Quantitative assays of tumor microvascular characteristics based on dynamic MR imaging were correlated with histopathologic grade in mammary soft-tissue tumors. MATERIALS AND METHODS. A spectrum of tumors, benignthrough highlymalignant, was induced in 33 female rats by administration of N-ethyl-N-nitrosourea, a potent car cinogen. Dynamic contrast-enhanced MR imaging was performed using a small-molecular contrast medium (gadopentetate, molecular weight = 0.5 kDa) and a macromolecular contrast medium (albumin-(Gd-DTPA)30, molecular weight = 92 kDa) at an interval of 1â€"2 days. Per meability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (K@5), and fractional plasma volume (JPV) were calculated for each tumor and each contrast agent using a two-compartment bidirectional kinetic model. MR imaging mi crovascular characteristics were correlated with histopathologic tumor grade. RESULTS. Tumorpermeability to macromolecular contrast medium,characterized byK@5, showed a highly positive correlation with tumor grade (r2 = .76, p < lO_10). K@5 values were zero for all benign and some low-grade carcinomas, greater than zero in all other carci nomas, and increased in magnitude with higher tumor grade. A considerably smaller but sig nificantly positive correlation was found betweenfPV and tumor grade using macromolecular contrast medium (r2 = .25, p < .003). No correlation between K@5orfPV values and tumor grade was found using gadopentetate (r2 = .01, p > .95 and r2 = .03, p > .15, respectively).CONCLUSION. Quantitative tumormicrovascular permeability assays generated with macromolecular MR imaging contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate. Parnassus Ave.,San Francisco, CA94143-0628. Address correspondence to R.C.Brasch.

MRI enhanced with a macromolecular contrast medium (MMCM) has previously been shown to estimate tumor microvascular characteristics that correlate closely with histologic microvascular density, an established surrogate of tumor angiogenesis. A similar MMCM-enhanced MRI technique has now been used to investigate the acute tumor microvascular effects of antibody-mediated inhibition of vascular endothelial growth factor (VEGF), a well-studied and potent angiogenesis stimulator. Athymic rats xenografted with a human breast carcinoma (MDA-MB-435) were imaged after administration of albumin-gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA30) using a heavily T1-weighted three dimensional-spoiled gradient-refocused acquisition in a steady-state pulse sequence before and 24 hours after treatment with anti-VEGF antibody (single dose of 1 mg). Changes in longitudinal relaxivity (delta R1) were analyzed using a bidirectional two-compartment kinetic model to estimate tumor fractional blood volume (fBV) and permeability surface area product (PS). Data showed a significant decrease (P < 0.05) of tumor PS with respect to macromolecular contrast medium at 24 hours after treatment with anti-VEGF antibody. No significant change was observed in fBV. Suppression of tumor microvascular permeability induced by anti-VEGF antibody can be detected and quantified by MMCM-enhanced MRI. MRI grading of tumor angiogenesis and monitoring of anti-angiogenesis interventions could find wide clinical application.

Scoring of CT studies in patients with cystic fibrosis seems to offer a reliable way to monitor disease status and progression and may provide a reasonable tool to assess treatment interventions.

A simple, linear kinetic model has been developed for the noninvasive assessment of capillary permeability to macromolecules in the rat by dynamic magnetic resonance imaging using albumin-Gd-DTPA. Data required by the model are signal intensity responses from a target tissue and a venous structure such as inferior vena cava before and after bolus intravenous injection of albumin-Gd-DTPA. Additional requirements include an early temporal resolution of approximately one image/min and a blood sample for hematocrit. The model does not require measurement of albumin-Gd-DTPA concentration in either arterial or venous blood. Pilot experiments suggest that this technique is adequate for estimation of the fractional leak rate of macromolecules from plasma to interstitial water as well as tissue plasma volume, the product of which yields a measure of the permeability surface area product of the tissue if the extraction fraction is modest (< 0.2). The technique may be generally applicable to the study of abnormal capillary permeability in humans as well as animals.

Purpose: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. Materials and Methods:MD-MBA-435, a poorly differentiated human breast cancer cell line, was implanted into 31 female homozygous athymic rats. Animals were assigned randomly to a control (saline) or drug treatment (monoclonal antibody vascular endothelial growth factor (Mab-VEGF) antibody) group. In both groups, dynamic MR imaging (MRI) was performed in each animal using up to three different contrast media on sequential days at baseline and follow-up examination. The MWs of the contrast media used ranged from 557 Da to 92 kDa. Using a bidirectional kinetic model, tumor microvessel characteristics, including the fractional plasma volume (fPV) and transendothelial permeability (K PS ), were estimated for each contrast medium. These microvascular characteristics were compared between drug and control groups and between contrast media of different MWs.Results: Tumors grew significantly slower (P Ͻ 0.0005) in the drug treatment group than in the control group. Mean K PS and fPV values decreased significantly (P Ͻ 0.05) in the Mab-VEGF antibody-treated group compared to baseline values using intermediate or macromolecular contrast media (MMCM), but did not change significantly using small molecular contrast media (SMCM). In the control groups, mean K PS and mean fPV values did not reach statistical significance for any of the contrast media used. Conclusion:Therapeutic effects of a Mab-VEGF antibody on tumor microvessel characteristics can be monitored by dynamic MRI. Intermediate-size agents, such as Gadomer-17, offer a substantial dynamic range and are less limited by imaging precision and therefore should be considered a practical alternative to monitor antiangiogenesis treatment effects in a clinical setting.