This work presents a methodology for obtaining quantitative oxygen concentration images in the tumor-bearing legs of living C3H mice. The method uses high-resolution electron paramagnetic resonance imaging (EPRI). Enabling aspects of the methodology include the use of injectable, narrow, single-line triaryl methyl spin probes and an accurate model of overmodulated spectra. Both of these increase the signal-to-noise ratio (SNR), resulting in high resolution in space (1 mm) 3 and oxygen concentrations (ϳ3 torr). Thresholding at 15% the maximum spectral amplitude gives leg/tumor shapes that reproduce those in photographs. The EPRI appears to give reasonable oxygen partial pressures, showing hypoxia (ϳ0 -6 torr, 0 -10 3 Pa) in many of the tumor voxels. EPRI was able to detect statistically significant changes in oxygen concentrations in the tumor with administration of carbogen, although the changes were not in- The central role of oxygen in virtually all life processes as the ultimate oxidative substrate for metabolism is well known (1). Oxygenation has a crucial effect on the malignant state (2). Lack of oxygen in a tissue (hypoxia) appears to predispose its surviving cells to mutagenesis, thereby increasing the likelihood that a malignant state will develop (3). Hypoxia affects, most often detrimentally, treatment with conventional anticancer therapies (4). In particular, radiation has been known for nearly a century to be potentiated by oxygen and inhibited by hypoxia (5).Electron paramagnetic resonance imaging (EPRI) can provide a quantitative image of the oxygen concentrations in tissues and tumors of living animals (6,7). The image derives from the EPR spectrum of the unpaired electron from a stable injected spin probe. Oxygen is measured in the distributional compartment of the spin probe. The EPR linewidth is a direct measure of the frequency with which the spin probe encounters molecular oxygen, and is directly proportional to the oxygen concentration (8). One great advantage to imaging the EPR linewidth (and not the line height) is the desensitization to other aspects of the animal or tissue physiology, such as the vasculature. The spectral line height (but not the linewidth) depends on the effectiveness of the delivery of the spin probe to a voxel. Within broad limits, the line height depends on the operating conditions of the imager and the complicated RF distributions in an animal, whereas the linewidth does not.The approach described herein differs from that taken by other groups pursuing in vivo EPRI. Spectral-spatial imaging and in vivo spectral-spatial imaging have been described previously (9,10). In vivo spectral-spatial EPRI for small animals has also been discussed by us and other researchers (6,(11)(12)(13)(14)(15). The present work takes spectralspatial imaging to its logical conclusion: obtaining a full spectrum from each voxel and fitting that spectrum to an accurate spectral shape function with adjustable spectral parameters. These spectral parameters contain the physiologic information fr...

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.

Electron paramagnetic resonance imaging (EPRI) promises to

Experiments were performed to determine whether T2* and resonance frequency weighted MR images are sensitive to effects of hyperoxia on model tumors. Hyperoxia can increase tumor oxygen tension and thus affect T2* and/or the average resonance frequency within each image voxel due to the paramagnetism of oxygen itself or through modulation of the oxidation state of hemoglobin. Alternatively, changes in T2* during hyperoxia may reflect changes in tumor water content due to changes in systemic blood pressure. Mammary adenocarcinomas implanted in the flanks of rats were studied. Imaging sequences were preceded by two 90 degrees pulses separated by an evolution period of 50 or 75 ms and followed by a crusher gradient to eliminate transverse magnetization. This pulse sequence produced images which were sensitized to both T2* and the average resonance frequency of each voxel. Images were produced at 2 T using a gradient echo imaging method with a TR of 3 s. Images obtained during inhalation of air and 100% O2 were compared. Significant increases in image intensity were observed in most tumors during hyperoxia, particularly at the tumor center. The increase was accentuated when the evolution period was increased and greatly reduced when a 180 degrees refocusing pulse was placed at the center of the evolution period. These results suggest that hyperoxia reduces local magnetic susceptibility gradients leading to an increase in T2* or causes a shift in resonance frequency. The magnitude of this change may be a function of the rate at which oxygen is delivered to and metabolized by tumors and may also reflect tumor oxygen tension under normoxic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

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.