Incorporating cross-voxel exchange for the analysis of dynamic contrast-enhanced imaging data: pre-clinical results.

Tumours exhibit abnormal interstitial structures and vasculature function often leading to impaired and heterogeneous drug delivery. The disproportionate spatial accumulation of a drug in the interstitium is determined by several microenvironmental properties (blood vessel distribution and permeability, gradients in the interstitial fluid pressure). Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the quantification of tracer perfusion based on contrast enhancement measured with non-invasive imaging techniques. An advanced cross-voxel exchange model (CVXM) was recently developed to provide a comprehensive description of tracer extravasation as well as advection and diffusion based on cross-voxel tracer kinetics (Sinnoet al2021). Transport parameters were derived from DCE-MRI of twenty TS-415 human cervical carcinoma xenografts by using CVXM. Tracer velocity flows were measured at the tumour periphery (mean 1.78-5.82µm.s-1) pushing the contrast outward towards normal tissue. These elevated velocity measures and extravasation rates explain the heterogeneous distribution of tracer across the tumour and its accumulation at the periphery. Significant values for diffusivity were deduced across the tumours (mean 152-499µm2.s-1). CVXM resulted in generally smaller values for the extravasation parameterKext(mean 0.01-0.04 min-1) and extravascular extracellular volume fractionve(mean 0.05-0.17) compared to the standard Tofts parameters, suggesting that Toft model underestimates the effects of inter-voxel exchange. The ratio of Tofts' extravasation parameters over CVXM's was significantly positively correlated to the cross-voxel diffusivity (P< 0.0001) and velocity (P= 0.0005). Tofts' increasedvemeasurements were explained using Sinnoet al(2021)'s theoretical work. Finally, a scan time of 15 min renders informative estimations of the transport parameters. However, a duration as low as 7.5 min is acceptable to recognize the spatial variation of transport parameters. The results demonstrate the potential of utilizing CVXM for determining metrics characterizing the exchange of tracer between the vasculature and the tumour tissue. Like for many earlier models, additional work is strongly recommended, in terms of validation, to develop more confidence in the results, motivating future laboratory work in this regard.

Incorporating cross-voxel exchange into the analysis of dynamic contrast-enhanced imaging data: theory, simulations and experimental results.

Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the estimation of perfusion properties of tumour tissues but many assume no dispersion associated with tracer transport away from the capillaries and through the tissue. At the level of a voxel, this translates to assuming no cross-voxel tracer exchange, often leading to the misinterpretation of derived perfusion parameters. Tofts model (TM), a compartmental model widely used in oncology, also makes this assumption. A more realistic description is required to quantify kinetic properties of tracers, such as convection and diffusion. We propose a Cross-Voxel Exchange Model (CVXM) for analysing cross-voxel tracer kinetics.In silicodatasets quantifying the roles of convection and diffusion in tracer transport (which TM ignores) were employed to investigate the interpretation of Tofts' perfusion parameters compared to CVXM. TM returned inaccurate values ofKtransandvewhere diffusive and convective mechanisms are pronounced (up to 20% and 300% error respectively). A mathematical equation, developed in this work, predicts and gives the correct physiological interpretation of Tofts've.Finally, transport parameters were derived from dynamic contrast enhanced-magnetic resonance imaging of a TS-415 human cervical carcinoma xenograft by using TM and CVXM. The latter deduced lower values ofKtransandvecompared to TM (lower by up to 63% and 76% respectively). It also allowed the detection of a diffusive flux (mean diffusivity 155µm2s-1) in the tumour tissue, as well as an increased convective flow at the periphery (mean velocity 2.3µm s-1detected). The results serve as a proof of concept establishing the feasibility of using CVXM for accurately determining transport metrics that characterize the exchange of tracer between voxels. CVXM needs to be investigated further as its parameters can be linked to the tumour microenvironment properties (permeability, pressure…), potentially leading to enhanced personalized treatment planning.

Unified platform for multimodal voxel-based analysis to evaluate tumour perfusion and diffusion characteristics before and after radiation treatment evaluated in metastatic brain cancer.

OBJECTIVE:: Early changes in tumour behaviour following stereotactic radiosurgery) are potential biomarkers of response. To-date quantitative model-based measures of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI parameters have shown widely variable findings, which may be attributable to variability in image acquisition, post-processing and analysis. Big data analytic approaches are needed for the automation of computationally intensive modelling calculations for every voxel, independent of observer interpretation. METHODS:: This unified platform is a voxel-based, multimodality architecture that brings complimentary solute transport processes such as perfusion and diffusion into a common framework. The methodology was tested on synthetic data and digital reference objects and consequently evaluated in patients who underwent volumetric DCE-CT, DCE-MRI and DWI-MRI scans before and after treatment. Three-dimensional pharmacokinetic parameter maps from both modalities were compared as well as the correlation between apparent diffusion coefficient (ADC) values and the extravascular, extracellular volume (Ve). Comparison of histogram parameters was done via Bland-Altman analysis, as well as Student's t-test and Pearson's correlation using two-sided analysis. RESULTS:: System testing on synthetic Tofts model data and digital reference objects recovered the ground truth parameters with mean relative percent error of 1.07 × 10-7 and 5.60 × 10-4 respectively. Direct voxel-to-voxel Pearson's analysis showed statistically significant correlations between CT and MR which peaked at Day 7 for Ktrans (R = 0.74, p <= 0.0001). Statistically significant correlations were also present between ADC and Ve derived from both DCE-MRI and DCE-CT with highest median correlations found at Day 3 between median ADC and Ve,MRI values (R = 0.6, p < 0.01) The strongest correlation to DCE-CT measurements was found with DCE-MRI analysis using voxelwise T10 maps (R = 0.575, p < 0.001) instead of assigning a fixed T10 value. CONCLUSION:: The unified implementation of multiparametric transport modelling allowed for more robust and timely observer-independent data analytics. Utility of a common analysis platform has shown higher correlations between pharmacokinetic parameters obtained from different modalities than has previously been reported. ADVANCES IN KNOWLEDGE:: Utility of a common analysis platform has shown statistically higher correlations between pharmacokinetic parameters obtained from different modalities than has previously been reported.