Delta-projection Imaging on Contrast-enhanced Ultrasound to Quantify Tumor Microvasculature and Perfusion

Rationale and Objectives

The aim of this study was to assess the Δ-projection image processing technique for visualizing tumor microvessels and for quantifying the area of tissue perfused by them on contrast-enhanced ultrasound images.

Materials and methods

The Δ-projection algorithm was implemented to quantify perfusion by tracking the running maximum of the difference (Δ) between the contrast-enhanced ultrasound image sequence and a baseline image. Twenty-five mice with subcutaneous K1735 melanomas were first imaged with contrast-enhanced grayscale and then with minimum-exposure contrast-enhanced power Doppler (minexCPD) ultrasound. Delta-projection images were reconstructed from the grayscale images and then used to evaluate the evolution of tumor vascularity during the course of contrast enhancement. The extent of vascularity (ratio of the perfused area to the tumor area) for each tumor was determined quantitatively from Δ-projection images and compared to the extent of vascularity determined from contrast-enhanced power Doppler images. Delta-projection and minexCPD measurements were compared using linear regression analysis.

Results

Delta-projection was successfully performed in all 25 cases. The technique allowed the dynamic visualization of individual blood vessels as they filled in real time. Individual tumor blood vessels were distinctly visible during early image enhancement. Later, as an increasing number of blood vessels were filled with the contrast agent, clusters of vessels appeared as regions of perfusion, and the identification of individual vessels became difficult. Comparisons were made between the perfused area of tumors in Δ-projections and in minexCPD images. The Δ-projection perfusion measurements were correlated linearly with minexCPD.

Conclusion

Delta-projection visualized tumor vessels and enabled the quantitative assessment of the tumor area perfused by the contrast agent.

Vascular targeting has evolved into an attractive approach for cancer therapy. Disruption of the tumor vasculature deprives the neoplasm of oxygen and eventually leads to tumor cell death. Several promising vascular disrupting agents (VDAs), including pharmaceutical ( ) and non-pharmaceutical ( ) agents, are currently being investigated in different phases of clinical trials. Such VDA evaluation requires an accurate method for the direct assessment of tumor vascularity in response to treatment. Measurement of tissue microvessel density by tumor biopsy is a potential approach for monitoring therapy. However, repeated assessment is often not possible, because of the invasive nature of the technique, and the procedure is prone to sampling error due to the small sample size. The destruction of blood vessels by the probing biopsy needle could further complicate the assessment. The direct visualization of tumor vasculature by imaging is an attractive alternative for assessing VDAs because it can be performed repeatedly, and it provides a global view of the change in tumor vascularity, either across an anatomic plane or over the entire tumor volume.

Diagnostic ultrasound is one of the most commonly used modalities for cancer imaging. The equipment is portable and is widely available in large and small imaging centers. It provides both high spatial and temporal resolution, and the Doppler mode enables the direct visualization of tumor blood vessels. Currently, clinical scanners allow the visualization of blood vessels that are 0.2 to 0.5 mm in diameter, but to image smaller blood vessels similar to those targeted by VDAs, ultrasound contrast agents must be used. Various ultrasound techniques have been proposed that use contrast agents in combination with power Doppler ( ) or grayscale imaging (fundamental ( ), harmonic ( ), or subharmonic ( )). Each approach has its strengths and weaknesses.

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Materials and Methods

Animal and Imaging Studies

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Description of the Δ-Projection Imaging Algorithm

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Image Analysis for Δ-Projection and minexCPD