Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha.

Pharmacological effects of recombinant human tumor necrosis factor alpha (TNF) were studied in a mouse fibrosarcoma model using magnetic resonance imaging enhanced with a macromolecular contrast agent, albumin(gadolinium-diethylenetriamine pentaacetic acid)35. TNF was administered i.v. in a dose of 150 micrograms/kg, 60 to 80 min prior to imaging. Contrast-enhanced and nonenhanced magnetic resonance images of TNF-treated (n = 10) and untreated (n = 8) Meth A fibrosarcomas were obtained at 2.0 Tesla using T1-weighted spin-echo pulse sequences. Serial images spanning an interval of 60 to 120 min after TNF administration showed that the TNF-treated tumors enhanced significantly more overall than did untreated tumors (43% versus 31%). The most marked differential tumor enhancement was observed in the tumor rim (59% versus 40%). Nontumorous tissue, including muscle and brain, revealed no significant enhancement differences between TNF-treated animals and controls. The observed tumor enhancement corresponded strongly with Evans blue staining; the TNF-treated tumors stained deep blue, while untreated tumors and normal tissues observed did not stain. The different enhancement and Evans blue staining patterns between TNF-treated tumors and untreated tumors are attributed to TNF-induced changes in tumor capillary integrity. The data indicate that TNF effects on tumors include an increased capillary permeability for macromolecules at early times after administration. The ability to detect changes in capillary permeability in vivo using contrast-enhanced magnetic resonance imaging may prove to be clinically useful to monitor tumor response to TNF.

Influence of severity of myocardial injury on distribution of macromolecules: extravascular versus intravascular gadolinium-based magnetic resonance contrast agents.

OBJECTIVES: This study sought to 1) compare the distribution of extravascular (573 Da) and intravascular (92 kDa) magnetic resonance (MR) contrast agents in reperfused infarcted myocardium, and 2) investigate the effect of injury severity on these distribution patterns. BACKGROUND: Myocardial distribution of low and high molecular weight contrast agents depends on vascular permeability, diffusive/convective transport within the interstitium and accessibility of the intracellular compartment (cellular integrity). METHODS: To vary the severity of myocardial injury, 72 rats were subjected to 20, 30, 45 or 75 min (n = 18, respectively) of coronary artery occlusion. After 2 h of reflow, the animals received either 0.05 mmol/kg of gadolinium-diethylenetriaminepentaacetic acid-bismethylamide (Gd-DTPA-BMA) (n = 24), (Gd-DTPA)30-albumin (n = 24) or saline (control group, n = 24). Three minutes after injection, the hearts were excised and imaged (spin-echo imaging parameters: repetition time 300 ms, echo time 8 ms, 2-tesla system), followed by triphenyltetrazolium chloride staining for infarct detection and sizing. RESULTS: Histomorphometric and MR infarct size (expressed as percent of slice surface) correlated well: r = 0.96 for Gd-DTPA-BMA; r = 0.95 for (Gd-DTPA)30-albumin. On Gd-DTPA-BMA-enhanced images, reperfused myocardial infarctions were homogeneously enhanced. The ratio of signal intensity of infarcted/ normal myocardium increased with increasing duration of ischemia (overall p < 0.0001, analysis of variance [ANOVA]), indicating an increase in the distribution volume of Gd-DTPA-BMA in postischemic myocardium. On (Gd-DTPA)30-albumin-enhanced images, reperfused infarctions consisted of a bright border zone and a less enhanced central core. The extent of the core increased with increasing duration of ischemia (overall p value < 0.0001, ANOVA). CONCLUSIONS: At 2 h of reperfusion, the distribution of MR contrast agents in postischemic myocardium is 1) specific for extravascular and intravascular agents, and 2) modulated by the duration of ischemia.

Delay in the prehospital phase of acute myocardial infarction. Lack of influence on incidence of sudden death.

Prehospital delay is considered to be an important cause of out-of-hospital coronary mortality. Behavior of patients and physicians in response to the symptoms of myocardial infarction (MI) or impending out-of-hospital death (OHD) was studied for 107 consecutive acute coronary events in Framingham, Mass. Delay due to inappropriate patient behavior was the most important component of total delay. Delay related to patient-physician contact occurred in two thirds of MI cases and was more than 30 minutes in half of these. Office visits and inappropriate triage by nurses and receptionists were important factors in physician delay. However, 60% to 75% of OHDs occur so rapidly that their prevention by reduction of prehospital delay seems impossible. A strategy for reduction of delay that might be of benefit in preventing some of the remaining OHDs is described.

Magnetic resonance imaging in pediatric hematology/oncology. Part I. Basic technology.

Magnetic resonance imaging (MRI) is a promising new diagnostic modality that is well suited for the evaluation of children with hematological or oncological diagnosis. The side effects of ionizing radiation are avoided, the tomographic pathological anatomy in three orthogonal planes can be obtained, and differences between normal and abnormal tissues are often present. In order to present our preliminary clinical experience with MRI in pediatric hematology and oncology, the historical background of MRI, the technique, and possibilities for tissue characterization are reviewed.

Magnetic resonance imaging in pediatric hematology/oncology. Part II. Illustrative cases and assessment of technique.

Preliminary clinical experience with magnetic resonance imaging (MRI) in 28 pediatric patients with 20 different hematological diseases, benign tumors, or malignant neoplasms is presented. The clinical results are presented in the form of case presentations that are discussed in the context of alternative diagnostic imaging modalities. Also discussed are the known biological effects, or lack thereof, the need for sedation, the effect of motion, the effect of MRI on foreign metallic objects, the financial considerations, and the trends for the future of MRI. This imaging modality has many unique merits. Present difficulties should be overcome by future innovations, making MRI even more efficacious for the diagnosis of blood diseases and cancer in children.

Clinical nuclear magnetic resonance imaging of the body.

NMR promises great advances in diagnosis and has delivered so much already that it is expected that in the future it will replace many applications of the currently used imaging modalities. Although x-ray computed tomography is continuing to advance in speed of scanning and resolving power, NMR will most likely soon eliminate its use in many studies of the central nervous system and also in many other areas of the body. The promise of combining topical spectroscopy with imaging is also exciting and should provide further information about metabolic processes of various organs. Progress in NMR is so rapid and the future is so bright that one of the great problems will be to develop a new breed of radiologists who are versatile in biochemistry, mathematics, and computers, as well as competent in morphologic anatomy and pathologic physiology. As time goes on, advances in NMR will be achieved only by teams of clinical and basic scientists encompassing multiple disciplines.

Evidence supporting an antibody mediation of contrast media reactions.

Despite past doubts of the existence of antibodies to radiographic contrast material, there is now both clinical and experimental data to indicate that such antibodies do exist and that in certain individuals the antibodies may lead to severe or even fatal contrast media reactions. This article will detail the accumulated evidence supporting an allergic theory of contrast media toxicity in an attempt to stimulate interest and further investigation into this previously abandoned theory of mediation.

The allergic theory of radiocontrast agent toxicity: demonstration of antibody activity in sera of patients suffering major radiocontrast agent reactions.

An allergic, immunologic mechanism for certain adverse reactions to radiocontrast agents has been postulated on the basis of clinical and theoretical considerations. One obstacle to the acceptance of this allergic theory has been the inability to demonstrate significant antibodies with specificity for these agents. In our studies, rabbits were immunized with 4 analogues of radiocontrast agents which induced IgG or IgE antibodies specific for the contrast media analogues. Then, to determine if antibodies to contrast agents were present in man a prospective, one-year surveillance of radiocontrast agent reactions was undertaken. Sera from 27 patients suffering severe reactions and 37 control subjects were analyzed by radioimmunoassay for antibodies reactive with radiocontrast media. Binding of radiolabeled contrast media was significantly elevated (p less than 0.01) by the serum globulin fraction of the patients suffering severe reactions. Demonstration of this antibody activity, although not proof of cause and effect between the presence of antibody activity and clinical symptoms, nonetheless adds support to the hypothesis that some adverse reactions to radiocontrast agents are due to antibodies.

Metalloporphyrin contrast enhancement of tumors in magnetic resonance imaging. A study of human carcinoma, lymphoma, and fibrosarcoma in mice.

The diagnostic use of Mn(III)TPPS4, a paramagnetic metalloporphyrin, for MR contrast enhancement was examined in human--mouse xenograph models of carcinoma, lymphoma, and sarcoma. Spin-echo images of 15 mice, five mice for each implanted tumor type, were obtained before and at 20 minutes, and 2, 4, and 24 hours following administration of 0.09 mmol/kg of Mn(III)TPPS4. All tumors had a uniform moderate signal intensity on precontrast images. After administration of Mn(III)TPPS4, all tumors demonstrated significant enhancement of signal intensity that persisted to 24 hours. T1 relaxation times were maximally depressed at 2-4 hours and remained low to 24 hours for all three tumors. Kidney signal intensity reached a maximum at 20 minutes and remained significantly above background for 24 hours. The high relaxivity and apparent avidity of Mn(III)TPPS4 for divergent tumor histologies support the potential use of this agent for improved diagnostic specificity of MR imaging for neoplastic masses.

AUR Memorial Award 1991. Immunogenicity of gadolinium-based contrast agents for magnetic resonance imaging. Induction and characterization of antibodies in animals.

To evaluate the immunogenic potential of gadolinium-based magnetic resonance imaging (MRI) contrast agents, Sprague-Dawley rats were sensitized with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) dimeglumine and with Gd-DTPA covalently linked to either human serum albumin, dextran, or polylysine. IgG antibodies directed against Gd-DTPA were detected in immune sera by an enzyme-linked immunosorbent assay (ELISA), and were confirmed by competitive inhibition of antibody binding using free Gd-DTPA dimeglumine. Antiserum induced by immunization with human serum albumin-(Gd-DTPA) was characterized by a monophasic competition curve with 50% inhibition (IC50) = 5.5 x 10(-4) M when Gd-DTPA dimeglumine was used as both the well-coating and the displacing agent in a competition ELISA. Antiserum induced by Gd-DTPA dimeglumine alone was characterized by a biphasic competition curve with IC50 = 6.5 x 10(-7) M and 7.9 x 10(-4) M. Antisera obtained after exposure to either dextran-(Gd-DTPA) or polylysine-(Gd-DTPA) were of insufficient titer for characterization. The detection of antibodies specific for Gd-DTPA suggests in vivo protein binding with formation of hapten-carrier conjugates. This hypothesis is supported by increased relaxivity values observed when Gd-DTPA dimeglumine is incubated in serum rather than in water. Gd-DTPA dimeglumine and albumin-(Gd-DTPA) are immunogenic in rats under idealized experimental conditions. Additional studies will be necessary to determine the potential for immunologic response in humans to gadolinium chelates under conditions of exposure inherent in clinical use.

Aerosolized gadolinium-DTPA enhances the magnetic resonance signal of extravascular lung water.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), a contrast agent for magnetic resonance imaging, was administered by either aerosol or intravenous injection to rats. Proton relaxation times in excised lungs and kidneys were then measured. With increasing concentrations of aerosolized Gd-DTPA, the spin-lattice relaxation time (T1) of lungs decreased (enhanced) significantly (P less than .001), an effect that persisted for at least 80 minutes; there was no change in kidney T1. After intravenous injection of Gd-DTPA, lung T1 did not change, but kidney T1 decreased significantly (P less than .001), confirming previous observations of renal clearance. It is concluded that aerosolized Gd-DTPA is a more efficacious method of delivery of paramagnetic contrast agent to the lungs than intravenous injection, and that the lack of systemic effect after aerosolization indicates that enhancement was limited to the extravascular compartment.

Comparison of vascular opacification after bolus injection of iodixanol-320 iohexol-350.

RATIONALE AND OBJECTIVES: The vascular opacification characteristics of a new nonionic, dimeric contrast agent, iodixanol, have been compared with a nonionic, monomeric agent, iohexol, using ultrafast computed tomography (UFCT). METHODS: In 10 experiments with mongrel dogs, the contrast agents were alternately injected into the animal's left atrium, and UFCT images were obtained at four cross-sectional levels through the carotid arteries. Time-density curves were then obtained for each carotid artery and each agent. The peak height and area under the curves were compared for each agent. RESULTS: Iohexol provided significantly (P < or = .05) greater opacification, determined by paired Student's t tests. CONCLUSION: This result was predicted from the greater iodine concentration of iohexol (350 mg/mL) compared with iodixanol (320 mg/mL); the difference was greater than expected based on iodine content alone.

Pyrroxamide, a nonionic nitroxyl spin label contrast agent for magnetic resonance imaging. Mutagenesis and cell survival.

Pyrroxamide [N-(1-hydroxymethyl-2,3-dihydroxypropyl)-2,2,5,5-tetramethyl pyrrolidine-1-oxyl-3-carboxyamide] is a newly tested nonionic monomeric nitroxyl compound with demonstrated effectiveness for MRI contrast enhancement at doses as low as 10(-3) M. Pyrroxamide and its hydroxylamine metabolic derivative were tested in concentrations from 10(-9) to 10(-2) M with a battery of cytotoxic and mutagenic assays using mammalian Chinese hamster ovary cells. Loci-specific mutation induction was examined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and the Na+/K+ ATPase loci, both in the presence and absence of a liver microsomal metabolic activating mixture (S-9 mix). Cell survival and induction of sister chromatid exchanges also were studied. All tests yielded negative results indicating that pyrroxamide and and hydroxylamine derivative were both noncytotoxic and nonmutagenic at the doses tested.

Gadolinium-ethoxybenzyl-DTPA, a new liver-specific magnetic resonance contrast agent. Kinetic and enhancement patterns in normal and cholestatic rats.

OBJECTIVES: Gadolinium-ethoxybenzyl-DTPA (Gd-EOB-DTPA) is a new hepatobiliary magnetic resonance imaging (MRI) contrast agent with a dual elimination: 70% via the liver and bile and 30% via the kidney in normal rats. The abdominal enhancement patterns of this new compound and the uptake mechanism by the liver were studied in rats using tissue relaxometry and MRI. METHODS: Twelve normal rats, 33 rats treated with agents designed to inhibit biliary excretion of the agent, and 6 rats with surgically ligated common bile ducts received Gd-EOB-DTPA intravenously. Distribution and excretion were measured by MR relaxometry. MR signal intensity was measured over time for liver, kidney, and bowel. RESULTS: In normal animals, 0.1 mmol/kg Gd-EOB-DTPA induced a significantly greater (200%) and more prolonged liver signal enhancement (100% at 30 minutes) than Gd-DTPA at the same dose. Either hyperbilirubinemia, induced by common bile duct ligation, or bromosulfophtalein (BSP) infusion inhibited liver uptake of Gd-EOB-DTPA, resulting in a preferential elimination via the kidney. Taurocholate (TC), an inhibitor of the bile acid transporter, was unable to block the liver uptake of Gd-EOB-DTPA. Blood half-lives of Gd-EOB-DTPA in rats were 2.4 minutes for the first component and 8.2 minutes for the second. CONCLUSIONS: Data indicate that transport of Gd-EOB-DTPA through the liver into bile is driven by the organic anion transporter. The relation between enhancement of liver and kidney may be diagnostically useful to indirectly evaluate liver excretory function. Yet, persistent enhancement of liver, even in the presence of severe hyperbilirubinemia, should be sufficient to identify focal mass lesions.

In vitro histamine release induced by magnetic resonance imaging and iodinated contrast media.

RATIONALE AND OBJECTIVES: To investigate the mechanism of anaphylactoid reactions to contrast media, in vitro histamine release induced by magnetic resonance imaging, and iodinated contrast agents was examined in a dog mastocytoma cell line. METHODS: Two gadolinium (Gd)-based magnetic resonance contrast agents, Gd diethylenetriamine pentaacetic acid (Gd-DTPA), dimeglumine, and Gd-bismorpholide, and two iodinated contrast agents, diatrizoate meglumine and iohexol, were incubated with histamine-containing canine mastocytoma cells. Release of histamine into the supernatant was determined at various contrast-medium concentrations after incubation at 37 degrees C for 30 minutes. RESULTS: Iodinated and Gd-based contrast agents caused release of histamine from mastocytoma cells at similar concentrations (50-150 mM). Mannitol, an osmotic stimulus, caused release of histamine only at concentrations greater than 1,000 mM. CONCLUSIONS: Histamine release from canine mastocytoma cells does not appear to be solely due to osmotic effects, but results from direct stimulation by contrast media. For all agents examined, the concentration at which in vitro histamine release occurs far exceeds the serum contrast media concentration expected in routine clinical application. Direct release of histamine from mast cells does not completely explain the pathogenesis of idiosyncratic anaphylactoid responses to contrast media.

Antibodies to radiographic contrast agents. Induction and characterization of rabbit antibody.

An allergic, immunologic mechanism for certain adverse reactions to radiocontrast agents has been postulated on the basis of clinical and theoretical considerations. One obstacle to the acceptance of this allergic theory has been the inability to demonstrate significant antibodies with specificity for these agents. We attempted the induction of antibodies in the rabbit using analogues of radiocontrast media. The synthesis of four different analogues of commonly used radiocontrast agents allowed for testing the haptenic potential of various portions of the contrast medium molecule. Each analogue was conjugated to a carrier protein, emulsified in a suitable adjuvant, and repeatedly injected into several rabbits. Optimal immunization conditions were selected to increase the probability of antibody induction. Specific antibody was produced in good titer to each of the four haptens and in all injected rabbits. Antibodies were characterized by means of precipitation assays and radioimmunoassay using contrast agents labeled with 125I. Antibody concentrations ranged from 0.23 to 2.7 mg/ml and varied with interval and frequency of booster injections. In addition to antibodies specific for the contrast media analogues, antibodies to the carrier protein were also detected. Antibodies were of the IgG class and in selected sera were 83-92% precipitable. The induction of antibodies to radiocontrast agents supports the allergic theory of contrast medium toxicity.

Nitroxyl spin label contrast enhancers for magnetic resonance imaging. Studies of acute toxicity and mutagenesis.

Two nitroxyl spin label (NSL) compounds that are used experimentally as in vivo contrast enhancers in magnetic resonance (MR) imaging were tested for acute toxicity in rats and for genotoxic effects in cell cultures. These compounds, 2,2,5,5-tetramethyl-1-pyrrolidinyl-oxy-3-carboxylic acid (PCA) and 2,2,6,6-tetramethyl-1-oxido-4-piperidinyl-1-succinic acid (TES) and their hydroxylamine and amine derivatives did not induce sister chromatid exchanges or mutations in Chinese hamster ovary cells at the HGPRT or Na+/K+ ATPase loci. The acute LD50 doses in rats for PCA and TES are 15.1 mmol/kg or greater, suggesting relatively high tolerance.

Albumin labeled with Gd-DTPA. An intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization.

A paramagnetic-labeled macromolecule, albumin-(Gd-DTPA), was prepared for use as an intravascular contrast agent for magnetic resonance imaging. An average of 19 Gd-DTPA chelates were covalently conjugated to human serum albumin through the bifunctional anhydride of DTPA. The albumin-(Gd-DTPA) was characterized with use of high-performance liquid chromatography, sodium dodecyl sulfate gel electrophoresis, atomic absorption, biuret and Bradford protein tests, and by its effect on proton relaxation (relaxivity). The average molecular weight was 92,000 daltons, indicating the albumin conjugate was predominantly monomeric. The T1 relaxivity of albumin-(Gd-DTPA) was 273 mM-1 sec-1 relative to carrier concentration, which corresponds to a relaxivity of 14.9 mM-1 sec-1 relative to gadolinium concentration. The average conditional stability constant for albumin-bound Gd-DTPA chelate was log K = 20.0. Spin-echo images of rats demonstrated persistent enhancement of vascular tissues and slowly flowing blood. Application of albumin-(Gd-DTPA) may augment the MR assessments of blood volume, tissue perfusion, and flow characteristics.

Magnetic resonance imaging of experimental renal hemorrhage.

Experimental renal hemorrhage was induced by injecting autologous blood into the left kidney of 13 rats. To investigate the magnetic resonance (MR) characteristics of acute renal hemorrhage and subsequent stages of resolution, repetitive MR images were obtained using a 0.35 Tesla imager during a period of 21 days postinduction. A dual spin-echo imaging (TR 500 and 2,000 msec, TE 28 and 56 msec) was used to calculate the relaxation times and record the intensities in the renal medulla and cortex. Histologic examination (n = 9) indicated that blood was dispersed intrarenally, and no encapsulated hematoma developed. The signal intensity on the T1- and T2-weighted images, as well as the relaxation times in the hemorrhagic renal parenchyma were unchanged during 21 days when compared with intact kidney values. Subcapsular fresh blood had a high signal intensity on T2-weighted images. A marked overlap of the relaxation parameters between intact kidney parenchyma and diffuse intrarenal hemorrhage was observed. Detection of dispersed intrarenal blood using spin echo MR imaging may be difficult.

Ascorbate-induced cancellation of nitroxide contrast media enhancement of MR images.

Ascorbate (Vitamin C), a naturally occurring reducing substance, was tested as an in vivo chemical agent to cancel magnetic resonance imaging (MRI) tissue contrast enhancement induced by a nitroxide spin label contrast agent. Paramagnetic nitroxide compounds can be reduced in vitro by ascorbate to nonparamagnetic hydroxylamine derivatives. A nitroxide agent, TES, was injected intravenously, 2 mmol/kg, in 11 anesthetized rats. Renal cortical and hepatic intensities were monitored by serial T1-weighted images (TR/TE 310/15) acquired precontrast and postcontrast. Fourteen minutes after TES administration, ascorbate (1 mmol/kg) was injected in 6 rats, and saline in 5 control rats. At twenty-nine minutes postcontrast, a second TES-injection was given to all rats. The initial TES-injection resulted in a marked enhancement of kidney cortex and liver. Ascorbate administration immediately cancelled this enhancement. Contrast enhancement could be successfully reinduced by a repeat administration of TES. Results indicate that in vivo administration of reducing agents can be used to immediately cancel enhancement induced by nitroxide contrast media, thus nonenhanced images could be obtained after enhanced images without lengthy delays for contrast media elimination.