Kjetil G. Brurberg

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.

Fluctuations in pO2 in Irradiated Human Melanoma Xenografts

Abstract Brurberg, K. G., Thuen, M., Ruud, E. B. M. and Rofstad, E. K. Fluctuations in pO2 in Irradiated Human Melanoma Xenografts. Radiat. Res. 165, 16–25 (2006). Several studies have demonstrated that untreated tumors may show significant fluctuations in tissue oxygen tension (pO2). Radiation treatment may induce changes in the tumor microenvironment that alter the pO2 fluctuation pattern. The purpose of the present study was to investigate whether pO2 fluctuations may also occur in irradiated tumors. A-07 human melanoma xenografts were irradiated with single doses of 0, 5 or 10 Gy. Fluctuations in pO2 were recorded with OxyLite probes prior to irradiation and 24 and 72 h after the radiation exposure. Radiation-induced changes in the tumor microenvironment (i.e. blood perfusion and extracellular volume fraction) were assessed by dynamic contrast-enhanced magnetic resonance imaging. Seventy-two hours after 10 Gy, tumor blood perfusion had decreased to ∼40% of that prior to irradiation, whereas the extracellular volume fraction had increased by ∼25%. Fluctuations in pO2 were seen in most tumors, irrespective of radiation dose and time after irradiation. The mean pO2, the number of fluctuations around the mean pO2, the number of fluctuations around threshold pO2 values of 1, 2, 3, 5, 7 and 10 mmHg, and the amplitude of the fluctuations were determined for each pO2 trace. No significant differences were detected between irradiated and unirradiated tumors. The results showed that pO2 fluctuations may occur in irradiated tumors and that the pO2 fluctuation pattern in A-07 tumors exposed to 5 or 10 Gy is similar to that in untreated tumors. Consequently, these doses did not induce changes in the tumor microenvironment that were sufficient to cause detectable alterations in the pO2 fluctuation pattern.

Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure

BACKGROUND AND PURPOSE High interstitial fluid pressure (IFP) in the primary tumor has been shown to promote metastasis in melanoma xenografts and to predict for poor survival in cervical cancer patients. The potential usefulness of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessing tumor IFP noninvasively was investigated in the present study. MATERIALS AND METHODS A-07 and R-18 melanoma xenografts with and without necrotic regions were subjected to DCE-MRI and subsequent measurement of IFP. Tumor images of E.F (E is the initial extraction fraction of Gd-DTPA and F is blood perfusion) and lambda (lambda is proportional to extracellular volume fraction) were produced by Kety analysis of DCE-MRI series. RESULTS In tumors without necrosis, significant inverse correlations were found between E.F and IFP, both for A-07 and R-18 tumors, and between lambda and IFP for A-07 tumors. Significant correlations between E.F and IFP or between lambda and IFP could not be detected for tumors with necrotic regions. CONCLUSIONS DCE-MRI may be developed to be a useful noninvasive method for assessing IFP in tumors without necrosis. This possibility warrants further studies involving several physiologically different experimental tumor lines, as well as human tumors.

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).