Hepatocyte-mediated transport to the bile of AMI-HS, a particulate contrast agent.

RATIONALE AND OBJECTIVES: The elimination of hepatocyte-directed particulate contrast agents has not been studied in the same detail as particles eliminated mainly by the mononuclear phagocyte system. The aim of the present study was to elucidate the fate of these particles by a multidisciplinary approach. METHODS: After intravenous injection of AMI-HS particles directed to the hepatocytes, rats were killed and cytological studies, by both electron microscopy and histochemistry, and spectroscopic studies of the bile were performed. The data were compared with a dynamic magnetic resonance study of the heart and liver. RESULTS: The particles were rapidly cleared from the blood by Kupffer cells and hepatocytes and then found first in the vascular and later in the biliary pole of the hepatocytes. After 24 hours, a relaxometric characterization of the bile showed the presence of unchanged particles in the bile. CONCLUSIONS: These results show the capacity of the liver to excrete unchanged AMI-HS particles directly into the bile.

Contrast-enhanced MR imaging of experimental acute tubular necrosis.

PURPOSE: To demonstrate the involvement of the various renal structures in acute tubular necrosis (ATN). MATERIAL AND METHODS: In 15 rats, using a T1-/T2-weighted sequence, either gadodiamide alone, or gadodiamide in combination with sprodiamide (a susceptibility agent) were used to enhance the various anatomical substrates of the kidney. The results were compared to those of pathological verification. RESULTS: Experimentally induced ATN of the rat kidney causes profound changes in the medulla, leaving the cortex largely intact. The difference between the normal cortex and the partially necrotic outer medulla, on the one hand, and the papillary region, was significantly enhanced with the combination, whereas a larger region composed of the inner and outer medulla was enhanced after the gadolinium chelate alone. CONCLUSION: The results varied considerably between the two procedures; the double contrast demonstrated a clear difference between the inner and outer medulla, and the gadolinium chelate alone demonstrated a clear difference between the medulla and the cortex. These results demonstrated a clear difference in the compartmentalization between the inner and outer medullary regions, providing complementary information about the pathological condition of the kidney.

Gadolinium-enhanced MR imaging of normal renal transplants. An evaluation of a T1-weighted dynamic echo-planar sequence.

PURPOSE: To evaluate the potential usefulness of dynamic MR with echoplanar imaging (EPI) in assessing the renal function in patients with renal allografts. MATERIAL AND METHODS: Using a T1-weighted sequence, EPI was performed after injection of a Gd-chelate in 17 patients with normally functioning renal allografts. Time-intensity curves were plotted from the signal intensity (SI) measurements of the cortex and the medulla. RESULTS: The pattern of corticomedullar differentiation (CMD) observed after contrast enhancement was divided into four phases using the T1-EPI. After a rapid decrease in the SI of cortical structures, and a subsequent return to precontrast levels, a gradual fall in the SI of the medulla was observed. The average time between the two periods of signal loss was 60 s. CONCLUSION: This study illustrated the potential use of dynamic T1-EPI to demonstrate contrast-induced CMD in renal allografts.

Synergistic effects of relaxation and susceptibility in differentiation between compartmentalized and noncompartmentalized tissues.

RATIONALE AND OBJECTIVES: This study illustrates the synergistic effects of relaxation- and susceptibility-based contrast enhancement. Using a combination of gadolinium (Gd) and dysprosium (Dy) complexes and a sequence capable of taking advantage of the particular relaxation behavior of this combination, the difference between compartmentalized and noncompartmentalized regions was significantly enhanced. METHODS: Magnetic resonance imaging of the rat kidney was performed before and immediately after the administration of a combination of Gd and Dy chelates (Gd-DTPA-BMA and Dy-DTPA-BMA). RESULTS: The signal intensity (SI) of the renal parenchyma was reduced by 85%, whereas the collecting tubes had a 100% increase of their SI as demonstrated by a short repetition time (600 msec), long echo time (50 msec), and spin-echo sequence. CONCLUSIONS: The high R2* effect, specific to the compartmentalized tissues, associated with the moderately high R1 and R2 developed in the remaining areas, results in an important improvement in tissue differentiation, which potentially is useful for the evaluation of pathological changes as in tubular necrosis.

Delineation of liver necrosis using double contrast-enhanced MRI.

The purpose of this study was to demonstrate the potential usefulness of the combination of gadolinium and dysprosium to enhance the different between normal and necrotic liver tissue. Small regions of acute necrosis were induced by injecting 200-300 microliters of 95% alcohol into the liver of 26 rats. MRI was performed 24 hours after necrosis induction, before and immediately after injection of one or both contrast agents. Using a mixed T1/T2-weighted sequence, the signal intensity of (SI) of the normal liver was reduced by 70%, whereas the necrotic regions had more than a 50% increase in SI after double contrast. The region that was enhanced corresponded largely with the region of necrosis as observed postmortem. The lesion size, when identified, was largely underestimated using either of the agents along, albeit using the common pulse sequences. The double contrast effect of simultaneous administration of gadolinium and dysprosium allows accurate delineation of liver necrosis.

Dysprosium-enhanced MR imaging for tumor tissue characterization. An experimental study in a human xenograft model.

PURPOSE: To evaluate dysprosium-enhanced MR imaging for differentiation between morphologically intact and necrotic tumor tissue in a tumor model. MATERIAL AND METHODS: A human colon carcinoma was transplanted subcutaneously into 9 nude (immunodeprived) rats. MR imaging was performed before and after injection of the dysprosium agent Dy-DTPA-BMA. T1-, T2- and T2*-weighted sequences were acquired. The tumors were dissected, histological sections were prepared, and compared with corresponding MR images. RESULTS: In intact tissue, the MR signal intensity in the T2- and T2*-weighted images decreased after Dy injection and the delineation of the intact regions were sharp and corresponded well to the gross histological sections. CONCLUSION: Dy-enhanced MR imaging facilitated the differentiation between intact and necrotic tumor tissue.

Combination of gadolinium and dysprosium chelates as a cellular integrity marker in MR imaging.

A combination of gadolinium (Gd) and dysprosium (Dy) chelates was investigated as a potential marker of cell-membrane integrity by means of a double-contrast effect in MR imaging. Blood samples with varying hematocrit (Hct) levels containing intact or lysed cells were used as model systems. With intact cells, the agents were assumed to be distributed solely extracellularly and the highest Hct studied (69%) was assumed to mimic the ratio of extracellular to intracellular water in tissue. The combined effect on image intensity of Gd (in a concentration corresponding to 0.2 mmol/kg b.w. in humans) and Dy (0.6 mmol/kg b.w.) applied simultaneously was a marked difference in signal intensity between samples with intact and lysed cells in both the T1- and T2-weighted spin-echo images with a corresponding increase in the contrast-to-noise ratio. This was the result of a T1 reduction caused by Gd with a negligible Dy susceptibility effect in areas with lysed cells. On the other hand, the Dy susceptibility effect (i.e. reduced apparent T2) dominated in areas with intact cells. Thus, the combination of Gd and Dy may serve as a marker of cell-membrane integrity in MR examinations.

MR imaging of the pancreas at 0.3 T using a super-paramagnetic oral contrast medium.

Twenty patients with carcinoma of the pancreas identified with ultrasonography and/or CT and confirmed by histology, were examined with MR before and after administration of an oral super-paramagnetic contrast medium. Ten patients were examined after administration of the contrast medium through a duodenal tube. Ten patients drank the contrast medium mixed with a viscosity-increasing agent. Organ delineation and diagnostic information were improved in the postcontrast scans in both groups and the viscous contrast suspension yielded better delineation and diagnostic information than the aqueous suspension. The viscous contrast suspension also showed better tolerance, contrast distribution and less artifacts than the aqueous suspension.

Superparamagnetic iron oxide for liver imaging. Comparison among three different preparations.

OBJECTIVES: The effects of differently sized superparamagnetic iron oxide (SPIO) particles as liver contrast agents were evaluated by relaxation analysis and magnetic resonance imaging in normal rabbits. METHODS: We performed relaxivity measurements in agarose gels; T1 was measured by saturation recovery. Rabbits were injected with SPIO particles to evaluate hepatocellular localization and magnetic resonance appearance. RESULTS: Small (30 nm), medium (300 nm) and large SPIO particles (3,500 nm) reduced the T2 of liver by 50%, 40% and 15%, respectively, and the T2 of spleen by approximately 60%, 65%, and 25%, respectively, at 1 mg Fe/kg intravenous injection. Both small and medium SPIO particles decreased the T1 of spleen by approximately 35%, with no effect on liver T1. Magnetic resonance imaging showed decreased signal intensity ratios (SIliver/SImuscle) by approximately 80% and 60% for small and medium SPIO particles, respectively. Iron oxide (positive Perls blue staining) was observed in Kupffer cells after injection of medium and large SPIO particles, and also in hepatocytes after injection of small SPIO particles. CONCLUSION: The liver contrast effect seemed to be related to cellular distribution; the widely distributed small SPIO particles were most effective.

Abdominal MRI using a negative contrast agent.

A dose of 0.5 g of a negative oral contrast agent for labelling the bowel, was given to 40 patients in a clinical trial. Oral magnetic particles (OMP) consist of crystals of iron oxide with superparamagnetic properties, and are administered in 800 ml of a viscous suspension in order to obtain a uniform distribution. The aim of the study was to identify any adverse effects up to 1 week following ingestion, as well as the contrast distribution and effect, together with the induction of artifacts. A comparison of diagnostic value of the pre and postcontrast ingestion series was also performed. Vomiting followed ingestion in a single patient already nauseated and was the only adverse effect. Good contrast distribution and effect with no artifacts were present. The diagnostic information was greatly improved after OMP ingestion, and the diagnosis would not have been possible without the use of the contrast agent in 41% of the examinations.

Oral magnetic particles. Results from clinical phase II trials in 216 patients.

Oral magnetic particles (OMP) have been evaluated in a clinical phase II trial program comprising 216 patients in 7 European centers. Adult patients referred for MR imaging for various abdominal pathologies were examined. The patients received OMP at a concentration of 0.1 g/l (ultralow field) or 0.5 g/l (mid/high field) and OMP was diluted in water or in a more viscous liquid formulation. Depending on the area of interest, OMP was ingested in a volume of 300 to 800 ml. OMP was well tolerated with no serious adverse events and the patient acceptability was good. OMP had a good contrast effect on all applied pulse sequences. The viscous formulation of OMP was homogeneously distributed through the entire gastrointestinal tract without inducing disturbing susceptibility artifacts. The postcontrast diagnostic information was improved in 70% of the cases. Based on the encouraging results in phase II, OMP has been advanced to phase III clinical trials.

Ferrimagnetic susceptibility contrast agents.

Contrast agents based on superparamagnetic particles have been in clinical development for more than 5 years, and the complexity of their effects is still not elucidated. The relaxivities are frequently used to give an idea of their efficacy, but these parameters can only be used if they are concentration independent. For large superparamagnetic systems, the evolution of the transverse magnetization is biexponential, after an initial loss of magnetization. Both these characteristics of large superparamagnetic systems should lead to prudence in using the relaxivities as indicators of contrast medium efficacy. Susceptibility induced artefacts have been associated with the use of superparamagnetic contrast agents since the first imaging evaluation took place. The range of concentrations where good contrast effect was achieved without inducing artefacts, as well as blurring and metal artefacts were evaluated. The influence of motion on the induction of artefacts was studied, and compared to the artefacts induced by a paramagnetic agent subject to motion. With a suitable concentration of a negative contrast agent, a signal void could be achieved in the region prone to motion, and no artefacts were induced. If the concentration was too high, a displacement of the region close to the contrast agent was observed. The artefacts occurred in a volume surrounding the contrast agent, i.e., also outside the imaging plane. In comparison a positive, paramagnetic contrast agent induced heavy artefacts in the phase encoding direction, appearing as both high intensity regions and black holes, in a mosaic pattern. Clinical trials of the oral contrast agent OMP for abdominal MR imaging showed this agent to be safe and efficacious. OMP increased the diagnostic efficacy of abdominal MR imaging in 2 of 3 cases examined, with a significant decrease in motion artefacts. Susceptibility contrast agents may also be of use in the evaluation of small lesions in the liver. Particulate material injected i.v. will be targeted to the liver and spleen by way of the mononuclear phagocyte system (MPS). Small particles, without specific receptor affinities were targeted to the hepatocytes and the MPS. The distribution correlated with a high efficiency as a contrast agent, whereas no correlation to in vitro relaxation rates and relaxivities could be found. Superparamagnetic particles have important possibilities as contrast agents. The identification of in vitro properties of these agents may help the comparison of various agents before in vivo imaging.

Contribution of oral magnetic particles in MR imaging of the abdomen with spin-echo and gradient-echo sequences.

An open phase III clinical trial of the oral contrast agent OMP (oral magnetic particles) was performed in 35 patients undergoing abdominal magnetic resonance (MR) imaging at 1.5 T with axial spin-echo and gradient-echo sequences. The diagnostic efficacy of OMP was examined by comparing pre-and postcontrast images. Bowel loops and abdominal organs were more easily recognizable after OMP ingestion, and the general quality of the images was improved because of fewer bowel-related artifacts. The diagnostic value of the postcontrast abdominal MR examination was superior or equal to that of the precontrast study, and additional information was obtained in 44% of the cases. Postcontrast gradient-echo sequences increased confidence in the MR examination in 18% of cases. OMP was well tolerated and increased the quality and amount of diagnostic information acquired during the examination. Gradient-echo imaging was found to be a useful complement, but the need for a reduction in susceptibility artifacts was apparent and indicates that a decrease in TE or the use of rapid spin-echo sequences might be advantageous.

Motion associated susceptibility artifacts.

A bowel labeling agent is important for improving abdominal MR. Besides providing contrast between the bowel and other organs, the contrast agent itself is a potential source of artifacts. The artifacts created by superparamagnetic particles (SPP) subjected to motion have been studied in vitro at 0.5 T, and compared to artifacts created by a paramagnetic compound. Apart from the expected static effects of the SPP, movement induced additional artifacts were seen as signal displacements in the phase-encoding direction. The artifacts were obvious at an iron concentration of 1 mg Fe/ml, barely visible at 0.2 mg Fe/ml, and completely absent at 0.1 mg Fe/ml. Artifacts were also evident with the SPP outside the imaging slice. This further emphasizes the importance of choosing the lowest effective dose when using SPP contrast agents. For the paramagnetic agent, motion propagated artifacts consisted of high and low signal regions in a mosaic pattern.

Superparamagnetic particles as oral contrast medium in MR imaging of malignant lymphoma.

Non-biodegradable superparamagnetic particles, in plain and viscous aqueous suspensions, were used as an oral contrast medium in 34 patients with known or suspected malignant lymphoma. The contrast effect, the occurrence of artifacts, and the distribution were evaluated in the plain and the viscous aqueous suspensions, and the diagnostic information received from abdominal MR examinations performed without bowel contrast medium was compared with that of post-contrast examinations. Magnetic particles in the concentration of 0.5 g/l displayed a good contrast effect at 0.5 T, and helped in differentiating the intestine from adjacent tissues, resulting in increased diagnostic information in abdominal MR imaging. In the patients given the viscous aqueous suspension the occurrence of artifacts caused by the magnetic particles decreased considerably, and the distribution was homogeneous and improved compared with that in patients given the plain aqueous suspension.

Effect of superparamagnetic particles in agarose gels. A magnetic resonance imaging study.

The effect of different preparations of superparamagnetic particles, designed as potential MR contrast media for the gastrointestinal tract (oral magnetic particles, OMP, diameter of 3.5 microns, iron content 20% by weight) and for the reticuloendothelial system (intravenous magnetic particles, IMP, mean diameter of 0.3 micron, iron content 30% by weight), were evaluated in agarose gels in vitro, using a 0.5 T whole body MR system. The iron content ranged from 2.1 x 10(-4) to 2.1 x 10(-1) mg Fe/ml in both preparations. Both preparations reduced the signal intensities substantially over a range of concentrations in spin echo sequences. Generally, the signal intensity decreased monotonously with concentration, except for IMP at low concentrations, at which a minor signal intensity increase was observed on T1 and proton density weighted images. The reduction of the signal intensity was stronger in gradient echo and phase contrast sequences, as compared to corresponding spin echo sequences with similar timing. Both IMP and OMP had a pronounced T2 effect, the effect of IMP being stronger than that of OMP. IMP had a relatively smaller T1 effect, whereas T1 was almost unaffected by OMP. Susceptibility artifacts occurred at higher concentrations of both OMP and IMP, in all sequences used. Thus, OMP reduced the signal intensity, without causing significant artifacts, on both T1 and T2 weighted images over a relatively wide range of concentrations.

Superparamagnetic particles as gastrointestinal contrast agent in magnetic resonance imaging of lower abdomen.

Negative gastrointestinal contrast enhancement can be achieved by oral administration of superparamagnetic particles. Their feasibility for the MR imaging of the female pelvis and lower abdomen was evaluated in studies on 32 follow-up patients with treated gynaecologic cancer. All the applied doses (0.2-1.0 mg particles/ml given in a volume of 600-800 ml) of contrast medium decreased the intraluminal signal. However, there was unpredictable individual variation in segmental distribution, and in some cases only a limited contrast effect was obtained. Image distortion was detected when the applied particle concentration exceeded 0.5 mg/ml, especially of the sagittal sections.

Oral superparamagnetic particles for magnetic resonance imaging. Effect in plain and viscous aqueous suspensions.

As a potential gastrointestinal MR contrast medium magnetic particles have been evaluated in preclinical studies as well as in healthy volunteers. The main problem was to achieve an even distribution of the aqueous suspension of magnetic particles in the entire intestine. To improve the distribution of the contrast medium, a viscosity-increasing agent was added to the preparation. In the plain aqueous suspension the magnetic particles sedimented rapidly and caused artifacts, whereas no such sedimentation occurred in the viscous preparation. The contrast effect, as well as the presence of artifacts, increased with particle concentration. The general contrast effect was good in all 5 volunteers, and the contrast medium was well distributed in the small intestine, including the duodenum. There were no artifacts observed, and the contrast medium was well tolerated. The viscosity-increasing agent will thus be introduced in further clinical studies.