Noninvasive Quantification of Solid Tumor Microstructure Using VERDICT MRI

Abstract

There is a need for biomarkers that are useful for noninvasive imaging of tumor pathophysiology and drug efficacy. Through its use of endogenous water, diffusion-weighted MRI (DW-MRI) can be used to probe local tissue architecture and structure. However, most DW-MRI studies of cancer tissues have relied on simplistic mathematical models, such as apparent diffusion coefficient (ADC) or intravoxel incoherent motion (IVIM) models, which produce equivocal results on the relation of the model parameter estimate with the underlying tissue microstructure. Here, we present a novel technique called VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) to quantify and map histologic features of tumors in vivo. VERDICT couples DW-MRI to a mathematical model of tumor tissue to access features such as cell size, vascular volume fraction, intra-and extracellular volume fractions, and pseudo-diffusivity associated with blood flow. To illustrate VERDICT, we used two tumor xenograft models of colorectal cancer with different cellular and vascular phenotypes. Our experiments visualized known differences in the tissue microstructure of each model and the significant decrease in cell volume resulting from administration of the cytotoxic drug gemcitabine, reflecting the apoptotic volume decrease. In contrast, the standard ADC and IVIM models failed to detect either of these differences. Our results illustrate the superior features of VERDICT for cancer imaging, establishing it as a noninvasive method to monitor and stratify treatment responses. Cancer Res; 74(7); 1902-12. Ó2014 AACR.

Time-Dependent Diffusion MRI in Cancer: Tissue Modeling and Applications

“…This model successfully differentiated two human colorectal carcinoma cell lines based on their vascular fraction [16]: SW1222 xenografts exhibited dense perfusion (f v = 0.22) while LS174T ( Figure 5) were properly categorized as densely packed (f ecs < 0.05) with low perfusion (f v = 0.12). In addition, significant changes in intravascular and intracellular volume fractions were observed in response to a chemotoxic agent leading to cell apoptosis (gemcitabine), as confirmed by flow cytometry [16].…”

“…Additional parameters are required to describe the ECS diffusion outside the tortuosity limit (D = cste) and short-time regime (Equations 1-2), or to model additional compartments, such as vasculature with VERDICT [16]. In practice, multiple PGSE [16,45] or a combination of PGSE and OGSE [14,15] measurements are combined in order to probe diffusion in a specific or over several frequency/time domains.…”

“…Cancer cells are modeled by spheres, the extracellular diffusivity by an isotropic diffusion tensor, and the vascular compartment by an additional highly anisotropic tensor [16], although its precise form can vary depending on the application [49].…”

“…Using these results, the main models used to characterize tumor tissue using TDD are reviewed: IMPULSED [14], POMACE [15], and VERDICT [16]. Modeling cells as impermeable spheres, additional assumptions are made to describe the ECS, and finally estimate diffusivities, cell size and volume fraction ex vivo and in vivo.…”

Ground Truth for Diffusion MRI in Cancer: A Model-Based Investigation of a Novel Tissue-Mimetic Material

“…A model comprising monodisperse impermeable cylinders has also been used to estimate indices of axonal diameter and density in human brains [6]. Recently, impermeable spheres have been used to model tumour tissue, allowing cell size and volume fractions to be estimated in vivo [7]. The increasing interest in using such model-based analyses to extract specific microstructural information from DW-MRI data motivates the development of model systems where the ground truth can be independently determined and used to validate microstructural models.…”