David M. Shames

Thallium-201 myocardial perfusion scintigraphy for the clinical clarification of normal, abnormal and equivocal electrocardiographic stress tests☆

Sixty-five patients were studied with stress electrocardiography and thallium-20 1 relative myocardial perfusion scintigraphy. Results were correlated with selective coronary angiography. Scintigraphy was more sensitive (85 versus 67 percent), more specific (89 versus 63 percent) and significantly more accurate (87 versus 65 percent) than stress electrocardiography for the diagnosis of significant coronary arterial lesions in patients with isoelectric S-T segments at rest. Stress scintigraphy helped clarify the equivocal stress test due to left bundle branch block, left ventricular hypertrophy, drugs, hyperventilation and other conditions and was more accurate than the stress electrocardiogram (89 versus 53 percent) even in the presence of a depressed S-t segment at rest. Thallium-20 1 scintigraphy is a safe and simple noninvasive method for identifying abnormal myocardial perfusion, stress-induced ischemia and, indirectly, significant coronary arterial lesions.

The noninvasive diagnosis of right ventricular infarction.

SUMMARYWe evaluated scintigraphy and echocardiography for the diagnosis of right ventricular (RV) infarction. Of 26 patients with acute transmural myocardial infarction (MI), six with inferior MI had abnormal radionuclide uptake localized to the RV free wall on infarct scintigraphy or segmental akinesis of the RV free wall on gated radioangiography or both. These six patients with RV involvement (group I) were compared with the remaining nine with inferior MI (group II) and 11 with anterior MI (group III). RV/LV area ratios determined radioangiographically were significantly greater in group I than group II in diastole and systole. Echocardiographic RV enddiastolic dimension and RV/LV end-diastolic dimension ratio were significantly greater in group I than group II. Mean RV filling pressure was significantly greater and RV stroke work index was significantly lower in group I than in group II. Predominant RV involvement in inferior MI may occur commonly. Anatomic and functional evidence of this diagnosis can be obtained noninvasively.

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme

To evaluate the effects of a neutralizing anti‐vascular endothelial growth factor (anti‐VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model.

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.

Correlation of dynamic contrast-enhanced magnetic resonance imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media

Background. The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic magnetic resonance imaging (MRI) were correlated with histopathologic grade in mammary soft tissue tumors. Materials and methods. A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N -ethyl-N -nitrosourea (ENU), a potent carcinogen. Dynamic contrast-enhanced MRI was performed using a small-molecular contrast medium [gadopentetate, MW = 0.5 kDa] and a macromolecular contrast medium [albumin-(Gd-DTPA)30, MW = 92 kDa] at an interval of 1–2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (KPS), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bi-directional kinetic model. MRI microvascular characteristics were correlated with histopathologic tumor grade. Results. Tumor permeability to macromolecular contrast medium, characterized by KPS, showed a highly positive correlation with tumor grade (r2 = 0.76, P < 10− 10). KPS values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r2 = 0.25, P < 0.003). No correlation between KPS or fPV values and tumor grade was found using gadopentetate (r2 = 0.01, P > 0.95 and r2 = 0.03, P > 0.15, respectively). Conclusion. Quantitative tumor microvascular permeability assays generated with macromolecular MRI contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

Relationship of regional myocardial perfusion to segmental wall motion: a physiologic basis for understanding the presence and reversibility of asynergy.

SUMMARY Experimental work has shown that even small reductions in myocardial perfusion impair contractile performance. We, therefore, studied the relationship between regional perfusion, assessed by thallium- 201 scintigraphy and segmental wall motion, quantitated on biplane contrast ventriculograms, in patients with coronary artery disease. We evaluated 270 segments in 54 patients, including 27 without evidence of myocardial infarction. Most normally perfused regions (125 of 140) contracted normally, whereas those with scintigraphic defects at rest were usually asynergic (42 of 46). Surprisingly, 57% (48 of 84) of regions with exercise-induced perfusion defects were also asynergic, including 48% (25 of 52) of those in patients without myocardial infarction. In 22 patients who had intervention ventriculograms, improvement of perfusion abnormalities at rest correlated closely with reversibility of asynergy. Although there was an association between the location and severity of coronary artery stenosis and segmental wall motion, myocardial perfusion during exercise was a significantly better predictor of asynergy.These findings suggest that resting asynergy may occur even in patients without previous infarction, predominantly in regions with jeopardized perfusion. Asynergy in regions with exercise-induced perfusion abnormalities may, therefore, be an indicator of resting ischemia and may be reversible by coronary artery revascularization.

Contrast-enhanced magnetic resonance imaging estimation of altered capillary permeability in experimental mammary carcinomas after X-irradiation.

RATIONALE AND OBJECTIVES.Dynamic magnetic resonance imaging (MRI) enhanced with a macromolecular contrast medium, albumin-(Gd-DTPA)35, was used to detect changes in microvascular characteristics in R3230 mammary adenocarcinomas induced by x-irradiation. METHODS.Tumors were implanted in either flank in nine rats. One of the tumors was exposed to single-dose x-irradiation (30 Gy) 3 days before MRI. The contralateral control tumor was shielded from irradiation. RESULTS.Capillary permeability to macromolecular contrast medium in irradiated tumors was elevated significantly (P<.05) compared to the control nonirradiated tumors. The mean estimated permeability surface area product for the irradiated tumors increased more than three-fold; 0.511 ± .046 mL hr-1 cm-3 compared with 0.121 ± .011 mL hr-1 cm-3 for the nonirradiated tumors. This radiation-induced increase in permeability was corroborated using a macromolecular Evans blue-protein complex measured in the same tumors using an invasive spectrophotometric technique. CONCLUSIONS.Dynamic MRI-enhanced with macromolecular contrast medium permits noninvasive quantitative estimates of capillary permeability in tumors, with and without xirradiation. Because the transendothelial permeability for macromolecular solutes likely influences tumoral accumulation of macromolecular chemotherapeutic agents, this noninvasive technique may prove to be clinically useful in tailoring tumor treatment programs which combine radiation and chemotherapy.

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.