Dynamic contrast-enhanced MR microscopy identifies regions of therapeutic response in a preclinical model of colorectal adenocarcinoma.

Abstract

A typical dynamic contrast-enhanced (DCE)-MRI study often compares the derived pharmacokinetic parameters on manually selected tumor regions or over the entire tumor volume. These measurements include domains where the interpretation of the biomarkers may be unclear (such as in necrotic areas). Here, the authors describe a technique for increasing the sensitivity and specificity of DCE-MRI by identifying tumor regions with a variable response to therapy. Two cohorts (n = 8/group) of nu/nu mice with LS-174T implanted in the mammary fat pad were imaged at five time points over four weeks. The treatment/control group received bevacizumab/saline at a dose of 5 mg/kg or 5 ml/kg twice weekly; imaging experiments were performed weekly. MR images were acquired at an isotropic resolution of 156 μm(3)(2.4 nl) and with a sampling rate of 9.9 s. The histogram of the time-to-peak (TTP) was used to identify two (fast- and slow-enhancing) regions based on a threshold of TTP = 1000 s. The regions were correlated with histology, and the effect of therapy was locally examined. Tumors in the treatment group had a significantly longer doubling time. The regions defined by thresholding the TTP histogram identified two distinct domains correlating significantly with tumor permeability and microvessel density. In the fast-enhancing region, the mean permeability constant (K(trans)) was significantly lower in the treatment group at day 9; in the slow-enhancing region, K(trans) was not different between the control and treatment groups. At day 9, the relative volume of the fast-enhancing region was significantly lower in the treatment group, while that of the slow-enhancing region was significantly higher. Two regions with distinct kinetic parameters were identified based on the histogram of TTP. The effect of bevacizumab, as measured by a decrease in K(trans), was confined to one of these regions. High spatiotemporal resolution MR studies may contribute unique insights into the response of the tumor microenvironment to therapy.