Marta Zamora

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.

MRI measurements correctly predict the relative effects of tumor oxygenating agents on hypoxic fraction in rodent BA1112 tumors.

PURPOSE We evaluate whether magnetic resonance imaging (MRI) with blood oxygenation level-dependent (BOLD) contrast correctly predicts the relative effects of tumor-oxygenating agents on hypoxic fraction in BA1112 rhabdomyosarcomas in WAG/Rij rats. METHODS AND MATERIALS The response of ten tumors to carbogen (95% O(2)/5% CO(2)), a perfluorocarbon emulsion (PFC), and the combination of PFC + carbogen was studied with high spectral and spatial resolution MR imaging of the water resonance at 4.7 Tesla. Decreases in MR signal linewidth indicate increases in tumor blood oxygen levels. RESULTS Average MR signal linewidth was decreased 2.0% by carbogen, 2.5% by PFC + air, and 4.9% by PFC + carbogen. PFC + carbogen caused a larger linewidth decrease than either treatment alone (p < 0.04 by ANOVA). Maps of pixels responding to treatment indicate that combining PFC with carbogen significantly enlarges the area of the tumor in which oxygen levels are increased (p < 0.01 by ANOVA). CONCLUSION MRI predicts that PFC + carbogen will increase radiosensitivity more than either treatment alone; this agrees with the known effects of these treatments on hypoxic fraction. Utilizing MRI to choose the treatment that maximizes the size and extent of increases in tumor oxygenation could reduce hypoxic fraction.

Reproducibility assessment of a multiple reference tissue method for quantitative dynamic contrast enhanced–MRI analysis

Bone metastases of 16 prostate cancer patients were scanned twice 1 week apart by dynamic contrast enhanced (DCE) –MRI at 2‐s resolution using a two‐dimensional gradient‐echo pulse sequence. With a multiple reference tissue method (MRTM), the local tissue arterial input function (AIF) was estimated using the contrast agent enhancement data from tumor subregions and muscle. The 32 individual AIFs estimated by the MRTM, which had considerable intra‐patient and inter‐patient variability, were similar to directly measured AIFs in the literature and using the MRTM AIFs in a pharmacokinetic model to derive estimated individual cardiac outputs provided physiologically reasonable results. The MRTM individual AIFs gave better fits with smaller sum of squared errors and equally reproducible estimate of kinetic parameters compared with a previous reported population AIF measured from remote arteries. The individual MRTM AIFs were also used to obtain a mean local tissue AIF for the unique population of this study, which further improved the reproducibility of the estimated kinetic parameters. The MRTM can be applied to DCE‐MRI studies of bone metastases from prostate cancers to provide an AIF from which reproducible quantitative DCE‐MRI parameters can be derived, thus help standardize DCE‐MRI studies in cancer patients. Magn Reson Med, 2009.

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.

Reduction of spectral ghost artifacts in high‐resolution echo‐planar spectroscopic imaging of water and fat resonances

Echo‐planar spectroscopic imaging (EPSI) can be used for fast spectroscopic imaging of water and fat resonances at high resolution to improve structural and functional imaging. Because of the use of oscillating gradients during the free induction decay (FID), spectra obtained with EPSI are often degraded by Nyquist ghost artifacts arising from the inconsistency between the odd and even echoes. The presence of the spectral ghost lines causes errors in the evaluation of the true spectral lines, and this degrades images derived from high‐resolution EPSI data. A technique is described for reducing the spectral ghost artifacts in EPSI of water and fat resonances, using echo shift and zero‐order phase corrections. These corrections are applied during the data postprocessing. This technique is demonstrated with EPSI data acquired from human brains and breasts at 1.5 Tesla and from a water phantom at 4.7 Tesla. Experimental results indicate that the present approach significantly reduces the intensities of spectral ghosts. This technique is most useful in conjunction with high‐resolution EPSI of water and fat resonances, but is less applicable to EPSI of metabolites due to the complexity of the spectra. Magn Reson Med 49:1113–1120, 2003.

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.

High-resolution magnetic resonance colonography and dynamic contrast-enhanced magnetic resonance imaging in a murine model of colitis

Inflammatory bowel disease, including ulcerative colitis, is characterized by persistent or recurrent inflammation and can progress to colon cancer. Colitis is difficult to detect and monitor noninvasively. The goal of this work was to develop a preclinical imaging method for evaluating colitis. Herein, we report improved MRI methods for detecting and characterizing colitis noninvasively in mice, using high‐resolution in vivo MR images and dynamic contrast‐enhanced MRI studies, which were confirmed by histologic studies in a murine model of colitis. C57Bl6/J male mice were treated with 2.5% dextran sulfate sodium in their drinking water for 5 days to induce colitis. MR images were acquired using a 9.4‐T Bruker scanner from 5–25 days following dextran sulfate sodium treatment. In dynamic contrast‐enhanced MRI studies, Gd uptake (Ktrans) and its distribution (ve) were measured in muscle and normal and inflamed colons after administering Gd‐diethyltriaminepentaacetic acid (Gd‐DTPA). T2‐weighted MR images distinguished normal colon from diffusely thickened colonic wall occurring in colitis (P <0.0005) and correlated with histologic features. Values of Ktrans and ve obtained from dynamic contrast‐enhanced MRI were also significantly different in inflamed colons compared to normal colon (P < 0.0005). The results demonstrate that both T2‐weighted anatomic imaging and quantitative analysis of dynamic contrast‐enhanced MRI data can successfully distinguish colitis from normal colon in mice. Magn Reson Med 63:922–929, 2010.

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.

Sensitivity to tumor microvasculature without contrast agents in high spectral and spatial resolution MR images

Contrast‐enhanced (CE)‐MRI is sensitive to cancers but can produce adverse reactions and suffers from insufficient specificity and morphological detail. This research investigated whether high spectral and spatial resolution (HiSS) MRI detects tumor vasculature without contrast agents, based on the sensitivity of the water resonance line shape to tumor blood vessels. HiSS data from AT6.1 tumors inoculated in the hind legs of rats (N = 8) were collected pre‐ and post–blood pool contrast agent (iron‐oxide particles) injection. The waterline in small voxels was significantly more asymmetric at the tumor rim compared to the tumor center and normal muscle (P < 0.003). Composite images were synthesized, with the intensity in each voxel determined by the Fourier component (FC) of the water resonance having the greatest relative image contrast at that position. We tested whether regions with high contrast in FC images (FCIs) contain vasculature by comparing FCIs with CE‐MRI as the “gold standard” of vascular density. The FCIs had 75% ± 13% sensitivity, 74% ± 10% specificity, and 91% ± 4% positive predictive value (PPV) for vasculature detection at the tumor rim. These results suggest that tumor microvasculature can be detected using HiSS imaging without the use of contrast agents. Magn Reson Med 61:291–298, 2009.

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.