Comparing post-operative human breast specimen radiograph and MRI in lesion margin and volume assessment.

The purpose of this research is to evaluate the potential for identifying malignant breast lesions and their margins on large specimen MRI, in comparison to specimen radiography and clinical dynamic contrast enhanced MRI (DCE-MRI). Breast specimens were imaged with an MR scanner immediately after surgery, with an IRB-approved protocol and with the patients' informed consent. Specimen sizes were at least 5 cm in diameter and approximately 1 to 4 cm thick. Coronal and axial gradient echo MR images without fat suppression were acquired over the whole specimens using a 9.4T animal scanner. Findings on specimen MRI were compared with findings on specimen radiograph, and their volumes were compared with measurements obtained from clinical DCE-MRI. The results showed that invasive ductal carcinoma (IDC) lesions were easily identified using MRI and the margins were clearly distinguishable from nearby tissue. However, ductal carcinoma in situ (DCIS) lesions were not clearly discernible and were diffused with poorly defined margins on MRI. Calcifications associated with DCIS were visualized in all specimens on specimen radiograph. There is a strong correlation between the maximum diameter of lesions as measured by radiograph and MRI (r = 0.93), as well as the maximum diameter measured by pathology and radiograph/MRI (r>0.75). The volumes of IDC measured on specimen MRI were slightly smaller than those measured on DCE-MRI. Imaging of excised human breast lumpectomy specimens with high magnetic field MRI provides promising results for improvements in lesion identification and margin localization for IDC. However, there are technical challenges in visualization of DCIS lesions. Improvements in specimen imaging are important, as they will provide additional information to standard radiographic analysis.

High-resolution MRI of excised human prostate specimens acquired with 9.4T in detection and identification of cancers: validation of a technique.

PURPOSE: To evaluate feasibility of high-resolution, high-field ex vivo prostate magnetic resonance imaging (MRI) as an aid to guide pathologists' examination and develop in vivo MRI methods. MATERIALS AND METHODS: Unfixed excised prostatectomy specimens (n = 9) were obtained and imaged immediately after radical prostatectomy under an Institutional Review Board-approved protocol. High-resolution T2-weighted (T2W) MRI of specimens were acquired with a Bruker 9.4 T scanner to correlate with whole-mount histology. Additionally, T2 and apparent diffusion coefficient (ADC) maps were generated. RESULTS: By visual inspection of the nine prostate specimens imaged, high-resolution T2W MRI showed improved anatomical detail compared to published low-resolution images acquired at 4 T as published by other investigators. Benign prostatic hyperplasia, adenocarcinomas, curvilinear duct architecture distortion due to adenocarcinomas, and normal radial duct distribution were readily identified. T2 was ≈10 msec longer (P < 0.03) and the ADC was ≈1.4 times larger (P < 0.002) in the normal peripheral zone compared to the peripheral zone with prostate cancer. CONCLUSION: Differences in T2 and ADC between benign and malignant tissue are consistent with in vivo data. High-resolution, high-field MRI has the potential to improve the detection and identification of prostate structures. The protocols and techniques developed in this study could augment routine pathological analysis of surgical specimens and guide treatment of prostate cancer patients.

Can DCEMRI assess the effect of green tea on the angiogenic properties of rodent prostate tumors?

The purpose of this research was to test whether dynamic contrast enhanced MRI could assess the effect of green tea on the angiogenic properties of transplanted rodent tumors. Copenhagen rats bearing AT6.1 prostate tumors inoculated in the hind limbs were randomly assigned to cages in which they were allowed to only drink either plain water (control group) or water containing green tea extract (treated group). Assignments were made after a baseline MRI experiment (week 0) was performed on each rat at 4.7T. All the rats were subsequently imaged at day 7 (week 1) and day 14 (week 2) to follow tumor growth and vascular development. The two-compartment pharmacokinetic model was used to analyze the dynamic contrast Gd-DTPA enhanced MRI data on a pixel-by-pixel basis over the tumor area to obtain the volume transfer constant (K(trans)) and extravascular extracellular space (v(e)). An identity Chi-squared test showed that the distributions of averaged histograms (n=6) of K(trans) and v(e) were significantly different from week 0 to both weeks 1 and 2 (p<0.001) in both the control and the treated rats due to increasing areas of tumor necrosis. However, the tumor growth rate was statistically indistinguishable between control and treated rats. There was no significant difference in the distributions of K(trans) and v(e) between control and treated rats. The results showed that no effects of green tea on tumor micro-vasculature were measurable by dynamic Gd-DTPA enhanced MRI.

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.

Multi-slice DCE-MRI data using P760 distinguishes between metastatic and non-metastatic rodent prostate tumors.

An intermediate molecular weight contrast agent P760 was used to investigate the ability of multi-slice dynamic contrast-enhanced MRI (DCE-MRI) to distinguish metastatic from non-metastatic rodent prostate tumors. Non-metastatic AT2.1 and metastatic AT3.1 prostate tumors originally derived from the Dunning prostate cancer model were implanted on the hind leg of Copenhagen rats. Multi-sliced DCE-MRI data were acquired on a SIGNA 1.5 T scanner and analyzed using a recently developed empirical mathematical model. The P760 multi-slice DCE-MRI data in combination with the empirical mathematical model successfully distinguished between metastatic and non-metastatic rodent prostate tumors. Specifically, fitting the data with the empirical model showed that metastatic tumors had significantly faster contrast media uptake (p<0.001) and slower washout rates (p<0.01) than non-metastatic tumors.

Comparison of high-resolution echo-planar spectroscopic imaging with conventional MR imaging of prostate tumors in mice.

High spectral and spatial resolution (HiSS) MRI of rodent tumors has previously been performed using conventional spectroscopic imaging to obtain images with improved contrast and anatomic detail. The work described here evaluates the use of much faster echo-planar spectroscopic imaging (EPSI) to acquire HiSS data from rodent tumor models of prostate cancer. A high-resolution EPSI pulse sequence was implemented on a 4.7 T Bruker scanner. Three-dimensional EPSI data were Fourier-transformed along the k-space and temporal (free-induction decay) axes to produce detailed water and fat spectra associated with each small image voxel. The data were used to generate images of spectral parameters, e.g. peak-height images for each small voxel. Two variants of EPSI were performed; gradient-echo or spin-echo excitation with EPSI readout. These imaging methods were tested in commonly used rodent prostate cancers, including seven mice implanted with non-metastatic AT2.1 (n=3) and metastatic AT3.1 (n=4) prostate tumors on the hind leg, and 10 mice implanted with LNCaP prostate cancers in situ. The peak-height images derived from EPSI datasets provide more detailed tumor anatomy, improved signal-to-noise and contrast-to-noise ratios compared with the gradient-echo or spin-echo images at all echo times. The results suggest that HiSS MRI data from small animal models of prostate cancer can be acquired using EPSI, and that this approach improves imaging of heterogeneous tissue and vascular environments inside the tumors compared with conventional MR techniques.

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.

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 (approximately 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 (approximately 0-6 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 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.

Effect of carbogen on tumor oxygenation: combined fluorine-19 and proton MRI measurements.

PURPOSE: Blood oxygen level dependent (BOLD) contrast in magnetic resonance imaging (MRI) has been widely used for noninvasive evaluation of the effects of tumor-oxygenating agents. However, there have been few tests of the validity of this method. The goal of the present work was to use the T(1) of fluorine-19 in perfluorocarbon (PFC) emulsions as a "gold standard" for comparison with BOLD MRI. MATHODS AND MATERIALS: Rats bearing R3230AC tumors implanted in the hind limb were injected with an emulsion of perfluoro-15-crown-5-ether for 2-3 days before experiments, which ensured that the PFC emulsion concentrated in the tumors. We correlated changes in tumor oxygenation caused by carbogen inhalation measured by (1)H BOLD MRI with quantitative (19)F measurements. The (19)F spin-lattice relaxation rate R(1) (= 1/T(1)) was measured to determine initial oxygen tension (pO(2)) in each image pixel containing the PFC, and changes in pO(2) during carbogen (95% O(2), 5% CO(2)) breathing. In a second carbogen breathing period, changes in water signal linewidth were measured using high spectral and spatial resolution imaging. (19)F and (1)H measurements were used to classify pixels as responders to carbogen (pixels where oxygen increased significantly) or nonresponders (no significant change in tumor oxygenation). RESULTS: The (19)F and (1)H measurements agreed in 65% +/- 11% of pixels (n = 14). Agreement was even stronger among pixels where (1)H showed increased oxygenation; (19)F measurements agreed with (1)H measurements in over 79% +/- 11% of these pixels. Similarly, there was strong agreement between the two modalities in pixels where (19)F reported no change in pO(2); (1)H also showed no changes in 76% +/- 18% of these pixels. Quantitative correlation of changes T(2)* (DeltaT(2)*) in (1)H and changes R(1) (DeltaR(1)) in (19)F was weak during carbogen breathing, and averaged over the whole tumor was approximately 0.40 for 14 experiments. However, the spatial patterns of (1)H and (19)F changes were qualitatively very similar. In hypoxic regions that were identified based on long (19)F T(1) (>2.53 s), (19)F and (1)H MRI agreed that carbogen had relatively weak effects. CONCLUSIONS: These results suggest that (1)H BOLD MRI reliably identifies increases in tumor pO(2). In hypoxic regions where increases in pO(2) are most desirable, carbogen was ineffective. The data suggest that (19)F and (1)H MRI can be used individually or in combination to guide the design of improved tumor-oxygenating agents.

Spectrally inhomogeneous BOLD contrast changes detected in rodent tumors with high spectral and spatial resolution MRI.

MRI detects changes in blood-oxygenation-level dependent (BOLD) contrast in tumors caused by tumor oxygenating agents. These changes can be used to guide the design of improved tumor oxygenating treatments (TOXs). The conventional approach to detection of BOLD effects assumes that the water resonance is a single, homogeneously broadened Lorentzian line, and that changes in the T2* of this line owing to changes in deoxyhemoglobin are spectrally homogeneous. This model may not adequately describe BOLD contrast changes in complex water resonances that are often detected in tumors. The present work investigated: (a) whether changes in the water resonance in very small voxels caused by tumor oxygenating agents are spectrally inhomogeneous; and (b) whether high spectral and spatial resolution (HiSS) MRI of the water and fat resonances detects these changes more accurately than conventional gradient-recalled echo (GRE) imaging. Carbogen (95% oxygen, 5% CO2) was used to increase tumor oxygenation. In two tumor models [mammary adenocarcinoma (R3230Ac; n=5) and rhabdomyosarcoma (BA1112; n=5)] proton signals were often complex and inhomogeneously broadened. Spectrally inhomogeneous changes during carbogen breathing occurred in at least 10% of the R3230AC tumor voxels that responded to carbogen and 18% of BA1112 tumor voxels. The largest changes during carbogen breathing in many voxels occurred at frequencies that were significantly different from the frequency of the primary water peak. Carbogen-induced changes in proton T2* detected by simulated GRE and HiSS differed by more than 75% in 67% of voxels in R3230Ac tumors and in 65% of voxels in BA1112 tumors. The spectrally inhomogeneous effects of tumor oxygenating agents may reflect changes in sub-voxelar microenvironements and thus may be important for accurate evaluation of the effects of therapy.