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A Method for Assessing the Microvasculature in a Murine Tumor Model Using Contrast-Enhanced Ultrasonography

Institute of Imaging Science (M.E.L., X.L., B.D., J.C.G., T.E.Y.) and Departments of Biomedical Engineering (M.E.L., D.H., J.C.G., T.E.Y.), Electrical Engineering and Computer Science (X.L., B.D.), Radiation Oncology (J.H., D.H.), Radiology and Radiological Sciences (A.L., J.C.G., T.E.Y.), Physics and Astronomy (J.C.G., T.E.Y.), and Cancer Biology (T.E.Y.), Vanderbilt University, Nashville, Tennessee USA.

Address correspondence to Thomas E. Yankeelov, PhD, Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Ave S, MCN AA-1105, Nashville, TN 37232-2675 USA. E-mail: thomas.yankeelov{at}vanderbilt.edu

Objective. The purpose of this study was to develop a method for assessing tumor vascularity in a preclinical model of breast cancer using contrast-enhanced ultrasonography. Methods. Eight mice were injected with 67NR breast cancer cells on their hind limbs and imaged with ultrasonography 8 days later. Mice were injected with an ultrasound contrast agent (UCA), and a sequence of images of the resultant backscattered echoes was recorded before and after high-power "destruction" pulses for each of multiple parallel planes. From these, data maps of the maximum contrast enhancement (within each time course) were constructed for each pixel, which enabled reconstruction of high-resolution coregistered sections into a 3-dimensional (3D) volume reflecting tumor vascularity. Additional studies were performed to determine the duration and repeatability of image enhancement, and images were correlated with conventional 3D power Doppler measurements. Results. The lifetime of the UCA in vivo was found to be 4.3 ± 1.09 minutes (mean ± SD). The 3D contrast-enhanced ultrasonographic technique produced images that correlated well with power Doppler images in specific regions but also depicted additional regions of flow surrounding the power Doppler signal. The mean correlation coefficient between voxel measurements of the central slice for each animal was 0.64 ± 0.07 (P < .01). In addition, sequential studies in each animal were reproducible. Conclusions. A method producing high-resolution volumetric assessments of tumor vascularity in a preclinical model of breast cancer is shown that correlates with other ultrasonographic measures of blood flow, which may provide greater sensitivity to the microvasculature.

Key Words: contrast-enhanced ultrasonography • tumor • vascularity

Abbreviations: CEVI, contrast-enhanced vascular imaging • MIP, maximum intensity projection • ROI, region of interest • TIC, time-intensity curve • 3D, 3-dimensional • 2D, 2-dimensional • UCA, ultrasound contrast agent