Karl Turetschek

MRI characterization of tumors and grading angiogenesis using macromolecular contrast media: status report

Magnetic resonance imaging (MRI) enhanced with a macromolecular contrast medium (MMCM) has been applied successfully to assay tumor microvascular characteristics. These MRI-assayed characteristics correlate closely with histologic microvascular density, an established surrogate of tumor angiogenesis, and with pathologic tumor grade. The utility of MMCM-enhanced MRI for tumor characterizations has been established experimentally in a range of cancer types including breast, ovary, fibrosarcoma, and prostate. The MMCM-enhanced MRI technique can also be applied to monitor changes in tumor vessels that result from administration of an angiogenesis inhibitor, antibody against vascular endothelial growth factor (VEGF). Suppression of microvascular permeability (up to 98%) induced by this inhibitor of angiogenesis was detected and quantified as soon as 24 h after initiation of therapy. Thus, MRI assays of tumor microvascular characteristics, particularly macromolecular permeability, provide a means to non-invasively characterize tumors for prognostication, for individualization and optimization of treatment, and for monitoring therapeutic response. Pending successful completion of drug trials, now in progress, the availability of MMCM should permit the immediate application of these powerful techniques in clinical practice.

In vivo monitoring of tumor angiogenesis with MR imaging

Magnetic resonance (MR) imaging is a widely employed diagnostic method for the evaluation of patients with tumors. This method is noted for its remarkable soft-tissue definition, absence of ionizing radiation, high spatial and temporal resolution, and ability to generate images in any plane of the entire body. Equipment costs and, thus, examination costs are relatively high, however. MR imaging has been proposed and tested, both experimentally and clinically, as a method to characterize tumors regarding their state of angiogenesis. Multiple approaches to the challenge of MR imaging assays of angiogenesis have been proposed, some of which are potentially additive; all are intended to provide information regarding tumor microvessels. The quantitative end points that are sought include tissue plasma/blood volume, transendothelial permeability to water or solutes, perfusion/flow, and relative concentration of angiogenesis-specific molecules. The available approaches can be divided into intrinsic (non-contrast material enhanced) and contrast material-enhanced methods. The latter methods can be further divided by the type of contrast medium employed: small molecular agents that distribute rapidly in the extracellular space (so-called nonspecific or extracellular-fluid-space [ECF] agents), large molecular agents designed for prolonged intravascular retention (socalled macromolecular contrast media [MMCM] or bloodpool agents), and targeted agents intended to accumulate at the sites of concentrated angiogenesis mediator. Today, ECF contrast agents are commercially available and being used in clinical evaluations of antiangiogenesis drug treatments. Macromolecular contrast media are currently in clinical trials, but they are not now approved for use in humans. Molecular-targeted contrast media are in preclinical development. This section summarizes some of the many reports dealing with MR imaging assays of angiogenesis. For clarity, the discussion is divided by the specific MR imaging approach used. The rationale for that approach, limited information regarding the technique itself, accumulated experience, and limitations are provided, as well.

Tumor microvascular changes in antiangiogenic treatment: Assessment by magnetic resonance contrast media of different molecular weights

To test magnetic resonance (MR) contrast media of different molecular weights (MWs) for their potential to characterize noninvasively microvascular changes in an experimental tumor treatment model.

MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer.

To evaluate the diagnostic and prognostic potential of a new protein‐binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy.

Tumor microvascular characterization using ultrasmall superparamagnetic iron oxide particles (USPIO) in an experimental breast cancer model

The diagnostic potential of ultrasmall superparamagnetic iron oxide particles (USPIO) for quantitative tumor microvessel characterization was assessed by kinetic analysis of dynamic magnetic resonance imaging (MRI) in a rodent breast cancer model. Microvascular characteristics (transendothelial permeability (KPS) and fractional plasma volume (fPV)) were estimated in 32 female Sprague Dawley rats, bearing breast tumors of varying malignancy. These values were compared to a prototype macromolecular contrast medium standard, albumin‐(GdDTPA)30. Transendothelial permeability (KPS) correlated significantly (P < 0.05) with the tumor grade (Scarff‐Bloom‐Richardson (SBR) score) for the USPIO (r = 0.36), as well as for the reference macromolecule, albumin‐(GdDTPA)30 (r = 0.54). Estimates for the fPV did not show a statistically significant correlation with the tumor grade for either contrast medium. In conclusion, USPIO‐enhanced MRI data were capable to characterize tumor microvessel properties in this breast cancer model: microvascular permeability (determined using USPIO) correlated significantly with tumor grade. Thus, quantitative estimation of microvascular characteristics in tumors could provide a surrogate of new vessel formation (angiogenesis) and thus a further important clinical indication for USPIO, in addition to MR angiography. J. Magn. Reson. Imaging 2001;13:882–888.

MRI assessment of microvascular characteristics in experimental breast tumors using a new blood pool contrast agent (MS-325) with correlations to histopathology

A new contrast medium, MS‐325, was compared to albumin‐(Gd‐DTPA)30 in 18 chemically induced rat breast tumors based on quantitative estimates of microvascular permeability (KPS) and fractional plasma volume (fPV) using a two‐compartment bidirectional model. No significant correlation was found between MS‐325‐enhanced microvascular assays with either tumor grade or with microvascular counts (MVCs). In comparison, the correlation coefficient between KPS and histologic tumor grade using albumin‐(Gd‐DTPA)30 (r = .58) was statistically significant (P < .01). Also, using albumin‐(Gd‐DTPA)30, a significant correlation (r = .55, P < .05) was observed between the KPS and MVC, a biomarker of angiogenesis. Correlations between fPV and MVC were not statistically significant for either contrast medium. In conclusion, using MS‐325, no significant correlations between the MR‐estimated permeability values or plasma volumes were observed in experimental breast tumors with either the histologic tumor grade or MVC. This analysis confirms our previous determination that capillary permeability estimates, using a prototype large molecular contrast medium, albumin‐(Gd‐DTPA)30, correlate significantly with both histologic tumor grade and MVC. J. Magn. Reson. Imaging 2001;14:237–242.

Assessment of a rapid clearance blood pool MR contrast medium (P792) for assays of microvascular characteristics in experimental breast tumors with correlations to histopathology

The diagnostic potential of a new rapid clearance blood pool contrast medium (P792; MW = 6.47 kDa) for the MR assessment of microvessel characteristics was assessed in 42 chemically‐induced breast tumors, with comparisons to albumin‐(Gd‐DTPA). Microvessel characteristics, including the transendothelial permeability (KPS) and the fractional blood volume (fPV), were estimated by using dynamic MR data fit to a bidirectional two‐compartment model. The MR‐derived estimates for KPS and fPV using each contrast agent were compared, and assays using each contrast agent were correlated to the histologic tumor grade (SBR score) and the microvascular density (MVD) counts. Using P792‐enhanced data, neither KPS nor fPV showed a statistically significant correlation with the tumor grade or the MVD (P > .05). Conversely, using albumin‐(GdDTPA)30, KPS values correlated significantly with the histologic tumor grade (r = .55; P < .0005) and the MVD (r = .34, P < .05), whereas no correlation was established for fPV. In conclusion, based on P792 data no correlation between tumor microvascular characteristics and histologic markers (SBR score or MVD) was found in this breast tumor model. Our analysis suggests that contrast media of relatively large (on the order of 90 kDa) molecular size, such as albumin‐(GdDTPA)30, are more accurate for the characterization of tumor microvessels. Magn Reson Med 45:880–886, 2001.

A new polysaccharide macromolecular contrast agent for MR imaging: Biodistribution and imaging characteristics

The aims of this study were to characterize certain physicochemical, pharmacokinetic, and enhancement properties of a new macromolecular contrast agent, carboxymethyl hydroxyethyl starch‐(Gd‐DO3A)35 [CMHES‐(Gd‐DO3A)35], consisting of a polysaccharide backbone covalently derivatized with multiple macrocyclic chelating groups for gadolinium. CMHES‐(Gd‐DO3A)35 has an average molecular weight of 72 kD and a plasma half‐time of 8.4 hours. T1 and T2 relaxivities are 14.1 ± 0.1 L mmol−1 • sec−1 and 17.8 ± 0.9 L mmol−1 • sec−1, respectively, for each gadolinium ion measured at 39°C and 20 Mhz; this T1 relaxivity is more than 4 times that of gadopentetate. Seven days after intravenous administration only relatively small amounts of gadolinium could be detected in blood or other tissues of rats. The compound was well tolerated in diagnostic dosages by all experimental animals. Magnetic resonance angiography performed within 1 hour of CMHES‐(Gd‐DO3A)35 administration showed a near‐constant and strong enhancement of blood in arteries and veins. Analysis of dynamic enhancement patterns of experimental tumors (MAT‐LyLu prostate cancer implanted in rats) following intravenous CMHES‐(Gd‐DO3A)35 administration yielded quantitative estimates of tumor plasma volume and microvessel permeability; the demonstrated hyperpermeability of tumor microvessels was easily distinguished from the absence of measurable microvascular permeability in non‐neoplastic soft tissues. J. Magn. Reson. Imaging 2000;11:694–701.

The choice of region of interest measures in contrast-enhanced magnetic resonance image characterization of experimental breast tumors

Objectives:The objectives of this study were to determine if magnetic resonance (MR) estimates of quantitative tissue microvascular characteristics from regions of interest (ROI) limited to the tumor periphery provided a better correlation with tumor histologic grade than ROI defined for the whole tumor in cross-section. Methods:A metaanalysis was based on 98 quantitative MR image breast tumor characterizations acquired in 3 separate experimental studies using identical methods for tumor induction and contrast enhancement. Results:The endothelial transfer coefficient (KPS) of albumin (Gd-DTPA)30 from the tumor periphery correlated (r = 0.784) significantly more strongly (P < 0.001) with the pathologic tumor grade than KPS derived from the whole tumor (r = 0.604). KPS estimates, either from the tumor periphery or from the whole tumor, correlated significantly more strongly with histologic grade (P < 0.01) than MR image estimates of fractional plasma volume (fPV) from either tumor periphery (r = 0.368) or whole tumor (r = 0.323). Conclusions:KPS estimates from the tumor periphery were the best of these measurable MR image microvascular characteristics for predicting the histologic grade.

Noninvasive assessment of wound-healing angiogenesis with contrast-enhanced MRI

Angiogenesis is a process by which new vessels grow toward and into the tissue (1,2) and is a critical component of the wound-healing process. During this process, angiogenesis leads to increased endothelial permeability of the microvasculature, which is triggered by plasma proteins such as the vascular endothelial growth factor (1,2). Based on physiologic data, there are similarities between wounds and tumors (1). Previous studies demonstrated that macromolecular contrast material–enhanced magnetic resonance imaging (MRI) is able to quantify microvascular permeability and plasma volume, representatives of angiogenesis, in tumors (3,4). The purpose of this study was twofold: (a) to quantitatively assess the time course of microvascular permeability and fractional plasma volume (fPV), representatives of angiogenesis, in an established wound-healing model induced in rodents; and (b) to correlate the MRI parameters with histologic and physiologic data of the wound-healing process.