This study describes a new method for analysis of dynamic MR contrast data that greatly increases the time available for data acquisition. The capillary input function, CB(t), is estimated from the rate of contrast agent uptake in a reference tissue such as muscle, based on literature values for perfusion rate, extraction fraction, and extracellular volume. The rate constant for contrast uptake (the product of perfusion rate, F, and extraction fraction, E; F x E) is then determined in each image pixel using CB(t), extracellular volume (relative to the reference tissue) measured from MR and the tissue concentration of contrast media as a function of time calculated from the MR data. The "reference tissue method" was tested using rats with mammary (n = 10) or prostate (n = 15) tumors implanted in the hindlimb. Dynamic MR images at 4.7 T were acquired before and after Gd-DTPA intravenous bolus injections to determine F x E(Gd-DTPA). Acquisition parameters were optimized for detection of the first pass of the contrast agent bolus, so that "first-pass analysis" could be used as the "gold standard" for determination of F x E. The accuracy of values of F x E determined using the reference tissue method was determined based on comparison with first-pass analysis. In some cases, deuterated water (D2O) was injected i.v. immediately after Gd-DTPA measurements, and the reference tissue method was used to calculate F, based on the rate of uptake of D2O. Comparison of rate constants for Gd-DTPA uptake and D2O uptake allowed calculation of E(Gd-DTPA). Values for F x E(Gd-DTPA), F, and E(Gd-DTPA) were determined for selected regions and on a pixel-by-pixel basis. Values for F x E and E(Gd-DTPA) measured using the reference tissue method correlated well (P = .90 with a standard error of +/- .016, n = 15) with values determined based on first-pass contrast media uptake. The reference tissue method has important advantages: (a) A large volume of reference tissue can be used to determine the contrast agent input function with high precision. (b) Data obtained for 20 minutes after injection are used to calculate F or F x E. The greatly increased acquisition time can be used to increase the spatial resolution, field of view or SNR of measurements. The reference tissue method is most useful when the volume of tissue that must be imaged and/or the spatial resolution required precludes use of traditional first-pass methods.
A variety of treatments that modulate tumor oxygen tension are used clinically to improve the outcome of radiotherapy. High resolution, noninvasive measurements of the effects of these treatments would greatly facilitate the development of improved therapies and could guide treatment of cancer patients. Previous work demonstrated that magnetic resonance (MR) gradient echo imaging of the water proton resonance detects changes in T2* and T1 in tumors during hyperoxia that may reflect increased tumor oxygenation. This report describes the use of high resolution MR spectroscopic imaging with short repetition time (TR = 0.2 s) to improve the accuracy with which changes in T2* and T1 are measured. Mammary adenocarcinomas grown in the hind limbs of rats were studied. Carbogen inhalation was used to induce hyperoxia. A single 2-mm slice through the center of tumors and underlying muscle was imaged at 4.7 Tesla with in-plane resolution of approximately 1.2 mm and frequency resolution of 5.8 Hz. The peak integral increased by an average of 6% in tumors during carbogen inhalation suggesting a decrease in T1 (n = 8, P < 0.001). Peak height increased by an average of 15% in tumors during carbogen inhalation (n = 8, P < 0.001). The large difference between increases in peak height and peak integral demonstrates that the width of the water resonance decreased. Assuming a Lorentzian lineshape, an average increase of 12% in T2* was observed in tumors. In muscle, peak integral and peak height increased slightly (about 1.2% and 3%, respectively; P < 0.02) during carbogen inhalation but no significant change in T2* was observed. Spectroscopic imaging detects changes in the water proton resonance in tumors during hyperoxia accurately and reproducibly with high signal-to-noise ratio and allows clear separation of T1 and T2* effects. Increases in T2* may be due to decreased deoxyhemoglobin in tumor blood vessels (i.e., the BOLD effect) and may provide a clinically useful index of increases in tumor oxygenation.
Tissue uptake of a fully extractable MR detectable tracer, deuterated water (D2O), was compared with that of a less extractable contrast agent, Gadolinium-DTPA-dimeglumine (Gd-DTPA), in rodent tumor and muscle tissue. This dual tracer method allowed calculation of relative (to muscle) tissue perfusion and extraction fraction of Gd-DTPA in each image pixel in vivo. Solutions of Gd-DTPA and D2O were injected intravenously into Fisher female rats (n = 9) with R3230 mammary adenocarcinomas implanted in the hind limb. Perfusion rate was approximately two times greater (P < 0.005 by paired t test) in tumor than in muscle. Gd-DTPA extraction fraction at the interface between tumor and muscle was 2.0 times the extraction fraction in normal muscle (P < 0.005 by paired t test). Extraction fraction at the tumor center was 1.6 times the extraction fraction in muscle (P < 0.01 by paired t test). High extraction fraction of Gd-DTPA correlated with high capillary permeability determined from Evans Blue staining. Low molecular weight Gd-DTPA derivatives are widely used in clinical practice, and their extraction fractions are crucial determinants of image contrast during the first few passes of the contrast agent bolus. Therefore spatially resolved measurements of contrast agent extraction fractions obtained in vivo have significant clinical utility. The data demonstrate that extraction of low molecular weight tracers is sensitive to increased permeability in tumor vasculature and that this increased permeability can be imaged.
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