Differentiation of nonmetastatic and metastatic rodent prostate tumors with high spectral and spatial resolution MRI.

MR images can be acquired with high spectral and spatial resolution to precisely measure lineshapes of the water and fat resonances in each image voxel. Previous work suggests that the high-resolution spectral information can be used to improve image contrast, SNR, sensitivity to contrast agents and to physiologic and biochemical processes that affect local magnetic susceptibility gradients. The potential advantages of high-resolution spectroscopic imaging (SI) suggest that it might be useful for early detection and characterization of tumors. The present experiments evaluate the use of high-resolution SI to discriminate between metastatic and nonmetastatic rodent Dunning prostate tumors. SI datasets were obtained at 4.7 Tesla with an in-plane resolution of 350-500 micron in a single 1.0-mm slice, and 6-8 Hz spectral resolution, before and after i.v. injection of an iron oxide contrast agent. Images of water signal peak height in nonmetastatic tumors were smoother in the tumor interior than images of metastatic tumors (P <.004 by t-test) before contrast media injection. This difference was stronger in contrast-enhanced images (P <.0004). In addition, the boundary between the tumor and muscle was more clearly demarcated in nonmetastatic than metastatic tumors. Combinations of image texture, tumor edge morphology, and changes in T2* following contrast media injection improved discrimination between metastatic and nonmetastatic tumors. The data presented here do not demonstrate that effective discrimination between metastatic and nonmetastatic tumors depends on the use of high-resolution SI. However, the results suggest that SI and/or other MR methods that provide similar contrast might be used clinically for early and accurate detection of metastatic disease.

Uptake of a superparamagnetic contrast agent imaged by MR with high spectral and spatial resolution.

Conventional MRI implicitly treats the proton signal as a single, narrow Lorentzian. However, water signals in vivo are often in homogeneously broadened and have multiple resolvable components. These components represent discrete populations of water molecules within each pixel which are affected differently by physiology and contrast agents. Accurate measurement of each component of the water resonance can improve anatomic and functional MR images and provide insight into the structure and dynamics of subpixelar microenvironments. This report describes high spectral and spatial resolution (HiSS) MR imaging of rodent prostate tumors before and after injection of a superparamagnetic contrast agent. HiSS datasets were used to synthesize images in which intensity is proportional to peak height, peak frequency, and linewidth. These images showed anatomic features which were not clearly delineated in conventional T(2) and gradient echo images. HiSS images obtained after injection of the contrast agent showed T *(2) and T(1) changes which were not seen in conventional images. These changes are associated with microvessel density and permeability. The results suggest HiSS with superparamagnetic contrast agents has the potential to improve characterization of tumors.

Correlation of magnetic resonance and oxygen microelectrode measurements of carbogen-induced changes in tumor oxygenation.

PURPOSE: The aim of this work was to test the hypothesis that decreases in the linewidth of magnetic resonance (MR) water signals in tumors caused by oxygenating treatments are due to increases in capillary and venous oxygen saturation of hemoglobin, which are tightly coupled to increases in extravascular oxygen tension (pO2). To establish this link, changes measured by MR were compared to changes in tissue pO2 measured directly by oxygen microelectrodes during carbogen (95% O2/5% CO2) inhalation. METHODS AND MATERIALS: Mammary adenocarcinomas (R3230AC) in nine rats were imaged at 4.7 Tesla. T1-weighted (TR = 200 ms, flip angle = 45 degrees) spectroscopic images of the water resonance in a single slice through each tumor were acquired with spectral resolution of 3.9 Hz and bandwidth of +/-1000 Hz. In the same slices in these tumors, microelectrode measurements were made using a non-Clark style oxygen electrode with a 350-micron tip. MR and microelectrode measurements were made during alternating periods of air and carbogen inhalation. RESULTS: Water resonance linewidth decreased significantly during carbogen-induced hyperoxia. Paired Student's t-test analysis of microelectrode data indicated that pO2 was significantly (p < 0.05) increased as a result of carbogen inhalation. MR and microelectrode data averaged over each tumor demonstrated that decreased MR water signal linewidth is strongly correlated (r = 0.92, p < 0.05) with increased tumor pO2 levels. CONCLUSION: Although tumor oxygenating agents increase response to radiation in rodent tumors, clinical studies have shown only marginal effects on the radiosensitivity of human tumors. This may be, in part, because the effects of tumor oxygenating treatments are highly heterogeneous both within each tumor and among a population of tumors. The noninvasive, high-resolution MR methods that are validated by the present work could guide the design of new and more effective tumor oxygenating agents and optimize treatments for individual patients.

Fast spectroscopic imaging of water and fat resonances to improve the quality of MR images.

RATIONALE AND OBJECTIVES: The authors evaluated whether fast spectroscopic imaging of water and fat resonances can produce high-quality anatomic magnetic resonance (MR) images of rodent tumors and human breast. MATERIALS AND METHODS: Fast MR spectroscopic images of eight rats with mammary tumors were acquired by using a 4.7-T MR unit equipped with self-shielded gradient coils. MR spectroscopic images of four human breasts were acquired with a 1.5-T MR unit. RESULTS: Artifacts due to eddy currents were minimal. Images synthesized from MR spectroscopic data, in which intensity was proportional to water signal peak height, were similar to T2-weighted MR images. Boundaries of rodent mammary tumors are similar but not identical on peak height-weighted and T2-weighted images. MR spectroscopic images of human breast showed improved detail compared to gradient-echo MR images. CONCLUSION: Preliminary results suggest that incorporation of fast MR spectroscopic imaging methods into many standard clinical MR imaging procedures may substantially improve image quality.

In vivo imaging of extraction fraction of low molecular weight MR contrast agents and perfusion rate in rodent tumors.

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.

Spectroscopic imaging of the water resonance with short repetition time to study tumor response to hyperoxia.

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.

Measurement of differences in pO2 in response to perfluorocarbon/carbogen in FSa and NFSa murine fibrosarcomas with low-frequency electron paramagnetic resonance oximetry.

We have used very low-frequency electron paramagnetic resonance (EPR) oximetry to measure the change in oxygen concentration (delta pO2) due to change in breathing atmosphere in FSa and NFSa fibrosarcomas implanted in the legs of C3H mice infused with perfluoro-octylbromine (PFOB). Measurements in each tumor were made before and after the administration of the high-density (47% v/v) perfluorocarbon PFOB, perflubron (Alliance Pharmaceutical Corporation, San Diego, CA). Measurements in each tumor were also made, after the administration of the PFOB, both before (PFOB/air) and after the administration of carbogen (95% O2 + 5% CO2, PFOB/carbogen). Large changes (delta p02) relative to PFOB/air oxygenation were seen with the administration of PFOB/carbogen. No significant difference in oxygen concentration was seen between air-breathing mice with and without PFOB. The mean delta pO2 for FSa tumors was 13 +/- 6 torr, while the mean for NFSa fibrosarcomas was 28 +/- 7 torr. There were such large intertumor differences that the trend toward a smaller change in the more hypoxic FSa tumors was not significant (P = 0.13). This paper describes a novel method of measuring differences in oxygenation in tumor tissues. The results of such measurements indicate large differences in pO2 response to different breathing atmospheres in PFOB-infused tumors of similar histology. The intertumor delta pO2 differences may correlate with differences in radiation response.

Changes in T2*-weighted images during hyperoxia differentiate tumors from normal tissue.

Experiments were performed to determine whether changes in T2*-weighted MR images during and after hyperoxia differentiate tumors from normal tissue. Mammary adenocarcinomas implanted in the right hind limbs of rats were studied. Gradient echo images were obtained at 2 Tesla with an evolution time of 20 ms and a recycle time of 1 s. Breathing gas was either air or 100% O2. Significant increases in image intensity were observed in tumor centers and rims during hyperoxia while much smaller changes were detected in the surrounding muscle. The relaxation rate (1/T2*) in tumors decreased during hyperoxia by an average of 2.5 +/- 1.0 s-1, while in muscle the average change was an increase of 0.6 +/- 2.1 s-1. The largest decreases in relaxation rate were detected in non-necrotic tumor regions with relatively low density of blood vessels. Immediately following hyperoxia significant decreases in intensity were detected in tumors while much smaller decreases were detected in the surrounding muscle.

Effects of hyperoxia on T2* and resonance frequency weighted magnetic resonance images of rodent tumours.

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)

Magnetic resonance imaging of rodent tumors using radiofrequency gradient echoes.

This paper evaluates the use of radiofrequency (RF) magnetic field gradient echoes to provide contrast in magnetic resonance (MR) images of model tumors. Decay of RF gradient echoes as a function of evolution time was measured and sensitivity of the decay to changes in blood pressure was evaluated. Previous investigators have demonstrated that static field (B0) gradient echoes provide MR image contrast which is sensitive to the rate of self-diffusion of tissue water and may also be sensitive to the rate of tissue perfusion. Gradient echoes produced by RF magnetic field gradients provide a useful alternative to the conventional B0 methods. Unlike B0 gradient echoes RF gradient echoes are relatively insensitive to local magnetic susceptibility gradients and to magnetic field gradients produced by eddy currents. Differences between the two methods may be particularly significant for studies of tumors where large concentrations of deoxyhemoglobin and other paramagnetic substances may cause significant susceptibility gradients. Mammary adenocarcinomas subcutaneously implanted in the flanks of female Fisher rats were studied. Magnetic resonance experiments were performed at 2 T. A surface coil was used to provide an RF gradient and to excite and detect signals from the tumors. The decay of echo amplitude as a function of evolution time was measured and the decay at short and long evolution times was analyzed independently to calculate two apparent diffusion coefficients (ADCs). The preparation was extremely stable and the standard error for 10 consecutive measurements of gradient echo amplitude made over 30-60 min with an RF gradient strength of 50 kHz/cm, gradient duration of 1 ms (i.e., 50 cycles/cm), and echo evolution time (td) of 1 s was generally +/- 0.8%. The ADC calculated from the decay at short evolution times was approximately 3 x 10(-5) cm2/s. The ADC calculated from the decay at longer evolution times was approximately 0.5 x 10(-5) cm2/s. Both ADCs decreased immediately following sacrifice and administration of Hydralazine. The experiments demonstrate that measurements of RF gradient echo amplitudes in tumors can be made in vivo with a high degree of reproducibility and suggest that RF gradient echo amplitudes are sensitive to acute physiological changes in tumors. This method may be useful for characterization of tumors and prediction and monitoring of effects of therapeutic agents.