of RA patients for 12 months. 23 RA patient volunteers were recruited for knee imaging. Six subjects were imaged at baseline only, six were imaged at baseline and again within an hour in the same imaging session, six subjects were imaged at baseline and 7 days, and 17 subjects were imaged at baseline, 4+/-2 months and 12 months. Imaging was performed at 1.0 T using a three-dimensional spoiled gradient-echo sequence with fat-suppression. Manual image segmentation was performed once or twice on the lateral tibial, medial tibial, patellar and femoral compartment by either one or two segmenters. Coefficients of variation (CoV) for repeated volume measurement of total cartilage were 2.2% (same segmenter, same scan), 5.2% (different segmenter, same scan), 4.9% (same segmenter, different scan, same session), and 4.4% (same segmenter, different scan, different session). Over the 12 month duration of the study there was no significant change in total cartilage volume, nor were there significant changes in volume in any individual compartment. This measurement technique is reproducible, but any net change in cartilage volume over 1 year is very small.

Ultrasound assessment of tendons in asymptomatic volunteers: a study of reproducibility.

The purpose was to evaluate the inter-visit, inter-observer and intra-observer variation of quantitative and qualitative tendon examinations in vivo for a cohort of asymptomatic volunteers. Eleven healthy male subjects were recruited. The following tendons were assessed by ultrasonography: Achilles tendon, patellar tendon, triceps tendon, extensor pollicis longus, flexor carpi radialis and supraspinatus. For each tendon a quantitative measurement of tendon size was made at a predefined anatomical location. Two experienced sonologists, blind to one another's findings, evaluated each of the tendons independently. Each tendon was evaluated on two occasions 1 week apart. No difference was found to be attributed to variation in tendon size between visits. Inter-observer variation was a source of error with intra-subject, inter-visit measurements proving more reproducible. There was some significant variation between observers. This variation was more marked with some tendon measures than others. Inter-observer variation for triceps, flexor carpi radialis and supraspinatus was most marked. Minimum detectable change in tendons varied from 13 to 57% depending on the plane of scanning and the tendon being examined. Good reproducibility of quantitative tendon measurements can be achieved within a study using two observers by following a defined scanning protocol. However, it is recommended that the same observer perform serial assessments. The data allow minimal detectable changes in tendon size to be calculated.

Magnetic resonance imaging measurement of knee cartilage volume in a multicentre study.

OBJECTIVE: To investigate the variability between different high-field scanners in magnetic resonance imaging (MRI) measurement of knee cartilage volume in healthy female volunteers. METHODS: Five volunteers had both knees scanned using three different MRI scanners. Cartilage volume in each compartment was measured from the images by image segmentation. The data were analysed using analysis of variance models. RESULTS: The mean total cartilage volume of the 10 knees scanned at three different centres was 16.15, 16.40 and 15.63 ml for the Siemens, GE and Philips scanners respectively. Small systematic differences were seen in the total knee cartilage volume results. CONCLUSIONS: Although there were small systematic differences in knee cartilage volume, the three MRI scanners gave broadly similar results.

Characterisation of the guinea pig model of osteoarthritis by in vivo three-dimensional magnetic resonance imaging.

OBJECTIVE: To characterise longitudinal changes in joint integrity and cartilage volume in vivo in the guinea pig spontaneous osteoarthritis (OA) model by magnetic resonance imaging (MRI). METHODS: Guinea pigs knee were imaged in vivo by high-resolution three-dimensional (3D) MRI between the ages of 3 and 12 months. Image analysis was performed to assess qualitative knee joint changes between 3 and 12 months (n=16) and quantitative volumetric changes of the medial tibial cartilage between 9 and 12 months (n=7). After imaging, animals were killed and knees were assessed macroscopically and histologically. RESULTS: From 3 to 6 months qualitative observation by MRI and histopathology indicated localised cartilage swelling on the medial tibial plateau. At 6 months, bone cysts had developed in the epiphysis. At 9 months, we observed by MRI and histopathology, fragmentation of the medial tibial cartilage in areas not protected by the meniscus. Cartilage degeneration had intensified at 12 months with evidence of widespread loss of cartilage throughout the tibial plateau. Segmentation of the MR cartilage images showed a 36% loss of volume between 9 and 12 months. CONCLUSIONS: We have achieved 3D image acquisition and segmentation of knee cartilage in a guinea pig model of chronic OA, which permits measurements previously only possible in man. High resolution and short acquisition time allowed qualitative longitudinal characterisation of the entire knee joint and enabled us to quantify for the first time longitudinal tibial cartilage volume loss associated with disease progression.

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 K(trans) was obtained, which reflects vascular permeability and perfusion. Mice were imaged immediately before, and following, acute treatment with ZD6474 (12.5-100 mg x kg(-1) orally). Whole tumours were analysed to obtain mean K(trans) values, and a histogram approach was used to examine intratumour heterogeneity. Reproducibility of K(trans) measurements gave inter- and intra-animal coefficients of variation of 40 and 18%, respectively. Dose-related reductions in K(trans) were evident following acute ZD6474 treatment. A K(trans) reduction of approximately 30% (P<0.001) was evident with 50 and 100 mg x kg(-1) ZD6474, a reduction of 12.5% (P<0.05) at 25 mg x 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 K(trans) 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.