Assessment of tumor blood perfusion by high‐resolution dynamic contrast‐enhanced MRI: A preclinical study of human melanoma xenografts

Abstract

A noninvasive method to obtain high-resolution images of tumor blood perfusion is needed for individualized cancer treatments. In this study we investigated the potential usefulness of dynamic contrast-enhanced MRI (DCE-MRI), using human melanoma xenografts as models of human cancer. Gadopentetate dimeglumine (Gd-DTPA) was used as the contrast agent, and DCE-MRI was performed at a voxel size of 0.5 ؋ 0.2 ؋ 2.0 mm 3 with spoiled gradient-recalled sequences. We obtained images of E ⅐ F (where E is the extraction fraction, and F is perfusion) by subjecting DCE-MR images to Kety analysis. We obtained highly reproducible E ⅐ F images, which we verified by imaging heterogeneous tumors twice. We hypothesized that the extraction fraction of Gd-DTPA would be high and would not vary significantly in tumor tissue, implying that E ⅐ F should be a well-suited parameter for describing tumor blood perfusion. Observations consistent with this hypothesis were made by comparison of E ⅐ F-images with immunostained histological preparations from the imaged sections. The E ⅐ F images mirrored the histological appearance of the tumor tissue perfectly. Quantitative studies showed that E ⅐ F was highest in nonhypoxic tissue with high microvascular density, second highest in nonhypoxic tissue with low microvascular density, third highest in hypoxic tissue, and lowest in necrotic tissue. Moreover, the radial heterogeneity in E ⅐ F was almost identical to that in the blood supply, as assessed by the use of Na 99m TcO 4 as a perfusion tracer. Taken together, our observations show that highresolution images reflecting tumor blood perfusion can be obtained by DCE-MRI. Magn Reson Med 52:269 -276, 2004.

Limitations of dynamic contrast‐enhanced MRI in monitoring radiation‐induced changes in the fraction of radiobiologically hypoxic cells in human melanoma xenografts

“…Second, the DCE-MRI data were analyzed with the use of a mean arterial input function rather than individual arterial input functions, and thus any variation in the injection rate among mice was ignored. However, the mean arterial input function was established by analyzing 24 blood samples from 12 mice, and the data points suggested that the arterial input function did not differ significantly among mice (15). Furthermore, complete arterial input functions have been determined for individual mice by DCE-MRI of the heart, and these curves did not differ significantly from each other or from the mean arterial input function (15).…”

“…The DCE-MRI experiments and the subsequent image processing and analysis were carried out by using a procedure described in detail previously (15,18). Briefly, Gd-DTPA (Schering, Berlin, Germany) was administered intravenously in a bolus dose of 0.3 mmol/kg of body weight by using the protocol developed by Benjaminsen et al (15). The imaging was performed with a 1.5-T whole-body scanner (Signa, General Electric, Milwaukee, WI, USA) by using a 13-cm-long cylindrical slotted tube resonator transceiver mouse coil with a diameter of 40 mm.…”

“…Tumor images were analyzed on a voxel-by-voxel basis by using software developed in IDL (Interactive Data Language, Boulder, CO). Gd-DTPA concentrations were calculated from signal intensities by using the method of Hittmair et al (22), and to determine values for E ⅐ F and , the modified Kety equation (10) was fitted to plots of Gd-DTPA concentration versus time by using the arterial input function determined by Benjaminsen et al (15). The uncertainty in the assessment of E ⅐ F and was investigated by Monte Carlo analysis, using noise randomly generated from the Gaussian distribution of the residuals of the Kety curve fits.…”

“…Comparative studies have shown that E ⅐ F is positively correlated to microvascular density (15,18) and blood perfusion (16) in A-07 human melanoma xenografts, suggesting that the E of A-07 tumors is uniformly close to unity (17)(18)(19). Moreover, has been shown to be positively correlated to extracellular volume fraction in A-07 tumors (17,18).…”

“…Highly reproducible images of E ⅐ F (E ⅐ F is the extraction-perfusion product, where E represents the initial extraction fraction of Gd-DTPA and F represents the blood perfusion of the imaged tissue) and ( is the partition coefficient of Gd-DTPA and is assumed to be proportional to the extracellular volume fraction of the imaged tissue) can be obtained by subjecting experimental tumors to DCE-MRI and subsequent Kety modeling (15)(16)(17)(18)(19). Comparative studies have shown that E ⅐ F is positively correlated to microvascular density (15,18) and blood perfusion (16) in A-07 human melanoma xenografts, suggesting that the E of A-07 tumors is uniformly close to unity (17)(18)(19).…”