Faculty Bibliography

Although there have been many advancements in cancer research, much is still unknown about the heterogeneous tumor microenvironment. Diffusion-weighted MRI has proven to be a viable and versatile microstructural probe. Diffusion-weighted sequences specifically sensitive to intravoxel incoherent motion (IVIM) have seen a recent resurgence of interest as they promise to provide a valuable window on the vascular microenvironment. To understand, test, and optimize IVIM-sensitive approaches, a complex flow phantom was constructed to mimic certain characteristics of the tumor microenvironment such as tortuous microvasculature, heterogeneous vascular permeability, and interstitial fluid pressure buildup. Results using this phantom on a clinical scanner platform confirmed IVIM sensitivity to microscopic flow effects. Biexponential fitting of signal decay curves enabled quantitative extraction of perfusion fraction, IVIM-related pseudodiffusivity, and tissue diffusivity. Parametric maps were also generated, illustrating the potential utility of IVIM-sensitive imaging in clinical settings. The flow phantom proved to be an effective test-bed for validating and optimizing the IVIM-MRI technique to provide surrogate markers for microvascular properties. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc

The effective delivery of a therapeutic drug to the core of a tumor is often impeded by physiological barriers, such as the interstitial fluid pressure (IFP). There are a number of therapies that can decrease IFP and induce tumor vascular normalization. However, a lack of a noninvasive means to measure IFP hinders the utilization of such a window of opportunity for the maximization of the treatment response. Thus, the purpose of this study was to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion parameters as noninvasive imaging biomarkers for IFP. Mice bearing the 4T1 mammary carcinoma model were studied using diffusion-weighted imaging (DWI), immediately followed by wick-in-needle IFP measurement. Voxelwise analysis was conducted with a conventional monoexponential diffusion model, as well as a biexponential model taking IVIM into account. There was no significant correlation of IFP with either the median apparent diffusion coefficient from the monoexponential model (r = 0.11, p = 0.78) or the median tissue diffusivity from the biexponential model (r = 0.30, p = 0.44). However, IFP was correlated with the median pseudo-diffusivity (D(p) ) of apparent vascular voxels (r = 0.76, p = 0.02) and with the median product of the perfusion fraction and pseudo-diffusivity (f(p) D(p) ) of apparent vascular voxels (r = 0.77, p = 0.02). Although the effect of IVIM in tumors has been reported previously, to our knowledge, this study represents the first direct comparison of IVIM metrics with IFP, with the results supporting the feasibility of the use of IVIM DWI metrics as noninvasive biomarkers for tumor IFP

Diffusion-weighted imaging plays important roles in cancer diagnosis, monitoring, and treatment. Although most applications measure restricted diffusion by tumor cellularity, diffusion-weighted imaging is also sensitive to vascularity through the intravoxel incoherent motion effect. Hypervascularity can confound apparent diffusion coefficient measurements in breast cancer. We acquired multiple b-value diffusion-weighted imaging at 3 T in a cohort of breast cancer patients and performed biexponential intravoxel incoherent motion analysis to extract tissue diffusivity (D(t) ), perfusion fraction (f(p) ), and pseudodiffusivity (D(p) ). Results indicated significant differences between normal fibroglandular tissue and malignant lesions in apparent diffusion coefficient mean (+/-standard deviation) values (2.44 +/- 0.30 vs. 1.34 +/- 0.39 mum(2) /msec, P < 0.01) and D(t) (2.36 +/- 0.38 vs. 1.15 +/- 0.35 mum(2) /msec, P < 0.01). Lesion diffusion-weighted imaging signals demonstrated biexponential character in comparison to monoexponential normal tissue. There is some differentiation of lesion subtypes (invasive ductal carcinoma vs. other malignant lesions) with f(p) (10.5 +/- 5.0% vs. 6.9 +/- 2.9%, P = 0.06), but less so with D(t) (1.14 +/- 0.32 mum(2) /msec vs. 1.18 +/- 0.52 mum(2) /msec, P = 0.88) and D(p) (14.9 +/- 11.4 mum(2) /msec vs. 16.1 +/- 5.7 mum(2) /msec, P = 0.75). Comparison of intravoxel incoherent motion biomarkers with contrast enhancement suggests moderate correlations. These results suggest the potential of intravoxel incoherent motion vascular and cellular biomarkers for initial grading, progression monitoring, or treatment assessment of breast tumors. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc