A new method for the high-precision assessment of tumor changes in response to treatment.

Motivation: Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both development and also in response to treatment. The large variations observed in control group, tumors can obscure detection of significant therapeutic effects due to the ambiguity in attributing causes of change. This can hinder development of effective therapies due to limitations in experimental design rather than due to therapeutic failure. An improved method to model biological variation and heterogeneity in imaging signals is described. Specifically, linear Poisson modeling (LPM) evaluates changes in apparent diffusion co-efficient between baseline and 72 h after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes is compared to those attainable using a conventional t-test analysis on basic apparent diffusion co-efficient distribution parameters. Results: When LPMs were applied to treated tumors, the LPMs detected highly significant changes. The analyses were significant for all tumors, equating to a gain in power of 4-fold (i.e. equivalent to having a sample size 16 times larger), compared with the conventional approach. In contrast, highly significant changes are only detected at a cohort level using t-tests, restricting their potential use within personalized medicine and increasing the number of animals required during testing. Furthermore, LPM enabled the relative volumes of responding and non-responding tissue to be estimated for each xenograft model. Leave-one-out analysis of the treated xenografts provided quality control and identified potential outliers, raising confidence in LPM data at clinically relevant sample sizes. Availability and implementation: TINA Vision open source software is available from www.tina-vision.net. Supplementary information: Supplementary data are available at Bioinformatics online.

DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6.

BACKGROUND: There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases. METHODS: Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan. RESULTS: In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan. CONCLUSION: Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.

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.

A two-part phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics.

BACKGROUND: Cediranib (RECENTIN™) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers. METHODS: Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF). RESULTS: In part A, plasma AUC and C (max) of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12-34% and C (max), 20-43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30 mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16 weeks, with significant reductions in DCE-MRI parameters and CT EnF. CONCLUSIONS: It is recommended that cediranib be administered at least 1 h before or 2 h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.

Cross-visit tumor sub-segmentation and registration with outlier rejection for dynamic contrast-enhanced MRI time series data.

Clinical trials of anti-angiogenic and vascular-disrupting agents often use biomarkers derived from DCE-MRI, typically reporting whole-tumor summary statistics and so overlooking spatial parameter variations caused by tissue heterogeneity. We present a data-driven segmentation method comprising tracer-kinetic model-driven registration for motion correction, conversion from MR signal intensity to contrast agent concentration for cross-visit normalization, iterative principal components analysis for imputation of missing data and dimensionality reduction, and statistical outlier detection using the minimum covariance determinant to obtain a robust Mahalanobis distance. After applying these techniques we cluster in the principal components space using k-means. We present results from a clinical trial of a VEGF inhibitor, using time-series data selected because of problems due to motion and outlier time series. We obtained spatially-contiguous clusters that map to regions with distinct microvascular characteristics. This methodology has the potential to uncover localized effects in trials using DCE-MRI-based biomarkers.

Identification of early predictive imaging biomarkers and their relationship to serological angiogenic markers in patients with ovarian cancer with residual disease following cytotoxic therapy.

BACKGROUND: Patients with recurrent ovarian cancer often achieve partial response following chemotherapy, resulting in persistent small volume disease. After completion of treatment, the dilemma of when to initiate subsequent chemotherapy arises. Identification of biomarkers that could be used to predict when subsequent treatment is needed would be of significant benefit. DESIGN: Twenty-three patients with advanced ovarian cancer and residual asymptomatic disease following chemotherapy underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at study entry, 4, 8, 12, 18 and 26 weeks or disease progression. A subgroup of patients provided plasma samples within which a panel of angiogenic biomarkers was quantified. RESULTS: By 4 weeks, significant differences in whole tumour volume, enhancing fraction and Ca125 were observed between patients whose disease progressed by 26 weeks and those who remained stable. Significant correlations between plasma soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and sVEGFR-2 concentrations, and blood volume and tumour endothelial permeability surface area product measured by DCE-MRI were observed. CONCLUSIONS: Imaging markers have a potential role in early prediction of disease progression in patients with residual ovarian cancer and may supplement current measures of progression. The correlation of DCE-MRI and serological biomarkers suggests that tumour angiogenesis affects these markers through common biological means and warrants further investigation.

Phase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2.

PURPOSE: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report the first phase I clinical trial evaluation of CDP791, a PEGylated di-Fab' conjugate that binds VEGFR-2. EXPERIMENTAL DESIGN: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses. RESULTS: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising 28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), there was a significant dose level-related reduction in tumor growth. While challenging the recent dogma that active VEGF inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no partial or complete responses were seen. CONCLUSION: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered at 10 mg/kg or more every 3 weeks.

Quantifying heterogeneity in dynamic contrast-enhanced MRI parameter maps.

Simple summary statistics of Dynamic Contrast-Enhanced MRI (DCE-MRI) parameter maps (e.g. the median) neglect the spatial arrangement of parameters, which appears to carry important diagnostic and prognostic information. This paper describes novel statistics that are sensitive to both parameter values and their spatial arrangement. Binary objects are created from 3-D DCE-MRI parameter maps by "extruding" each voxel into a fourth dimension; the extrusion distance is proportional to the voxel's value. The following statistics are then computed on these 4-D binary objects: surface area, volume, surface area to volume ratio, and box counting (fractal) dimension. An experiment using 4 low and 5 high grade gliomas showed significant differences between the two grades for box counting dimension computed for extruded v(e) maps, surface area of extruded K(trans) and v(e) maps and the volume of extruded v(e) maps (all p < 0.05). An experiment using 18 liver metastases imaged before and after treatment with a vascular endothelial growth factor (VEGF) inhibitor showed significant differences for surface area to volume ratio computed for extruded K(trans) and v(e) maps (p = 0.0013 and p = 0.045 respectively).

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.

Improved high resolution MR imaging for surface coils using automated intensity non-uniformity correction: feasibility study in the orbit.

This study examined the effects of a recently developed automated intensity non-uniformity correction on surface coil images using the orbit as an exemplar. Images were obtained using a standard head coil and a range of surface coils. Slices through the optic nerve head and cavernous sinus were subjected to the correction algorithm. Blind forced-choice rankings of the subjective image quality were performed. Quantitative measurements were taken of the similarity between vitreous humor at two depths from the coil, and of the conspicuity between orbital fat and temporalis muscle intensities. The combined qualitative ranks for corrected surface coil images were higher than for the equivalent uncorrected images in all cases. Intensity non-uniformity correction produced statistically significant improvements in orbital surface coil images, bringing their intensity uniformity in homogeneous tissue to the level of head coil images. The subjective quality of the corrected surface coil images was superior to head coil images, due to increased spatial resolution combined with improved signal to noise ratio across the image.

Abnormalities of the contrast re-circulation phase in cerebral tumors demonstrated using dynamic susceptibility contrast-enhanced imaging: a possible marker of vascular tortuosity.

Dynamic susceptibility contrast-enhanced magnetic resonance (MR) imaging in tumors is restricted by relaxivity effects, which may obscure any abnormality of first-pass kinetics in the re-circulation phase. The purposes of this study were a) to document the magnitude of relaxivity effects with a variety of commonly used MR susceptibility imaging techniques; and b) to determine whether the re-circulation phase of the first-pass curve in tumors differs from that in normal tissue. We have confirmed that residual relaxivity effects can be eliminated from dynamic susceptibility contrast-enhanced data by several techniques. Application of these methods to enhancing vascular tumors allows detection of abnormalities in the re-circulation phase, which would otherwise be obscured. These abnormalities are independent of relative cerebral blood volume (rCBV) and presumably represent deviations from the predicted gamma variat flow pattern seen in normal tissues. We believe that the parameter rR described here provides an indicator of the chaotic nature of neovascular angiogenesis, which may be of benefit in diagnosis and management.

MR angiography and MR imaging of symptomatic vascular malformations.

PURPOSE: To define the appearance of peripheral vascular malformations at magnetic resonance angiography (MRA) and assess the role of magnetic resonance imaging (MRI) and MRA in the investigation of these lesions. PATIENTS AND METHODS: Fourteen patients (aged 8-51 years) with clinical evidence of a vascular malformation were referred for MRI and MRA, performed on a 0.5T GE Vectra superconducting system (International General Electric, Slough, UK). Multisection T1-weighted spin-echo and T2-weighted fast spin-echo pulse sequences were performed, with an inversion recovery fast spin-echo sequence in two cases. Two-dimensional time of flight (2-D TOF) and/or 2-D phase contrast (PC) MRA was performed in 13 cases. Eleven patients had digital subtraction angiography (DSA) using a Phillips Integris V3000 digital angiographic unit. The findings at MRA and MRI were compared with the catheter angiograms, and the effective diagnostic input of MRA and MRI was determined. RESULTS: MRA demonstrated major feeding vessels and multiple intra-lesional vessels in relation to the high flow lesions, features absent in the low flow lesions. However, small feeding vessels to the AVMs were not clearly identified. MRI gave a clear demonstration of the anatomical extent of all lesions. AVMs (n = 6) and venous malformations (n = 6) were reliably distinguished, the former containing multiple serpentine signal voids on T1- and T2-weighted imaging, the latter being hyperintense to fat on T2-weighted images. Two other high-flow lesions diagnosed clinically as vascular malformations appeared solid on MRI, and were diagnosed histologically as a carotid body tumour and an angiomyolipoma. CONCLUSION: Although 2-D TOF MRA can distinguish AVMs from venous malformations, the technique adds little extra practical information to the diagnostic process, and cannot compete with catheter angiography for the detailed demonstration of AVM feeding vessels. These lesions can also be characterized using spin-echo sequences, though the primary role of MRI is to demonstrate their anatomical extent.

A comparison of 2-D and 3-D FSE imaging in MR of the cervical spine.

The aim of the study was to assess whether a 3-D FSE sequence with real-time multiplanar reconstruction could replace our standard 2-D imaging of the cervical spine. MRI was performed on a GE Vectra 0.5 T system using a quadrature surface neck coil. Signal intensity of CSF, spinal cord, surrounding tissue and background were measured. Contrast to noise ratio and contrast between the different tissues was calculated for the different sequences. A subjective assessment of the various lesions was made. No statistical difference in tissue contrast was found between 2-D and 3-D images when the contrast between cord and CSF, or between cord and marrow was calculated. Contrast between cord and marrow was better on 3-D images. The contrast to noise ratio was better on 2-D images compared with the 3-D images for both cord/CSF and CSF/marrow but there was no difference between the 2-D and 3-D images for cord/marrow. In three patients the lesion was better demonstrated on the 3-D sequence than on the 2-D combination, but only in one of these was the abnormality not visible on the 2-D images; in six patients the 2-D images were considered superior. Although the 3-D sequence reduced overall imaging time we found that at 0.5 T contrast was inadequate, and that lesions were less clearly demonstrated than on the 2-D sequences. We conclude that a single 3-D sequence cannot satisfactorily replace the 2-D combination routinely used at 0.5 T.

Skin: MR imaging findings at middle field strength.

Skin tumors were staged at magnetic resonance (MR) imaging on a 0.5-T (middle-field-strength) system, with use of a 2-cm-diameter receive-only surface coil. T1- and T2-weighted spin-echo (SE), fast SE, or three-dimensional (3D) spoiled gradient-recalled imaging were performed in three volunteers and in 13 patients with skin tumors (nine, basal cell carcinoma). MR findings correlated well with histologic findings in the patients (epidermis, relatively hyper-intense on all images; dermis, hypo-intense with irregular interface with subdermal fat). 3D images had the optimal combination of tissue contrast, signal-to-noise ratio, and spatial resolution. MR imaging depicts depth of skin tumor invasion, and findings are complementary to clinical staging.

Clock completion: an objective screening test for dementia.

OBJECTIVE: To develop a simple, readily administered and scored screening test for dementia utilizing the clock-drawing task. DESIGN: Retrospective analysis of clock-drawing errors and prospective validations. SETTING: Hospital-based outpatient geriatric assessment clinic, rehabilitation service, apartment building for older adults, and long-term care facility. PARTICIPANTS: Convenience sample of patients attending the geriatric assessment clinic, patients on the rehabilitation service, or residents of the above sites. MEASUREMENTS: Sensitivity and specificity of a clock-scoring system in identifying patients with dementia and the comparison of this system with the Short Blessed Test (SBT) in the diagnosis of dementia and in the prospective validation of the test. RESULTS: Of the 10 clock-drawing errors evaluated, placement of digits in a pre-drawn circle had the greatest sensitivity and specificity in distinguishing patients with irreversible dementia from patients with other disorders who did not meet NINCDS-ADRDA criteria for probable dementia. The derived scoring system had a sensitivity of 87% and a specificity of 82%, compared with a sensitivity of 82% and a specificity of 88% for the SBT in identifying dementia. Test-retest reliability for the distinction between demented and non-demented was 82%, with a Kappa of 0.63 for the clock completion, and 82%, with a Kappa of 0.62 for the SBT. Inter-rater reliability for clock completion was 0.90 to 0.93. CONCLUSION: A simple, completely objective scoring system for a clock completion test has been developed which involves only the number of digits placed in the fourth quadrant of a pre-drawn circle. This readily administered test is as effective in screening for dementia as the longer six-item SBT.

Diagnosis and assessment of mitral and aortic valve disease by cine-flow magnetic resonance imaging.

Seventy-six aortic and mitral valves, in 44 patients and 5 normal volunteers, were studied by Cine-Flow MRI (on a 0.26-T superconducting magnet system), utilizing compound oblique imaging planes and a Field Echo Even Rephasing sequence. All patients had had cardiac catheterization and echocardiography. All patients with valvular stenosis and aortic sclerosis (n = 45) showed complete signal loss distal to the respective valve. Length of signal loss distal to the aortic valve in those in whom it was measured (n = 15) allowed differentiation of aortic stenosis (n = 9) from sclerosis (n = 6). This also permitted grading of stenosis with highly significant correlation (T = 0.86; P less than 0.002) with pressure gradient measurement. In mitral stenosis (n = 12) calculation of the area of signal loss distal to the mitral valve as a percentage of left ventricular cross-sectional area showed a highly significant correlation (T = 0.77; P = 0.001) with pressure gradient measurement. Clinically significant valvular regurgitation was graded by size and duration of signal loss proximal to the value with concordance with angiocardiography. It is concluded that Cine-Flow MRI has a clinical role in the diagnosis and assessment of valvular heart disease.

Magnetic resonance imaging of the mini-pig heart: the effect of gadolinium-DTPA on normal myocardium.

The effect of gadolinium-diethylene-triamine-penta-acetic acid (Gd-DTPA) on normal, mini-pig myocardium was investigated with magnetic resonance imaging. Results indicate that intravenous administration of Gd-DTPA produces a significant enhancement of mini-pig myocardial signal intensity, which in all cases was maintained in excess of 50 min. No significant enhancement was demonstrated in skeletal muscle.

A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis.

A 2-year prophylactic trial was carried out in 31 bipolar manic-depressive subjects, comparing 300 mg/day methylene blue on a double-blind crossover basis with 15 mg/day. All patients were also maintained on lithium. Seventeen patients completed the 2-year trial. During the year the patients were treated with methylene blue at 300 mg/day, they were significantly less depressed than during the year on 15 mg/day. No significant difference in the severity of manic symptoms was shown. The trial had obvious limitations, e.g., a small number of subjects, a relatively large number of dropouts, relatively simple rating scales, doubts about blindness, and uncertainty as to whether or not 15 mg methylene blue per day could be considered a placebo. However, the results suggest that methylene blue may be a useful addition to lithium in the long-term treatment of manic-depressive psychosis and warrants further investigation.

Trial of digoxin in mania.

A suggestion that mania is associated with an increased membrane transport of sodium has been investigated in a double-blind trial of a specific Na-K A.T.P.ase inhibitor (digoxin) in twelve female inpatients with mania. Digoxin had no effect.