Image of time to 80% refill of contrast agent in a pagasagittal view of a kidney. (click to enlarge)
With the advent of anti-angiogenic cancer therapies, effective treatment will require imaging techniques and other surrogates that can establish the optimal dose, provide an early assessment of efficacy, and reduce toxicity associated with systemic delivery of hydrophic drugs. Ultrasound can play a major role in both the assessment of therapeutic efficacy and the improvement of therapeutic delivery. While molecular imaging will be important for understanding angiogenesis and anti-angiogenic therapies, ultrasound can continually evaluate the cumulative effects of biochemical pathway changes on the resulting vascular structure and function. Preliminary studies in a tumor model have shown that microvascular density and flow rate can be estimated over time, and the resulting map of viable tumor volume correlates with histology. Tumors that reach 1-3 centimeters in diameter demonstrate heterogeneous perfusion and include regions with a blood velocity less than 1 mm/s. Pre-clinical studies with new anti-angiogenic drugs will also be conducted in a cross-modality study to create spatial maps of flow rate, vascular density, vascular permeability, and glucose metabolism, using ultrasound, PET, and CT. A small molecule inhibitor of VEGF, bFGF, and PDGF receptor tyrosine kinase activity is the anti-angiogenic drug that is applied. As correlates, P53, bFGF, and VEGF expression and apoptosis and cell proliferation are evaluated. The resulting flow, permeability, and metabolic data are used to create measures that predict the success or failure of a therapy.
Both the time required for contrast agent refill and the integrated area under the echo amplitude curve can be estimated. An example of the time to 80% refill for a parasagittal view of the kidney is shown below. Large arteries with very rapid flow are shown in orange. In some regions, the subharmonic return consists of only a few discrete events, without a true rising exponential and these regions are shown as the slowest flow (red).
Image of time to 80% refill of contrast agent in a pagasagittal view of a kidney. (click to enlarge)
The contrast agent refill in the kidney occurs in a few seconds. Tumors exhibit substantially different flow patterns-the time required for refill can range up to 35 seconds.
We have completed a study of contrast-enhanced imaging in a mammary adenocarcinoma model. Images of integrated area and reperfusion time in experimental tumors were created and we are comparing the results to ultrasound images from the kidney, contrast-enhanced CT, and histology.
An image of tumor reperfusion in an adenocarcinoma using our technique (click to enlarge)
We are currently studying how the contrast enhancement and reperfusion times vary in response to an experimental anti-angiogenic therapy (anti-angiogenic therapies aim to halt or reverse tumor growth by interfering with the creation of new tumor blood vessels).
Images of time to 80% reperfusion in an mammary adenocarcinoma before, 6 hours after, and 24 hours after start of antiangiogenic therapy. (click to enlarge)