gadofluorine-m and Disease-Models--Animal

To compare the diagnostic performance of a diffusion-weighted imaging (DWI) dataset and a gadofluorine M-enhanced imaging dataset for identifying lymph node (LN) metastases in a rabbit rectal cancer model.. VX2 carcinomas were injected into the rectum of 26 rabbits. Four weeks later, T2-weighted imaging (T2WI), pre-T1WI, DWI, and post-T1WI were performed. Two radiologists independently reviewed the DWI set (T2WI, pre-T1WI, DWI) and the gadofluorine M set (T2WI, pre- and post-T1WI) and recorded their confidence scores for LN metastasis on a per-LN basis. Receiver operating characteristic (ROC) analysis was performed to compare the area under the ROC curve (A(z) ) of the two imaging sets. Histopathologic results were used as the reference standard.. The A(z) and sensitivity of the gadofluorine M set were comparable to those of the DWI set (A(z) , for reader 1, 0.849, 0.829, P = 0.571; for reader 2, 0.923, 0.876, P = 0.212; sensitivity, for reader 1, 97%, 97%; for reader 2, 97%, 92%, P = 0.304). The specificity of the former was greater than that of the latter (for reader 1, 65%, 53%, P = 0.0003; for reader 2, 81%, 68%, P = 0.01).. Gadofluorine M-enhanced images provided greater specificity than DWI for identifying LN metastases, whereas the A(z) and sensitivity of the former were comparable to those of the latter.

Topics: Animals; Cell Line, Tumor; Contrast Media; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Fluorocarbons; Image Enhancement; Lymphatic Metastasis; Magnetic Resonance Imaging; Neoplasm Transplantation; Neoplasms, Experimental; Organometallic Compounds; Rabbits; Rectal Neoplasms; ROC Curve; Sensitivity and Specificity

To compare the diagnostic performance of gadofluorine M with that of gadopentetate dimeglumine in the diagnosis of lymph node metastases with magnetic resonance (MR) imaging in a rabbit model of gastric cancer.. The study protocol was approved by the institutional animal care committee. VX2 carcinomas were inoculated into the wall of the stomach in 20 rabbits. Gadopentetate dimeglumine-enhanced MR imaging was performed 4-6 weeks after inoculation, and gadofluorine M-enhanced MR imaging was performed approximately 24 hours later. Both MR imaging sets were analyzed separately and independently by four radiologists with respect to confidence level regarding the presence of metastases in lymph nodes and lymph node conspicuity. Statistical analysis was performed by using multiple-reader multiple-case (MRMC) receiver operating characteristic curve analysis and the Wilcoxon signed rank test.. Metastases were confirmed at pathologic analysis in 32 of 104 lymph nodes from 16 rabbits. The area under the receiver operating characteristic curve (AUC) for confidence regarding the presence of metastases in lymph nodes was significantly greater for gadofluorine M than for gadopentetate dimeglumine (AUC, 0.947 vs 0.894; P = .009). However, most (81%, 25 of 32) metastatic nodes were necrotic, and no significant difference was obtained in nonnecrotic nodes. For lymph node conspicuity, the gadofluorine M MR imaging set was assigned a significantly higher score than was the gadopentetate dimeglumine MR imaging set by all readers (P < .001).. Gadofluorine M showed significantly higher accuracy and better conspicuity than gadopentetate dimeglumine in the diagnosis of metastatic nodes, most of which were necrotic, in this animal model of gastric cancer.

Topics: Animals; Contrast Media; Disease Models, Animal; Fluorocarbons; Gadolinium DTPA; Lymph Node Excision; Lymphatic Metastasis; Magnetic Resonance Imaging; Neoplasm Staging; Organometallic Compounds; Pilot Projects; Rabbits; ROC Curve; Sensitivity and Specificity; Statistics, Nonparametric; Stomach Neoplasms

The aim of the current study is to test the ability to label and detect murine embryonic stem cell-derived cardiovascular progenitor cells (ES-CPC) with cardiac magnetic resonance (CMR) using the novel contrast agent Gadofluorine M-Cy3 (GdFM-Cy3).. Cell therapy shows great promise for the treatment of cardiovascular disease. An important limitation to previous clinical studies is the inability to accurately identify transplanted cells. GdFM-Cy3 is a lipophilic paramagnetic contrast agent that contains a perfluorinated side chain and an amphiphilic character that allows for micelle formation in an aqueous solution. Previous studies reported that it is easily taken up and stored within the cytosol of mesenchymal stem cells, thereby allowing for paramagnetic cell labeling. Investigators in our laboratory have recently developed techniques for the robust generation of ES-CPC. We reasoned that GdFM-Cy3 would be a promising agent for the in vivo detection of these cells after cardiac cell transplantation.. ES-CPC were labeled with GdFM-Cy3 by incubation. In vitro studies were performed to assess the impact of GdFM-Cy3 on cell function and survival. A total of 500,000 GdFM-Cy3-labeled ES-CPC or control ES-CPC were injected into the myocardium of mice with and without myocardial infarction. Mice were imaged (9.4-T) before and over a 2-week time interval after stem cell transplantation. Mice were then euthanized, and their hearts were sectioned for fluorescence microscopy.. In vitro studies demonstrated that GdFM-Cy3 was easily transfectable, nontoxic, stayed within cells after labeling, and could be visualized using CMR and fluorescence microscopy. In vivo studies confirmed the efficacy of the agent for the detection of cells transplanted into the hearts of mice after myocardial infarction. A correspondence between CMR and histology was observed.. The results of the current study suggest that it is possible to identify and potentially track GdFM-Cy3-labeled ES-CPC in murine infarct models via CMR.

Topics: Animals; Carbocyanines; Cell Line; Cell Proliferation; Cell Survival; Contrast Media; Disease Models, Animal; Embryonic Stem Cells; Female; Fluorescent Dyes; Fluorocarbons; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Mice; Mice, SCID; Microscopy, Fluorescence; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Organometallic Compounds; Staining and Labeling; Time Factors

Inflammation and neovascularization play critical roles in the stability of atherosclerotic plaques. Whole-body quantitative assessment of these plaque features may improve patient risk-stratification for life-threatening thromboembolic events and direct appropriate intervention. In this report, we determined the utility of the MR contrast agent gadofluorine-M (GdF) for staging plaque stability and compared this to the conventional agent Gd-DTPA.. Five control and 7 atherosclerotic rabbits were sequentially imaged after administration of Gd-DTPA (0.2 mmol/kg) and GdF (0.1 mmol/kg) using a T(1)-weighted pulse sequence on a 3-T MRI scanner. Diseased aortic wall could be distinguished from normal wall based on wall-to-muscle contrast-to-noise values after GdF administration. RAM-11 (macrophages) and CD-31 (endothelial cells) immunostaining of MR-matched histological sections revealed that GdF accumulation was related to the degree of inflammation at the surface of plaques and the extent of core neovascularization. Importantly, an MR measure of GdF accumulation at both 1 and 24 hours after injection but not Gd-DTPA at peak enhancement was shown to correlate with a quantitative histological morphology index related to these 2 plaque features.. GdF-enhanced MRI of atherosclerotic plaques allows noninvasive quantitative information about plaque composition to be acquired at multiple time points after injection (within 1 and up to 24 hours after injection). This dramatically widens the imaging window for assessing plaque stability that is currently attainable with clinically approved MR agents, therefore opening the possibility of whole-body (including coronary) detection of unstable plaques in the future and potentially improved mitigation of cataclysmic cardiovascular events.

Topics: Animals; Aortic Diseases; Aortic Rupture; Atherosclerosis; Contrast Media; Disease Models, Animal; Feasibility Studies; Fluorocarbons; Gadolinium DTPA; Injections; Magnetic Resonance Angiography; Male; Organometallic Compounds; Predictive Value of Tests; Rabbits

Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M-enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis.. Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M-enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29+/-0.21 versus 3.00+/-0.32; P=0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P=0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P=0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis (r=0.67; P<0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels.. Gadofluorine-M-enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Contrast Media; Disease Models, Animal; Feasibility Studies; Fluorocarbons; Inflammation; Linear Models; Lipid Metabolism; Macrophages; Magnetic Resonance Angiography; Microscopy, Confocal; Microscopy, Fluorescence; Neovascularization, Pathologic; Organometallic Compounds; Predictive Value of Tests; Rabbits; Reproducibility of Results; Rupture

Magnetic resonance imaging plays a pivotal role in the diagnosis and treatment monitoring of multiple sclerosis. Currently available magnetic resonance-techniques only partly reflect the extent of tissue inflammation and damage. In the present study, application of the experimental magnetic resonance-contrast agent Gadofluorine M significantly increased the sensitivity of lesion detection in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Gadofluorine M-enhancement on T(1)-weighted (T(1)-w) images utilizing a clinical 1.5 T magnetic resonance unit showed numerous lesions in optic nerve, spinal cord and brain, the majority of which were not detectable on standard T(2)-weighted (T(2)-w) and Gd-DTPA enhanced T(1)-w sequences. Quantitative assessment by pixel counts revealed highly significant differences in sensitivity in favour of Gadofluorine M. Gadofluorine uptake closely corresponded to inflammation and demyelination on tissue sections. These unique features of Gadofluorine M in visualizing inflammatory CNS lesions hold promise for future clinical development in multiple sclerosis.

Topics: Animals; Brain Stem; Cerebellum; Contrast Media; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Fluorocarbons; Gadolinium DTPA; Magnetic Resonance Imaging; Multiple Sclerosis; Optic Nerve; Organometallic Compounds; Rats; Rats, Inbred Strains; Spinal Cord

Nerve imaging by magnetic resonance imaging (MRI) is an emerging tool for the diagnostic work-up of patients with PNS disorders. We have recently shown that the experimental MR contrast agent gadofluorine M (Gf, Bayer Schering Pharma AG, Berlin) accumulates in nerves undergoing Wallerian degeneration and in areas of acute focal demyelination allowing in-vivo assessment of nerve pathology. The exact pathomechanism underlying Gf accumulation in peripheral nerve disorders is unknown so far. In the present study we compared nerve signal alterations on T2-w and Gf-enhanced T1-w MRI in two different models of acute inflammatory and chronic degenerative demyelination: experimental autoimmune neuritis (EAN) induced by immunization with PNS myelin and experimental Charcot-Marie-Tooth (CMT) disease in rats overexpressing the myelin protein PMP22. During the acute stage of inflammation and demyelination, strong Gf enhancement on T1-w MRI was seen in nerve roots and peripheral nerves in EAN, which resolved with completed remyelination. Similarly, Gf accumulation was seen in CMT rats during early stages with active demyelination at 6 weeks while at chronic stages (9 months) Gf enhancement decreased despite numerous demyelinated axons and onion bulb formation. At all disease stages no signal alterations were seen on T2-w MRI. In conclusion, our data show that the novel MR contrast agent Gf, but not Gadolinium (Gd)-DTPA, facilitates detection of ongoing demyelination by MR neurography independent from the underlying pathology. It appears that the extent of Gf enhancement depends on the acuity of demyelination and is probably related to a transient disturbance of the blood-nerve barrier. Clinical development of Gf may help to further improve the sensitivity of nerve lesion assessment by MRI in patients with peripheral neuropathies.

Topics: Acute Disease; Animals; Chronic Disease; Contrast Media; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Fluorocarbons; Gadolinium DTPA; Inflammation; Magnetic Resonance Imaging; Myelin Proteins; Organometallic Compounds; Peripheral Nerves; Rats; Rats, Inbred Lew; Time Factors

Gadofluorine M has been reported to enhance early atherosclerotic plaque signals in magnetic resonance imaging (MRI). The aim of this study was to examine the use of Gadofluorine M to monitor the progression of advanced plaques in a rabbit model.. Focal advanced atherosclerosis was induced in the right femoral arteries of 6 New Zealand white rabbits using a combination of cholesterol-enriched diet, and sequential air-desiccation, and balloon-overstretch injury. MRI with conventional 3 contrasts (T1, T2, and proton density [PD]) was performed to monitor the progression of the atherosclerotic plaques with 2 MRI scans separated by 4 to 8 weeks. Gadofluorine M was given intravenously to the rabbits 24 hours before the first MRI scans, and before (n = 3) or during (n = 3) the second MRI scan. The left femoral arteries were used as a control. Histopathologic images localized individual plaque components.. The advanced plaque displayed multilayered neointima that included foam cells, smooth muscle cells, and extracellular matrix. The separate image contrasts offered similar T1-weighted enhancement patterns, but the combination of all 3 contrasts helped to delineate plaque and lumen boundaries. Gadofluorine M strongly enhanced neointima areas with an image contrast (contrast-to-noise ratio [CNR]) of approximately 15, versus 2 in the control femoral arterial wall. With improved images, significant changes in neointima and total plaque volumes over the 4 to 8 weeks between scans could be identified. Gadofluorine M remained within the plaques with significant image enhancements (contrast-to-noise ratio = 5.8) for 2 months after a single injection.. This preliminary study in rabbits indicated that Gadofluorine M provides specific enhancements of components associated with advanced atherosclerotic plaques and may help to monitor the progression of the plaque in a rabbit model of atherogenesis.

Topics: Algorithms; Animals; Atherosclerosis; Contrast Media; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Feasibility Studies; Fluorocarbons; Image Enhancement; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Organometallic Compounds; Rabbits; Reproducibility of Results; Sensitivity and Specificity

The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein-specific T-cell transfer in 26 female SJL/J mice, and applied high-field-strength magnetic resonance imaging (MRI) scans longitudinally, assessing blood-brain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP-C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast-enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico-radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.

Topics: Animals; Blood-Brain Barrier; Brain; Cerebellum; Contrast Media; Cranial Nerves; Disease Models, Animal; Endocytosis; Female; Fluorocarbons; Gadolinium DTPA; Image Processing, Computer-Assisted; Immunohistochemistry; Magnetic Resonance Imaging; Mice; Microglia; Multiple Sclerosis; Organometallic Compounds; Phagocytosis; Radiography; T-Lymphocytes