Ilana C. Benjaminsen

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

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 mm3 with spoiled gradient‐recalled sequences. We obtained images of E · F (where E is the extraction fraction, and F is perfusion) by subjecting DCE‐MR images to Kety analysis. We obtained highly reproducible E · 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 · F should be a well‐suited parameter for describing tumor blood perfusion. Observations consistent with this hypothesis were made by comparison of E · F‐images with immunostained histological preparations from the imaged sections. The E · F images mirrored the histological appearance of the tumor tissue perfectly. Quantitative studies showed that E · 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 · F was almost identical to that in the blood supply, as assessed by the use of Na99mTcO4 as a perfusion tracer. Taken together, our observations show that high‐resolution images reflecting tumor blood perfusion can be obtained by DCE‐MRI. Magn Reson Med 52:269–276, 2004.

Fluctuations in tumor blood perfusion assessed by dynamic contrast-enhanced MRI.

Temporal heterogeneity in blood perfusion is a common phenomenon in tumors, but data characterizing the nature of the blood flow fluctuations are sparse. This study investigated the occurrence of blood flow fluctuations in A‐07 melanoma xenografts by using gadopentetate dimeglumine (Gd‐DTPA)‐based dynamic contrast‐enhanced MRI (DCE‐MRI). Each tumor was subjected to two DCE‐MRI acquisitions separated by 1 hour. The data were processed by Kety analysis and resulted in two E · F images (E is the initial extraction fraction of Gd‐DTPA and F is the perfusion) and two λ images (λ is the partition coefficient of Gd‐DTPA) for each tumor. The E · F images were used to determine the changes in blood perfusion arising in the time between the two imaging sequences. The λ images were used to control the reproducibility of the experimental procedure. The study showed that DCE‐MRI with subsequent Kety analysis is a useful method for detection of blood flow fluctuations in A‐07 tumors, and strongly suggested that the peripheral regions of A‐07 tumors are more exposed to temporal changes in blood perfusion than are the central regions. Magn Reson Med 58:473–481, 2007.

Assessment of fraction of radiobiologically hypoxic cells in human melanoma xenografts by dynamic contrast-enhanced MRI

A noninvasive method for assessment of the extent of hypoxia in experimental and human tumors is highly needed. In this study, the potential usefulness of dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) was investigated, using gadopentetate dimeglumine (Gd‐DTPA) as contrast agent and A‐07 human melanoma xenografts as tumor model. DCE‐MRI was performed at a voxel size of 0.3 × 0.6 × 2.0 mm3 with spoiled gradient‐recalled sequences. Images of E · F (E is the initial extraction fraction of Gd‐DTPA and F is perfusion) and λ (the partition coefficient of Gd‐DTPA, which is proportional to extracellular volume fraction) were obtained by Kety analysis of DCE‐MRI data. The study was based on the hypothesis that hypoxic tissue would have low E · F (i.e., poor oxygen supply) and/or low λ (i.e., high cell density and, hence, high oxygen consumption rate). Twenty‐two tumors were first subjected to DCE‐MRI and then to measurement of fraction of hypoxic cells, using a radiobiological assay. E · F was found to be strongly correlated to fraction of hypoxic cells (P < 0.000001), whereas significant correlation between λ and fraction of hypoxic cells could not be detected. It is thus possible that E · F may be a useful parameter for the extent of hypoxia in experimental and human tumors with physiologic properties similar to those of A‐07 tumors. This possibility warrants further studies involving experimental tumors of several lines, as well as human tumors. Magn Reson Med, 2006.

Comparison of tumor blood perfusion assessed by dynamic contrast-enhanced MRI with tumor blood supply assessed by invasive imaging

To evaluate the potential of Gd‐DTPA‐based dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) for providing high‐resolution tumor blood perfusion images.

Intratumor heterogeneity in blood perfusion in orthotopic human melanoma xenografts assessed by dynamic contrast-enhanced magnetic resonance imaging

To determine the intratumor heterogeneity in blood perfusion of orthotopic human melanoma xenografts by use of gadopentetate dimeglumine (Gd‐DTPA)‐based dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI).

Assessment of Fraction of Hypoxic Cells in Human Tumor Xenografts with Necrotic Regions by Dynamic Contrast-Enhanced MRI

Abstract Egeland, T. A. M., Gaustad, J-V., Benjaminsen, I. C., Hedalen, K., Mathiesen, B. and Rofstad, E. K. Assessment of Fraction of Hypoxic Cells in Human Tumor Xenografts with Necrotic Regions by Dynamic Contrast-Enhanced MRI. Radiat. Res. 169, 689–699 (2008). The potential usefulness of gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessing hypoxia in tumors with significant necrosis was investigated. Small (100–350 mm3) and large (500–1000 mm3) D-12 and U-25 tumors were subjected to DCE-MRI, measurement of the fraction of necrotic tissue, and measurement of the fraction of radiobiologically hypoxic cells. Images of E·F (E is the initial extraction fraction of Gd-DTPA and F is perfusion) and λ (λ is proportional to extracellular volume fraction) were produced by subjecting the DCE-MRI data to Kety analysis. Necrotic tissue could be identified in λ images but not in E·F images of the tumors. Most voxels in viable tissue showed λ values of 0.15–0.70, whereas the λ values of most voxels in necrotic tissue were either <0.15 or >0.70. The E·F and λ frequency distributions of the viable tissue, but not the E·F and λ frequency distributions of the whole tissue, were consistent with the observation that the four groups of tumors showed similar fractions of radiobiologically hypoxic cells. E·F and λ images may thus provide useful information on the extent of hypoxia in tumors provided that voxels in necrotic tumor regions are identified and excluded from the images.

Dynamic contrast-enhanced magnetic resonance imaging of human melanoma xenografts with necrotic regions.

To investigate whether high‐resolution images of necrotic regions in tumors can be derived from gadopentetate dimeglumine (Gd‐DTPA)‐based dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) series.

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

To investigate the potential of gadopentetate dimeglumine (Gd‐DTPA)‐based dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in detecting radiation‐induced changes in the fraction of radiobiologically hypoxic cells in A‐07 human melanoma xenografts.