Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke.

Neonatal stroke occurs in one in 4,000 live births and leads to significant morbidity and mortality. Approximately two thirds of the survivors have long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after neonatal stroke are not clearly understood, and preventive measures and treatments are nonexistent in the clinical setting. In this study, we investigated the effect of vascular endothelial growth factor (VEGF) treatment on histological recovery and angiogenic response to the developing brain after an ischemic insult. Ten-day-old Sprague-Dawley rats underwent right middle cerebral arterial occlusion (MCAO) for 1.5 h. Diffusion-weighted MRI during occlusion confirmed focal ischemia that was then followed by reperfusion. On group of animals received 5-bromo-2-deoxyuridine and sacrificed at postnatal day (P)18 or P25. A second group of animals was treated with VEGF (1.5 µg/kg, icv) or phosphate-buffered saline (PBS) at P18 and perfusion fixed at P25. Based on Nissl and iron staining, a single VEGF injection reduced the injury score, compared to the animals that underwent MCAO and PBS injection. Furthermore, neurodegeneration represented by neuronal nuclei staining was markedly diminished. In addition, animals treated with VEGF revealed a positive trend in endothelial proliferation and a significant increase in total vessel volume in the peri-infarct region of the caudate. The number of Iba1-positive microglial cells was significantly reduced after a single VEGF injection, and myelin basic protein expression was enhanced in the caudate after ischemia without an effect of VEGF treatment. In conclusion, delayed treatment with VEGF ameliorates injury, promotes endothelial cell proliferation, and increases total vascular volume following neonatal stroke. These results suggest that VEGF has a neuroprotective effect, in part by enhancing endogenous angiogenesis. These data contribute to a better understanding of neonatal stroke.

Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke.

Cannabinoids have emerged as brain protective agents under neurodegenerative conditions. Many neuroprotective actions of cannabinoids depend on the activation of specific receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R). The aim of the present study was to determine whether the CB2R and CB1R agonist WIN 55,212-2 (WIN) protects neonatal brain against focal cerebral ischemia-reperfusion and whether anti-inflammatory mechanisms play a role in protection. Seven-day-old rats were subjected to 90-min middle cerebral artery occlusion (MCAO), and injured rats were identified by diffusion-weighted MRI during the occlusion. After reperfusion, rats were subcutaneously administered 1 mg/kg of WIN or vehicle twice daily until sacrifice. MCAO led to increased mRNA expression of CB2R (but not CB1R), chemokine receptors (CCR2 and CX3CR1), and cytokines (IL-1ß and TNFα), as well as increased protein expression of chemokines MCP-1 and MIP-1α and microglial activation 24 h after MCAO. WIN administration significantly reduced microglial activation at this point and attenuated infarct volume and microglial accumulation and proliferation in the injured cortex 72 h after MCAO. Cumulatively, our results show that the cannabinoid agonist WIN protects against neonatal focal stroke in part due to inhibitory effects on microglia.

Functional disability in paediatric patients with recurrent abdominal pain.

BACKGROUND: Recurrent abdominal pain (RAP) is common in childhood, affecting approximately 12% of children and adolescents. Children with RAP tend to experience impairments in functioning, such as increased school absences, anxiety and depression. METHODS: The current study investigated the potential influences on the relation between functional disability and RAP in 100 school-aged children. A series of hierarchical regression analyses were conducted to test two models: main effects and moderation of the relation between abdominal pain symptoms, child anxiety, child depression, maternal emotional distress, maternal encouragement of child illness behaviour and functional disability. RESULTS: The results indicated support for abdominal pain symptoms and child depression in predicting functional disability. The results also indicated that child anxiety and child depression each moderated the relation between pain symptoms and functional disability. CONCLUSIONS: Implications of the findings are discussed in terms of potential influences on the development of functional disability in youth.

Comparison of microvascular permeability measurements, K(trans), determined with conventional steady-state T1-weighted and first-pass T2*-weighted MR imaging methods in gliomas and meningiomas.

BACKGROUND AND PURPOSE: The widely accepted MR method for quantitating brain tumor microvascular permeability, K(trans), is the steady-state T1-weighted gradient-echo method (ssT1). Recently the first-pass T2*-weighted (fpT2*) method has been used to derive both relative cerebral blood volume (rCBV) and K(trans). We hypothesized that K(trans) derived from the ssT1 and the fpT2* methods will correlate differently in gliomas and meningiomas because of the unique differences in morphologic and functional status of each tumor vascular network. METHODS: Before surgery, 27 patients with newly diagnosed gliomas (WHO grade I-IV; n = 20) or meningiomas (n = 7) underwent conventional anatomic MR imaging and 12 dynamic ssT1 acquisitions followed by 60 dynamic fpT2* images before and after gadopentate dimeglumine administration. The 3 hemodynamic variables-fpT2* rCBV, fpT2* K(trans), and ssT1 K(trans)-were calculated in anatomically identical locations and correlated with glioma grade. The fpT2* K(trans) values were compared with ssT1 K(trans) for gliomas and meningiomas. RESULTS: All 3 hemodynamic variables displayed distinct distributions among grades 2, 3, and 4 gliomas by using the Kruskal-Wallis test. Only K(trans) values, and not rCBV, could differentiate between grade 4 and lower-grade gliomas by using the Wilcoxon rank sum test. The fpT2* K(trans) was highly predictive of ssT1 K(trans) for gliomas, with an estimated regression coefficient of 0.49 (P < .001). For meningiomas, however, fpT2* K(trans) values correlated poorly with ssT1 K(trans) values (r = 0.26; P = .74). CONCLUSION: Compared with rCBV, K(trans) values derived from either ssT1 or fpT2* were more predictive of glioma grade. The fpT2* K(trans) was highly correlated with ssT1 K(trans) in gliomas but not in meningiomas.

[MRI of arthritis with the USPIO SH U 555 C: optimization of T1 enhancement]. / MRT der Arthritis mit dem USPIO SH U 555 C: Optimierung des T1-Enhancements.

PURPOSE: To optimize contrast agent dose and pulse sequence parameters in order to achieve a maximal T1 enhancement in arthritic knee joints with ultra small superparamagnetic iron oxides (USPIO)-enhanced MRI. MATERIALS AND METHODS: Antigen-mediated arthritis was induced in the right knee of nine Sprague Dawley rats. The arthritic knee joint as well as the contralateral normal knee were investigated in a 2 Tesla MR scanner before as well as in short intervals up to 2 h after USPIO injection, using T1-weighted gradient echo (GE) sequences. Three rats each received intravenous injections of the new USPIO SHU 555 C (SH U 555 C, Schering AG, Berlin) at doses of 40, 100 and 200 micromol Fe/kg. Pulse sequence parameters of the GE-sequence were optimized by varying flip angles (alpha) and echo times (TE). Changes in signal intensities (SI) of the arthritic knee and contralateral normal knee were quantified as DeltaSI (%) = /([SIpost - SIpre] / SIpre) x 100 %/ and compared with histopathology. RESULTS: Histology of the arthritic knees demonstrated a marked inflammatory proliferation of the synovium. The USPIO SH U 555 C caused a significant increase in signal intensity of the arthritic joints on T1-weighted MR images (p < 0.05). This effect was optimized using a flip angle of 60-70 degrees, a minimal TE and a dose of 200 micromol Fe/kg. Visually the contralateral normal knee did not show any USPIO enhancement. CONCLUSION: Inflammation can be depicted with marked T1 enhancement by the USPIO SH U 555 C using high contrast agent doses and optimized MR pulse sequence parameters.

Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23.

The orphan receptor ChemR23 is a G-protein coupled receptor (GPCR) with homology to neuropeptide and chemoattractant receptors. Tazarotene, a synthetic retinoid activating retinoic acid receptor (RAR), up-regulates tazarotene-induced gene-2 (TIG2). The function and molecular target of this protein are now described. By means of reverse pharmacology screening using a peptide library generated from human hemofiltrate, we have isolated and identified TIG2 as the natural ligand of ChemR23 and report the specific molecular form of the bioactive, circulating TIG2, representing the amino-acid residues 21 to 154 of the 163 amino acid-containing prepropeptide. Based on the expression pattern of ChemR23 and TIG2, the physiological role in bone development, immune and inflammatory responses and the maintenance of skin is now being investigated.

Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain.

BACKGROUND AND PURPOSE: Different strategies for neuroprotection of neonatal stroke may be required because the developing brain responds differently to hypoxia-ischemia than the mature brain. This study was designed to determine the role of caspase-dependent injury in the pathophysiology of pure focal cerebral ischemia in the immature brain. METHODS: Postnatal day 7 rats were subjected to permanent or transient middle cerebral artery (MCA) occlusion. Diffusion-weighted MRI was used during occlusion to noninvasively map the evolving ischemic core. The time course of caspase-3 activation in ischemic brain tissue was determined with the use of an Asp-Glu-Val-Asp-aminomethylcoumarin cleavage assay. The anatomy of caspase-3 activation in the ischemic core and penumbra was mapped immunohistochemically with an anti-activated caspase-3 antibody in coronal sections that matched the imaging planes on diffusion-weighted MRI. RESULTS: A marked increase in caspase-3 activity occurred within 24 hours of reperfusion after transient MCA occlusion. In contrast, caspase-3 activity remained significantly lower within 24 hours of permanent MCA occlusion. Cells with activated caspase-3 were prominent in the penumbra beginning at 3 hours after reperfusion, while a more delayed but marked caspase-3 activation was observed in the ischemic core by 24 hours after reperfusion. CONCLUSIONS: In the neonate, caspase-3 activation is likely to contribute substantially to cell death not only in the penumbra but also in the core after ischemia with reperfusion. Furthermore, persistent perfusion deficits result in less caspase-3 activation and appear to favor caspase-independent injury.

Safety and immunogenicity of live recombinant Salmonella enterica serovar Typhi Ty21a expressing urease A and B from Helicobacter pylori in human volunteers.

Helicobacter pylori urease was expressed in the common live typhoid vaccine Ty21a yielding Ty21a(pDB1). Nine volunteers received Ty21a(pDB1) and three control volunteers received Ty21a. No serious adverse effects were observed in any of the volunteers. Ten out of 12 volunteers developed humoral immune responses to the Salmonella carrier as detected by antigen-specific antibody-secreting cells but only two volunteers seroconverted. A total of five volunteers showed responses in one or two out of three assays for cellular responses to the carrier (proliferation, IFN-gamma-secretion, IFN-gamma-ELISPOT). Three of the volunteers that had received Ty21a(pDB1) showed a weak but significant T-cell response to Helicobacter urease, while no volunteer had detectable humoral responses to urease. Ty21a(pDB1) is a suitable prototype to optimize Salmonella-based vaccination for efficient cellular responses that could mediate protective immunity against Helicobacter.

Assessment of nicorandil therapy in ischemic myocardial injury by using contrast-enhanced and functional MR imaging.

PURPOSE: To determine the potential of mesoporphyrin- and gadopentetate dimeglumine-enhanced and functional magnetic resonance (MR) imaging in the assessment of the acute effect of nicorandil on ischemic injury of the myocardium. MATERIALS AND METHODS: Spin-echo MR imaging was used to monitor changes in myocardial contrast and function in reperfused myocardial injury. Inversion-recovery echo-planar MR imaging was used to depict the injured region. Myocardial injury in rats was produced by using 30 minutes of coronary occlusion followed by 24 hours reperfusion. Nicorandil (n = 9) was infused during occlusion and early reperfusion. Control animals (n = 11) received no therapy. At 24 hours, after administration of mesoporphyrin and gadopentetate dimeglumine and histochemical staining, the function and size of the injured region of the left ventricle (LV) were determined. A t test was used to compare data between groups of animals, whereas regression and Bland-Altman analyses were used to determine correlation and agreement between MR imaging and histomorphometry, respectively. RESULTS: Treated animals showed reduced infarction size as compared with the control group from 25.6% +/- 7.9 (SD) to 7.9% +/- 6.8 of LV myocardial area (P < .001), as defined with mesoporphyrin-enhanced MR imaging; while the size of the rim increased from 10.8% +/- 10.0 to 16.1% +/- 14.4 (P < .05). The diastolic-midventricular cavity area was smaller in treated animals (15.2 mm(2) +/- 4.3) compared with the control group (28.5 mm(2) +/- 7.9; P < .001). At functional MR imaging, nicorandil improved systolic reduction in LV cavity area (57.5% +/- 17.3) compared with the control group (38.0% +/- 16.0; P < .05) and preserved regional LV wall thickening at the site of injury (12.2% +/- 11.1 in treated group vs 0.3% +/- 8.6 in the control group; P < .05). CONCLUSION: Contrast material-enhanced MR imaging has the potential to demonstrate reduction in size of ischemically injured myocardium, whereas functional MR imaging demonstrated the recovery of LV function 24 hours after nicorandil therapy.

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 (K(PS)) 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 K(PS) 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 K(PS) 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.

Accuracy of segmented MR velocity mapping to measure small vessel pulsatile flow in a phantom simulating cardiac motion.

The purpose of this study was to investigate the accuracy of conventional, segmented, and echo-shared MR velocity mapping sequences to measure pulsatile flow in small moving vessels using a phantom with simulated cardiac motion. The phantom moved either cyclically in-plane, through-plane, in- and through-plane, or was stationary. The mean error in average flow was -2% +/- 3% (mean +/- SD) for all sequences under all conditions, with or without background correction, as long as the region of interest (ROI) size was equal to the vessel cross-sectional size. Overestimation of flow as a result of an oversized ROI was less than 20%, and independent of field of view (FOV) and matrix, as long as the offset in angle between the imaging plane and flow direction was less than 10 degrees. Segmented velocity mapping sequences are surprisingly accurate in measuring average flow and render flow profiles in small moving vessels despite the blurring in the images due to vessel motion. J. Magn. Reson. Imaging 2001;13:722-728.

MR imaging characterization of microvessels in experimental breast tumors by using a particulate contrast agent with histopathologic correlation.

PURPOSE: To define the diagnostic potential of magnetic resonance (MR) imaging enhanced with ultrasmall superparamagnetic iron oxide (USPIO) particles for the quantitative characterization of tumor microvasculature. MATERIALS AND METHODS: NC100150 injection, a USPIO in clinical trials, and albumin-(Gd-DTPA)(30) were compared at MR imaging on sequential days in the same 19 rats with mammary tumors. Kinetic analysis of dynamic T1-weighted three-dimensional spoiled gradient-recalled imaging data with a two-compartment bidirectional model yielded MR imaging estimates of microvascular permeability (K(PS)) and fractional plasma volume (fPV) for each contrast medium. RESULTS: Strongly positive and significant correlations were observed between MR imaging-derived K(PS )estimates and histologic tumor grade with either the soluble albumin-(Gd-DTPA)(30) (r = 0.88; P <.001) or larger particulate USPIO (r = 0.82; P <.001). A significant correlation (P <.05) was observed with each contrast medium between K(PS) and the histologic microvascular density (MVD), an angiogenesis indicator. Despite the considerable difference in molecule and particle sizes, no significant difference was observed in the MR imaging-derived mean permeability values generated with the two contrast media. CONCLUSION: USPIO, a macromolecular particulate MR imaging contrast agent, can be applied successfully to characterize tumor microvessels in animals. USPIO-derived K(PS) correlated strongly with histopathologic tumor grade, MVD, and K(PS) values derived by using albumin-(Gd-DTPA)(30) in the same tumors.

Magnetic resonance characterization of the peri-infarction zone of reperfused myocardial infarction with necrosis-specific and extracellular nonspecific contrast media.

BACKGROUND: Because ischemically injured myocardium is frequently composed of viable and nonviable portions, a method to discriminate the two is useful for clinical management. METHODS AND RESULTS: Ischemically injured myocardium was characterized with extracellular nonspecific (Gd-DTPA) and necrosis-specific (mesoporphyrin) MR contrast media in rats. Relaxation rates (R1) were measured on day 1 and day 2 by inversion-recovery echoplanar imaging. Spin-echo imaging was used to define contrast-enhanced regions and regional wall thickening. Gadolinium concentration, area at risk, and infarct size were measured at postmortem examination. DeltaR1 ratio (DeltaR1(myocardium)/DeltaR1(blood)) after administration of Gd-DTPA was greater in ischemically injured myocardium (1.20+/-0.15) than in normal myocardium (0.47+/-0.05, P<0.05), which was attributed to differences in gadolinium concentration and water content. The Gd-DTPA-enhanced region on day 2 was larger (32.8+/-0.9%) than true infarction as demonstrated by triphenyltetrazolium chloride (TTC) (24.6+/-1.4%, P<0.001, r=0.21). Bland-Altman analysis revealed that the Gd-DTPA-enhanced region overestimated true infarct size by 7.8+/-5.9%. On the other hand, the mesoporphyrin-enhanced region (26.9+/-1.8%, P=NS, r=0.87) and true infarct size were identical. The difference in the areas demarcated by the 2 agents is the peri-infarction. Systolic and diastolic MR images revealed no wall thickening in the mesoporphyrin-enhanced region (0.3+/-3.3%) but reduced thickening in the Gd-DTPA-enhanced rim (8.5+/-5.5%, P<0.05). CONCLUSIONS: The Gd-DTPA-enhanced region encompasses both viable and nonviable portions of the ischemically injured myocardium. The Gd-DTPA-enhanced area overestimated infarct size, but the mesoporphyrin-enhanced area matched true infarct size. The salvageable peri-infarction zone can be characterized with double-contrast-enhanced and functional MR imaging; the mismatched area of enhancement between the 2 agents shows residual wall thickening.

Myocardial viability: magnetic resonance assessment of functional reserve and tissue characterization.

The determination of myocardial viability is crucial in patients with left ventricular dysfunction resulting from acute myocardial ischemia or chronic coronary artery disease. Viable myocardium will most likely benefit from revascularization procedures. However, the revascularization of scar tissue will not lead to improvement of ventricularfunction andfurthermore bears unnecessary riskfor the patient. Currently, echocardiographic and radionuclide techniques are the most established methods for the assessment of presence and extent of viable myocardium. Magnetic resonance imaging (MRI) also provides multiple approaches for determining viability of acute ischemically injured and hibernating myocardium. MRI can assess contractile reserve in a manner similar to echocardiography. Additionally, contrast-enhanced MRI can characterize myocardial ischemic injury, including the ability to discriminate viable from nonviable zones. Several new contrast media have been introduced for this purpose. This review addresses the progress toward the goal of defining myocardial viability based on MR techniques and focuses on the current and future role of MR in the assessment of viable myocardium.

Quantitative gadopentetate-enhanced MRI of breast tumors: testing of different analytic methods.

This study assessed several proposed imaging strategies and analytic methods based on gadopentetate-enhanced MRI to differentiate benign from malignant breast tumors in a blinded experimental animal study. Steady-state dynamic MRI and first-pass imaging, performed with either T(1)- or T*(2)- weighted sequences, were compared. Semiquantitative and quantitative analysis methods, based on empirical measures of the data or physiological models, were subsequently applied to the imaging datasets. Comparative measures provided pathologic distinction of benign from malignant tumors, tumor grading, and histologic determination of microvascular density. Of the eight tested methods, only one, an estimate of first-pass perfusion using T *(2)-weighted imaging, showed an almost significant (P = 0.05) difference between benign and malignant tumors and correlated almost significantly (r =.3, P = 0.06) with the tumor grade. All other tests, performed either with steady-state imaging or with T(1)-weighted first-pass imaging, failed to differentiate benign from malignant tumors. In addition, they yielded poor correlations with tumor grade and microvascular density.

Blood pool MR contrast agents for cardiovascular imaging.

Currently available magnetic resonance (MR) contrast agents are not confined to the intravascular space because of their small molecular size. These agents produce peak vascular enhancement for only a short period. Conversely, blood pool agents have longer intravascular residence time and higher relaxivity. Therefore these agents provide MR angiography with flexibility, versatility, and accuracy. With blood pool agents, the timing of contrast injection becomes less significant because the optimal imaging window is in tens of minutes rather than seconds. In addition, larger anatomic regions can be imaged optimally. Preliminary evidence appears to support the notion that blood pool agents may play a diagnostic role in coronary, peripheral, and pulmonary angiography. Besides their ability to increase vascular contrast, blood pool agents provide physiologic information, including rate of entry, rate of accumulation, and rate of elimination. MR imaging with blood pool agents also have proven to be of significant value in the assessments of myocardial perfusion and microvascular permeability. In anticipation of broad clinical use, blood pool agents are currently being evaluated in human trails. Examples include gadolinium-chelate that binds in vivo to albumin to form blood pool agents and ultrasmall superparamagnetic iron oxide particles. This review discusses the applications of MR blood pool agents in the cardiovascular system. J. Magn. Reson. Imaging 2000;12:890-898.

Coronary sinus flow measurement by means of velocity-encoded cine MR imaging: validation by using flow probes in dogs.

PURPOSE: To validate coronary sinus flow measurements for quantification of global left ventricular (LV) perfusion by means of velocity-encoded cine (VEC) magnetic resonance (MR) imaging and flow probes. MATERIALS AND METHODS: Measurements of coronary sinus flow were performed in seven dogs by using VEC MR imaging at baseline, single coronary arterial stenosis, dipyridamole stress, and reactive hyperemia. These measurements were compared with flow probe measurements of coronary blood flow (CBF) in the left anterior descending coronary (LAD) and circumflex (CFX) arteries (CBF(LAD+CFX)) and coronary sinus. LV blood perfusion was calculated in milliliters per minute per gram from coronary sinus flow, and LV mass was obtained by using VEC and cine MR imaging. LV mass was validated at autopsy. RESULTS: CBF(LAD+CFX) and coronary sinus flow at VEC MR imaging showed close correlation (r = 0.98, P: <.001). The difference between CBF(LAD+CFX) and MR coronary sinus flow was 3.1 mL/min +/- 8.5 (SD). LV mass at cine MR imaging was not significantly different from that at autopsy (73.2 g +/- 12.8 vs 69. 4 g +/- 12.8). At baseline, myocardial perfusion was 0.40 mL/min/g +/- 0.09 at VEC MR imaging, and CBF(LAD+CFX) was 0.44 mL/min/g +/- 0. 08 (not significant). Reactive hyperemia resulted in 2.7- and 2. 3-fold increases in coronary sinus flow at VEC MR imaging and flow probe CBF(LAD+CFX), respectively. CONCLUSION: VEC MR imaging has the potential to measure coronary sinus flow during different physiologic conditions and can serve as a noninvasive modality to quantify global LV perfusion in patients.

Comparison of Gadomer-17 and gadopentetate dimeglumine for differentiation of benign from malignant breast tumors with MR imaging.

RATIONALE AND OBJECTIVES: This study compared gadopentetate dimeglumine (molecular weight, 0.5 kD), a standard contrast medium, and Gadomer-17 (apparent molecular weight, approximately 35 kD), a new, clinically applicable, large-molecular contrast medium, with respect to their microvascular characterizations of experimentally induced breast tumors at magnetic resonance (MR) imaging. MATERIALS AND METHODS: A spectrum of breast tumors, benign through highly malignant, was induced in Sprague-Dawley rats (n = 30) by intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), a potent carcinogen. All animals underwent three-dimensional spoiled gradient-recalled MR imaging, with precontrast imaging and dynamic postcontrast imaging after injection of gadopentetate dimeglumine (0.1 mmol/kg) and Gadomer-17 (0.03 mmol/kg), administered in a random order at a 24-hour interval. Several microvascular parameters were compared: the endothelial transfer coefficient (K(PS)), a measure of microvascular permeability; the fractional plasma volume (fPV), and the plasma equivalent volume. Each MR imaging parameter was correlated with histopathologic findings. RESULTS: With Gadomer-17, the mean values for K(PS) and fPV were significantly greater in carcinomas than in fibroadenomas (P < .004 and .04, respectively). With gadopentetate dimeglumine, the mean values for fPV and PEV were significantly greater in carcinomas (P <. 004 and .02, respectively). Because of the high variability within both fibroadenoma and carcinoma groups, however, there were no significant correlations between K(PS), fPV, or PEV and histopathologic tumor grade as indicated by the Scarff-Bloom-Richardson score, for either agent. CONCLUSION: Although the K(PS) and fPV estimates obtained from dynamic MR imaging data with Gadomer-17 enhancement offer some potential for characterizing breast tumors, none of the quantitative microvascular parameters derived with either agent were significantly correlated with histopathologic tumor grade.

Magnetic resonance imaging in an experimental model of human ovarian cancer demonstrating altered microvascular permeability after inhibition of vascular endothelial growth factor.

OBJECTIVE: Magnetic resonance imaging enhanced with macromolecular contrast medium was used to monitor effects of angiogenesis inhibition on tumor microvascular permeability and ascites volume in an athymic rat model of human ovarian cancer. STUDY DESIGN: Groups of 6 athymic rats implanted intraperitoneally with SKOV-3, a human ovarian cancer cell line, were treated through a 14-day course with antibody to vascular endothelial growth factor or with saline solution for control animals. Dynamic magnetic resonance imaging was performed with a 92,000-d contrast agent, albumin-(gadolinium-diethylenetriaminepentaacetic acid)(30). Vascular permeability was estimated from dynamic enhancement data that were analyzed with a unidirectional 2-compartment kinetic model. RESULTS: Animals treated with vascular endothelial growth factor antibody accumulated significantly smaller volumes of peritoneal ascites (P <.05) and showed significantly lower magnetic resonance imaging-assayed tumor microvascular permeabilities (P <.05) than did control animals. CONCLUSION: Magnetic resonance imaging enhanced with a macromolecular contrast agent in an athymic rat model of human ovarian cancer treated with anti-vascular endothelial growth factor antibody can be used to measure a reduction in tumor microvascular permeability, corresponding to a reduction in ascites production.

MR contrast media for myocardial viability, microvascular integrity and perfusion.

Cardiovascular imaging requires an appreciation of rapidly evolving MR imaging sequences as well as careful utilization of intravascular, extracellular and intracellular MR contrast media. At the present time, clinical studies are restricted to the use of extracellular MR contrast media. MR imaging has the potential to noninvasively measure multiple parameters of the cardiovascular system in a single imaging session. Recent advances in fast and ultrafast MR imaging have considerably enhanced the capability of this technique, beyond the assessment of left ventricular wall motion and morphology into visualization of the coronary arteries and measurement of blood flow. During the course of the last several years, multiple strategies for imaging viable myocardium have been developed and validated using MR contrast media. Contrast enhanced dynamic MR imaging provides information regarding microvascular integrity and perfusion. Because these information can be provided noninvasively by MR imaging, repeated measurements can be performed in longitudinal studies to monitor the progression or regression of myocardial injury. Similar studies are needed to examine the effects of newly developed cardioprotective therapeutics. Development of suitable intravascular MR contrast medium may be essential for visualization of the coronary arteries and interventional therapies. MR imaging may emerge as one-stop-shop for evaluating the heart and coronary system. This capability will make MR imaging cost-effective in the first decade of this millennium.