Deirdre M. McGrath

Preliminary Study of Oxygen-Enhanced Longitudinal Relaxation in MRI: A Potential Novel Biomarker of Oxygenation Changes in Solid Tumors

PURPOSE There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.

Comparison of model-based arterial input functions for dynamic contrast-enhanced MRI in tumor bearing rats

When using tracer kinetic modeling to analyze dynamic contrast‐enhanced MRI (DCE‐MRI) it is necessary to identify an appropriate arterial input function (AIF). The measured AIF is often poorly sampled in both clinical and preclinical MR systems due to the initial rapid increase in contrast agent concentration and the subsequent large‐scale signal change that occurs in the arteries. However, little work has been carried out to quantify the sensitivity of tracer kinetic modeling parameters to the form of AIF. Using a preclinical experimental data set, we sought to measure the effect of varying model forms of AIF on the extended Kety compartmental model parameters (Ktrans, ve, and vp) through comparison with the results of experimentally acquired high temporal resolution AIFs. The AIF models examined have the potential to be parameterized on lower temporal resolution data to predict the form of the true, higher temporal resolution AIF. The models were also evaluated through application to the population average AIF. It was concluded that, in the instance of low temporal resolution or noisy data, it may be preferable to use a bi‐exponential model applied to the raw data AIF, or when individual measurements are not available a bi‐exponential model of the average AIF. Magn Reson Med, 2009.

Comparison of normal tissue R1 and R *2 modulation by oxygen and carbogen

Magnetic resonance imaging has shown promise for evaluating tissue oxygenation. In this study differences in the tissue longitudinal relaxation rate (R1) and effective transverse relaxation rate (R  *2 ), induced by inhalation of pure oxygen and carbogen, were evaluated in 10 healthy subjects. Significant reductions in R1 were demonstrated following both oxygen and carbogen inhalation in the spleen (both P < 0.001), liver (P = 0.002 air vs. oxygen; P = 0.001 air vs. carbogen), skeletal muscle (both P < 0.001), and renal cortex (P = 0.005 air vs. oxygen; P = 0.008 air vs. carbogen). No significant change in R  *2 occurred following pure oxygen in any organ. However, a significant increase in R  *2 was observed in the spleen (P < 0.001), liver (P = 0.001), skeletal muscle (P = 0.026), and renal cortex (P = 0.001) following carbogen inhalation, an opposite effect to that observed in many studies of tumor pathophysiology. Changes in R1 and R  *2 were independent of the gas administration order in the spleen and skeletal muscle. These findings suggest that the R1 and R  *2 responses to hyperoxic gases are independent biomarkers of oxygen physiology. Magn Reson Med 61:75–83, 2009.

Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times.

Molecular oxygen has been previously shown to shorten longitudinal relaxation time (T1) in the spleen and renal cortex, but not in the liver or fat. In this study, the magnitude and temporal evolution of this effect were investigated. Medical air, oxygen, and carbogen (95% oxygen/5% CO2) were administered sequentially in 16 healthy volunteers. T1 maps were acquired using spoiled gradient echo sequences (TR = 3.5 ms, TE = 0.9 ms, α = 2°/8°/17°) with six acquisitions on air, 12 on oxygen, 12 on carbogen, and six to 12 back on air. Mean T1 values and change in relaxation rate were compared between each phase of gas inhalation in the liver, spleen, skeletal muscle, renal cortex, and fat by one‐way analysis of variance. Oxygen‐induced T1‐shortening occurred in the liver in fasted subjects (P < 0.001) but not in non‐fasted subjects (P = 0.244). T1‐shortening in spleen and renal cortex (both P < 0.001) were greater than previously reported. Carbogen induced conflicting responses in different organs, suggesting a complex relationship with organ vasculature. Shortening of tissue T1 by oxygen is more pronounced and more complex than previously recognized. The effect may be useful as a biomarker of arterial flow and oxygen delivery to vascular beds. Magn Reson Med 58:490–496, 2007.

Tracer kinetic analysis of dynamic contrast‐enhanced MRI and CT bladder cancer data: A preliminary comparison to assess the magnitude of water exchange effects

The purpose of this study was to determine the impact of water exchange on tracer kinetic parameter estimates derived from T1‐weighted dynamic contrast‐enhanced (DCE)‐MRI data using a direct quantitative comparison with DCE‐CT. Data were acquired from 12 patients with bladder cancer who underwent DCE‐CT followed by DCE‐MRI within a week. A two‐compartment tracer kinetic model was fitted to the CT data, and two versions of the same model with modifications to account for the fast exchange and no exchange limits of water exchange were fitted to the MR data. The two‐compartment tracer kinetic model provided estimates of the fractional plasma volume (vp), the extravascular extracellular space fraction (ve), plasma perfusion (Fp), and the microvascular permeability surface area product. Our findings suggest that DCE‐CT is an appropriate reference for DCE‐MRI in bladder cancers as the only significant difference found between CT and MR parameter estimates were the no exchange limit estimates of vp (P = 0.002). These results suggest that although water exchange between the intracellular and extravascular‐extracellular space has a negligible effect on DCE‐MRI, vascular–extravascular‐extracellular space water exchange may be more important. Magn Reson Med, 2010.

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD

OBJECTIVES Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9μg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9μg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a β2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

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 Ktrans 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 vp 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 ve was in reasonable agreement only for low values. The study provides evidence that the biomarker Ktrans is a robust parameter indicative of the underlying physiology and relatively independent of the method of measurement. Magn Reson Med, 2011.

Measurement of arterial plasma oxygenation in dynamic oxygen‐enhanced MRI

Inhaled oxygen can be used as a contrast agent for magnetic resonance imaging, due to the T1 shortening effect of the oxygen dissolved in blood and tissue water. In this study, blood T1 was measured dynamically in 14 volunteers (seven smokers, seven never‐smokers) as the inhaled gas was switched from medical air to 100% oxygen and back to medical air. These T1 values were converted to changes in partial pressure of oxygen, which were found to be in agreement with literature values. There were differences in curve shape and curve height between the smoker and never‐smoker groups, suggesting differences in lung function due to smoking‐related damage. These curves could be used as an input function for modeling of oxygen uptake in tissues. The differences between groups highlight the importance of measuring such an input function for each individual rather than relying on an assumed measurement. Magn Reson Med, 2010.

Quasi-static magnetic resonance elastography at 7 T to measure the effect of pathology before and after fixation on tissue biomechanical properties

Evaluation of imaging for cancer detection and localization can be achieved by correlation of gold‐standard histopathology with imaging data. Usage of a 3D biomechanical‐based deformable registration for correlation of the histopathology of whole‐tissue specimens with ex vivo imaging necessitates measurement of the distribution of biomechanical properties in the ex vivo tissue specimen and changes that occur during pathology fixation. To measure high‐resolution 3D distributions of Youngs modulus (E) prefixation and postfixation, a quasi‐static magnetic resonance elastography method was developed at 7 T. Use of echo‐planar imaging allowed for shorter imaging times, in line with limited time frames allowable for pathology specimens. The finite element modeling algorithm produced voxel‐wise E measures, and mechanical indentation was used for comparison. An initial preclinical evaluation with canine prostate specimens (n = 5) demonstrated a consistent increase in E with fixation (P < 0.002) by a factor of 4 (±1). Increases were a function of distance from the tissue edge and correlated with fixation time (ρ = 1, P < 0.02). The technique will be used to generate population‐averaged data of E from clinical ex vivo specimens prefixation and postfixation to inform registration of whole‐mount histopathology with in vivo imaging. Magn Reson Med, 2012.

Biomechanical model-based deformable registration of MRI and histopathology for clinical prostatectomy

A biomechanical model-based deformable image registration incorporating specimen-specific changes in material properties is optimized and evaluated for correlating histology of clinical prostatectomy specimens with in vivo MRI. In this methodology, a three-step registration based on biomechanics calculates the transformations between histology and fixed, fixed and fresh, and fresh and in vivo states. A heterogeneous linear elastic material model is constructed based on magnetic resonance elastography (MRE) results. The ex vivo tissue MRE data provide specimen-specific information for the fresh and fixed tissue to account for the changes due to fixation. The accuracy of the algorithm was quantified by calculating the target registration error (TRE) by identifying naturally occurring anatomical points within the prostate in each image. TRE were improved with the deformable registration algorithm compared to rigid registration alone. The qualitative assessment also showed a good alignment between histology and MRI after the proposed deformable registration.