Shutter‐speed analysis of contrast reagent bolus‐tracking data: Preliminary observations in benign and malignant breast disease

Abstract

The standard pharmacokinetic model applied to contrast reagent (CR) bolus-tracking (B-T) MRI (dynamic-contrast-enhanced) data makes the intrinsic assumption that equilibrium transcytolemmal water molecule exchange is effectively infinitely fast. Theory and simulation have suggested that this assumption can lead to significant errors. Recent analyses of animal model experimental data have confirmed two predicted signature inadequacies: a specific temporal mismatch with the B-T time-course and a CR dose-dependent underestimation of model parameters. The most parsimonious adjustment to account for this aspect leads to the "shutter-speed" pharmacokinetic model. Application of the latter to the animal model data mostly eliminates the two signature inadequacies. Here, the standard and shutter-speed models are applied to B-T data obtained from routine human breast examinations. The MRI contrast reagent (CR) bolus-tracking (B-T) (also called dynamic-contrast-enhanced)] method holds great promise for quantitative in vivo evaluation of vascular properties under many different pathophysiological conditions (1). An area that has seen considerable such activity is breast disease (2-5). The many pharmacokinetic models applied to CR B-T data can be divided into two families; one in which the CR and H 2 O are assumed uniformly distributed within each compartment entered ["well-mixed," e.g., (1)] and one in which they are not ["heterogeneous," surveyed in (6)]. For a given number of compartments, the former models have fewer variable parameters: heterogeneous distributions require geometric quantities. Of course, for a given model family, the number of parameters increases with the number of compartments. Even the simplest well-mixed model, which considers only two compartments for CR (1), has seven potential parameters (listed below) (7). Most fittings employ versions in which only two of these, K trans [a pseudo-firstorder rate constant for CR transfer between blood plasma and extracellular, extravascular space (EES)] and the CR distribution volume, equated to v e (the EES volume fraction)-or combinations thereof-are varied (1). However, we have recently shown that this "standard model" embeds the intrinsic assumption that an important eighth parameter, the mean intracellular water lifetime ( i ), is effectively zero: that is, the equilibrium transcytolemmal water exchange system is constrained to the fast-exchangelimit (FXL) (7). This is inconsistent with cytolemmal water permeability coefficient (P) values (measured over many years), which when combined with mean cell sizes allow calculations of i [ϭ r/(3P), for a sphere of radius r]: this is reviewed in Ref. (8). These estimates, along with recent independent measurements (8 -11), yield i values that for almost all cells (except erythrocytes) range from hundreds of milliseconds to several seconds. Such magnitudes have significant effects on the two-compartment model B-T time-course amplitude and shape, causing data fitting with the standard model to underestimate the K tran...

Dynamic NMR effects in breast cancer dynamic-contrast-enhanced MRI

“…These images were acquired with adipose -1 H 2 C-suppression (institutional protocol required). In contrast to those (13,14) obtained with no fat suppression, these darker images show glandular regions brighter than fatty tissues. (Fig.…”

“…We also used the FXR-and SXR-allowed (FXR-a and SXR-a) versions of the first-generation ShutterSpeed Model (SSM1), BOLus Enhanced Relaxation Overview (BOLERO) (8,11). In the SM analyses, the parameters varied are K trans and v e , while the i value is (implicitly) zero (11,13,14).…”

“…In some SSM analyses, i is also varied. The complete 9-parameter set has been tabulated (14) and the constant values of the other parameters have been reported (13,14).…”

“…This corollary is not valid (2,6), and its assumption can effectively short circuit MRI determination of CR compartmentalization (2, 7)-the pharmacokinetic essence. In a series of papers (2,5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16), we have examined the significance of this implication. We refer to models incorporating equilibrium exchange effects in the pharmacokinetic derivation as belonging to the shutter-speed model (SSM) family.…”

Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy

“…This apparent discrepancy regarding the efficacy of PK parameters may be due to the relatively small number of cases included in various studies, or the wide variety of DCE-MRI acquisition and PK analysis techniques used. Intra-tumour vascular heterogeneity might also be significant in some breast cancers (Hayes et al, 2002), leading to the possible breakdown of PK model assumptions such as the fast exchange limit within better-perfused regions (usually located at the tumour rim) (Zhou et al, 2004;Li et al, 2005). This could present a complicating factor in obtaining reliable results, an issue not addressed in this study, which utilised a whole ROI approach so as to minimise the effects of intra-scan patient motion.…”