Jonathan N. River

Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): methodology and comparison with blood oxygen level-dependent (BOLD) MRI.

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 (∼3 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 (∼0–6 torr, 0–103 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 increased uniformly. As a demonstration of the method, EPRI was compared with nearly concurrent (same anesthesia) T  2* /blood oxygen level‐dependent (BOLD) MRI. There was a good spatial correlation between EPRI and MRI. Homogeneous and heterogeneous T  2* /BOLD MRI correlated well with the quantitative EPRI. This work demonstrates the potential for EPRI to display, at high spatial resolution, quantitative oxygen tension changes in the physiologic response to environmental changes. Magn Reson Med 49:682–691, 2003.

New model for analysis of dynamic contrast-enhanced MRI data distinguishes metastatic from nonmetastatic transplanted rodent prostate tumors.

Dynamic contrast‐enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low‐molecular‐weight contrast agent (Gd‐DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two‐compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd‐DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in “normal” tissue immediately adjacent to the tumors were evident: Gd‐DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd‐DTPA and P792 provides information regarding the microenvironment of tumors. Magn Reson Med 51:487–494, 2004.

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.

MRI of perfluorocarbon emulsion kinetics in rodent mammary tumours

Perfluorocarbon (PFC) emulsions can be imaged directly by fluorine-19 MRI. We developed an optimized protocol for preparing PFC droplets of uniform size, evaluated use of the resulting droplets as blood pool contrast agents, studied their uptake by tumours and determined the spatial resolution with which they can be imaged at 4.7 T. Perfluorocarbon droplets of three different average sizes (324, 293 and 225 nm) were prepared using a microemulsifier. Images of PFC droplets with good signal-to-noise ratio were acquired with 625 microm in-plane resolution, 3 mm slice thickness and acquisition time of approximately 4.5 min per image. Kinetics of washout were determined using a simple mathematical model. The maximum uptake of the PFC droplets was three times greater at the tumour rim than in muscle, but the washout rate was two to three times slower in the tumour. The results are consistent with leakage of the droplets into the tumour extravascular space due to the hyper-permeability of tumour capillaries. PFC droplets may allow practical and quantitative measurements of blood volume and capillary permeability in tumours with reasonable spatial resolution.

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.

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 μ 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 T  *2 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. Magn Reson Med 45:1046–1055, 2001.

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 inhomogeneously 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 T2 and gradient echo images. HiSS images obtained after injection of the contrast agent showed T *2 and T1 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. Magn Reson Med 43:633–639, 2000.

Functional and Anatomic Imaging of Tumor Vasculature ☆: High-Resolution MR Spectroscopic Imaging Combined with a Superparamagnetic Contrast Agent

The advantages of incorporating spectroscopic information into magnetic resonance imaging (MRI) data sets were demonstrated by Dixon (1) and later by others (2,3). This early work focused on imaging water and fat signals with low spectral resolution combined with high spatial resolution. More recently, improvements in MR instrumentation have encouraged detection of water and fat with both high spatial and spectral resolution (HiSS) MR to improve anatomic detail and contrast (4–8) in tissues with broad and complex water proton resonances. This is particularly important in tumors but may also be applicable to imaging regions in the brain that have been damaged by stroke and other conditions associated with hemorrhage and necrosis. HiSS can improve imaging of the effects of endogenous and injected contrast agents. For example, in this laboratory, HiSS has been used to image changes in deoxyhemoglobin levels in tumors caused by tumor-oxygenating agents and hemodynamic challenges (6,7,9). HiSS is also useful for imaging effects of synthetic contrast agents. The data presented here illustrate the use of HiSS to detect superparamagnetic contrast agents. Superparamagnetic MR contrast agents provide a unique opportunity to detect tumors, define tumor anatomy, delineate tumor boundaries, and evaluate vascular structure and function of tumors. The complexity of the effects of these agents provides new mechanisms for contrast in MR images but also poses a challenge for MRI. Iron oxide particles with small diameters have very large Rl and R2* (longitudinal and transverse relaxivities), and both effects may be spectrally inhomogeneous (ie, different components of the water resonance in each voxel are affected differently). The results presented here suggest that to measure these effects independently, accurately, and with a high signal-to-noise ratio, it is advantageous to acquire spectroscopic images with high spectral and spatial resolution.

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.

Prospects for Assessment of the Effects of Electrical Injury by Magnetic Resonancea

Magnetic resonance (MR) methods allow noninvasive studies of tissue anatomy, blood flow, and metabolism, with high spatial resolution. Therefore, MR methods may be useful for noninvasive assessment of the effects of electrical shock on living tissue and on the response of tissue to therapy. Serial studies of a single experimental animal can be performed before and after an injury and throughout the entire course of therapy. Such studies would allow the correlation of physiological and metabolic changes during therapy with the ultimate therapeutic outcome. MR methods that are developed using model systems may eventually be used to guide treatment of patients. A wide variety of MR methods can be applied to the study of effects of electrical injury. Examples of applications of these methods to study tissue pathology are described below and possible applications to the problem of electrical injury are discussed.