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The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic MR imaging were correlated with histopathologic grade in mammary soft-tissue tumors.A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N-ethyl-N-nitrosourea, a potent carcinogen. Dynamic contrast-enhanced MR imaging was performed using a small-molecular contrast medium (gadopentetate, molecular weight = 0.5 kDa) and a macromolecular contrast medium (albumin-(Gd-DTPA)30, molecular weight = 92 kDa) at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (K(PS)), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bidirectional kinetic model. MR imaging microvascular characteristics were correlated with histopathologic tumor grade.Tumor permeability to macromolecular contrast medium, characterized by K(PS), showed a highly positive correlation with tumor grade (r2 = .76, p10(-10)). K(PS) values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r2 = .25, p.003). No correlation between K(PS) or fPV values and tumor grade was found using gadopentetate (r2 = .01, p.95 and r2 = .03, p.15, respectively).Quantitative tumor microvascular permeability assays generated with macromolecular MR imaging contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

The value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of “blood-pool“-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed.

Paramagnetic nitroxyl-containing compounds have been useful as contrast agents in magnetic resonance imaging (MRI) experiments in animals. Preliminary information on the metabolic fate, pharmacokinetic behavior, stability in tissues, and chemical reduction of two prototypic nitroxides, PCA and TES, is presented. In the dog TES was eliminated more rapidly than PCA. More than 80 % of the dose of both nitroxides was recovered in urine within 6 hours. Nitroxides were reduced in vivo to their corresponding hydroxylamines. No other metabolite was observed. Measured reducing activity in tissue homogenates was greater in liver or kidney than in brain, lung or heart. In each tissue PCA was more stable than TES. PCA was also more resistant to reduction by ascorbic acid at physiologic pH. These preliminary results favor the use of PCA, a pyrrolidinyl nitroxide, over TES, a piperidinyl nitroxide, for MRI contrast enhancement.

Two nitroxide spin labels called PCA and TES have been used experimentally as contrast enhancing agents in magnetic resonance imaging. Pharmacokinetic data for these nitroxides, after intravenous administration to three dogs at two dose levels (0.1 and 2.5 mmole/kg), are presented. In this dose range, the clearance (13 ml/ min-kg) and half-life (22 min) of PCA stayed almost constant while TES clearance decreased (28 to 12 ml/min-kg) and half-life increased (8 to 17 min) with dose. The urinary recovery, determined from the sum of the nitroxide and its corresponding hydroxylamine, was 85 to 90% for both PCA and TES. PCA was investigated in more detail because of its lower clearance value and its lack of dose-dependence. The major pathways of elimination are renal excretion and metabolic reduction to the corresponding hydroxylamine which is eliminated by renal excretion. We estimated renal clearance of both PCA (5.5 ml/ min-kg) and its hydroxylamine (3.7 ml/min-kg) to be close to glomerular filtration rate (4 ml/min-kg) in the dog, while the metabolic clearance (7.5 ml/min-kg) was slightly higher. Approximately 35 % of the administered dose of PCA was excreted unchanged and half was reduced in the body.

The ability of macromolecular contrast agent (polylysine-[gadopentetate dimeglumine]) to allow differentiation of pulmonary fibrosis and alveolitis at magnetic resonance imaging was investigated. Lung damage was induced by means of left bronchial instillation of 200 micrograms of cadmium chloride. Rats were imaged 3 hours (early alveolitic stage, n = 5), 24 hours (late alveolitic stage, n = 5), and 8 days (fibrotic stage, n = 5) later. Rats imaged 3 hours after cadmium chloride instillation demonstrated a gradually increasing contrast enhancement over 45 minutes (from 314% +/- 110 to 476% +/- 69 over baseline [P less than .01]), indicating a leak of paramagnetic macromolecules from the intravascular into the extravascular spaces. Conversely, lung enhancement remained virtually constant after injection of contrast material in contralateral control lungs and in damaged lungs imaged 24 hours and 8 days after cadmium chloride instillation. Furthermore, the enhancement in the fibrotic lung was lower (170% +/- 50) than that in the alveolitic and control lungs (320% +/- 65 and 298% +/- 61, respectively), indicating a decrease in plasma volume in the fibrotic lung. A macromolecular contrast agent can facilitate the differentiation between the exudative and fibrotic phases of interstitial lung disease.

The use of aerosolized gadopentetate dimeglumine to define regional lung ventilation and of intravenously administered polylysine-(gadopentetate dimeglumine)40 to assess regional lung perfusion was investigated. In 10 healthy rats who breathed aerosolized gadopentetate dimeglumine (0.25 mol/L) for 5 minutes, pulmonary signal intensity increased diffusely in both lungs by more than 70%. When the same animals received intravenously administered polylysine-(gadopentetate dimeglumine)40 (0.1 mmol of gadolinium per kilogram), there was an additional 300% enhancement of the pulmonary parenchyma. In a rat model of acute unilateral pulmonary embolism (n = 5), perfusion defects were identified after administration of polylysine-(gadopentetate dimeglumine)40, but no ventilation abnormality was seen after inhalation of gadopentetate dimeglumine. In a rat model of acute unilateral airway obstruction (n = 5), only the ventilated right lung enhanced after inhalation of gadopentetate dimeglumine. In four of these animals, the focal ventilation defect was accompanied by a matched decrease in perfusion, seen after enhancement of the blood pool with polylysine-(gadopentetate dimeglumine)40.

To determine the effects of MRI-assayed vascular leakiness on the delivery of macromolecular therapeutics to tumors.MDA-MB 435 tumors, subcutaneously implanted into nude rats were treated with a single dose of bevacizumab at levels of 0.1 mg (n = 5) or 1.0 mg (n = 10) or received saline (control animals, n = 8). After 24 hours, albumin-(Gd-DTPA) (30)-enhanced MRI was performed. Just prior to MRI, the cytotoxic drug vinorelbine was administered intravenously. Upon completion of the MR experiment, tumor vinorelbine concentrations were quantified by high performance liquid chromatography (HPLC). Vascular leakiness (K (PS)) was calculated based on the MRI data using a pharmacokinetic model.K (PS) was calculated as 3.70 +/- 1.12 (control tumors), 1.95 +/- 0.70 (0.1 mg group) and 0.75 +/- 0.46 microl min (-1)cm (-3) (1.0 mg group). K (PS) was significantly higher in the control group compared to the 1.0 mg bevacizumab group. Vinorelbine concentrations were measured as 409.4 +/- 109.7 (control tumors), 387.5 +/- 47.5 (0.1 mg group) and 250.7 +/- 71.9 (1.0 mg group). These differences were not significant. A moderate and significant correlation was found between K (PS) and Vinorelbine concentrations in tumors (r = 0.49, p0.05).MRI-assayed K (PS) based on dynamic MRI enhanced by albumin-(Gd-DTPA) (30) correlated significantly with vinorelbine accumulation in experimental xenograft tumors under angiogenesis inhibition. Thus, the MRI technique applied in our study could potentially help to predict accumulation of macromolecular cytotoxic drugs and to optimize individual therapeutic regimes in tumors.

The ability of a macromolecular contrast agent (polylysine-[gadopentetate dimeglumine]40) to allow distinction of pulmonary capillary leak from hydrostatic pulmonary edema was investigated. Capillary leak edema was induced in 12 rats by means of venous injection of oleic acid; hydrostatic pulmonary edema was induced in 10 rats by means of continuous infusion of 0.9% sodium chloride. In the oleic acid pulmonary edema model, the signal intensity continued to increase for 12 minutes after administration of contrast material, indicating a leak of paramagnetic molecules from the intravascular to the extravascular spaces. Conversely, lung enhancement remained virtually constant after injection of contrast material in the hydrostatic edema model, as would be expected in the absence of endothelial damage. Hydrostatic edema tended to be distributed homogeneously throughout the lung, while capillary leak edema tended to occur predominantly in the peripheral portions of the lung. These findings indicate that macromolecular contrast agents can facilitate differentiation between edema caused by elevated intravascular pressure and edema induced by abnormal capillary permeability.

Dextran covalently linked to moieties of gadolinium diethylenetriamine pentaacetic acid (DTPA), for use as a macromolecular, intravascular blood pool marker for contrast material-enhanced magnetic resonance (MR) imaging was characterized by means of physicochemical and relaxivity measurements and MR imaging in healthy rats. Dextran labeled with 15 Gd-DTPA moities (molecular weight of approximately 75,000 d) had a T1 relaxivity at 0.25 T and 37 degrees C of 157.1 mmol-1.sec-1 per molecule and 10.5 mmol-1.sec-1 per gadolinium atom, more than twice that of unbound Gd-DTPA. Osmolality was 300-350 mOsm/kg at a gadolinium concentration of 0.01 mmol/L. Tissue enhancement was essentially linearly related to injected dose in the gadolinium dose range of 0.01-0.05 mmol/kg of body weight. Approximate typical enhancement values over baseline for normal tissues at 10 minutes after a gadolinium dose of 0.05 mmol/kg were as follows: cardiac muscle, adrenal gland, and liver, 40%-50%; lungs, 160%-200%; renal cortex, 130%; renal medulla, 240%; spleen, 75%; muscle, 15%; and brain, 5%-10%. Projection-subtraction images showed that dextran-(Gd-DTPA)15 remained intravascular for at least 1 hour after injection. The prolonged and easily appreciated levels of tissue enhancement with dextran-(Gd-DTPA)15, at a gadolinium dose less than that routinely used in Gd-DTPA, indicate further evaluation of this macromolecular marker.

The aims of this study were to characterize certain physicochemical, pharmacokinetic, and enhancement properties of a new macromolecular contrast agent, carboxymethyl hydroxyethyl starch-(Gd-DO3A)(35) [CMHES-(Gd-DO3A)(35)], consisting of a polysaccharide backbone covalently derivatized with multiple macrocyclic chelating groups for gadolinium. CMHES-(Gd-DO3A)(35) has an average molecular weight of 72 kD and a plasma half-time of 8.4 hours. T1 and T2 relaxivities are 14.1 +/- 0.1 L mmol(-1) * sec(-1) and 17.8 +/- 0.9 L mmol(-1) * sec(-1), respectively, for each gadolinium ion measured at 39 degrees C and 20 Mhz; this T1 relaxivity is more than 4 times that of gadopentetate. Seven days after intravenous administration only relatively small amounts of gadolinium could be detected in blood or other tissues of rats. The compound was well tolerated in diagnostic dosages by all experimental animals. Magnetic resonance angiography performed within 1 hour of CMHES-(Gd-DO3A)(35) administration showed a near-constant and strong enhancement of blood in arteries and veins. Analysis of dynamic enhancement patterns of experimental tumors (MAT-LyLu prostate cancer implanted in rats) following intravenous CMHES-(Gd-DO3A)(35) administration yielded quantitative estimates of tumor plasma volume and microvessel permeability; the demonstrated hyperpermeability of tumor microvessels was easily distinguished from the absence of measurable microvascular permeability in non-neoplastic soft tissues.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging may be used to quantify tissue fractional blood volume (fBV) and microvascular permeability. We tested this technique in patients with brain tumors to assess whether these measurements correlate with tumor histologic grade. METHODS: Twenty-two patients with newly diagnosed gliomas underwent MR imaging followed by surgery. Imaging consisted of one pre- and six dynamic postcontrast 3D spoiled gradient-recalled acquisition in the steady state data sets after administration of a single dose (0.1 mmol/kg) of contrast material. Signal intensity changes in blood and tissue were kinetically analyzed using a bidirectional two-compartment model, yielding estimates of fBV (mL/cm(3)) and microvascular permeability (mL/100 cm(3) per minute). Stained tumor specimens were scored on a four-point scale (1 = low grade, 4 = high grade). RESULTS: Histologic examination revealed one grade 1, eight grade 2, seven grade 3, and six grade 4 tumors. fBV values ranged from 0.5% to 13.7%. Permeability values ranged from −0.4 to 18.8, with a strong correlation (r = 0.83) to tumor grade. Despite some overlap between the permeability values of specific tumors from different grades, differences in the mean were statistically significant. There was a weak correlation (r = 0.39) between estimated fBV and tumor grade, and no statistically significant difference among fBV values in any of the groups. CONCLUSION: This relatively simple method of analysis provides quantitative estimates of fBV and microvascular permeability in human brain tumors, with the permeability being predictive of pathologic grade. The technique can be easily implemented on clinical scanners and may prove useful in the assessment of tumor biology and in therapeutic trials.

The purpose of this study was to compare liver contrast-enhancing characteristics of two superparamagnetic reticuloendothelial system (RES)-directed agents with different particle sizes, polycrystalline iron oxide nanocompounds (PION) and carboxydextran-coated maghemite (DDM128N/389, later referred to as DDM128), in an experimental model of focal radiation-induced hepatitis. PION, for the small particle size (31 nm), and DDM128, for the large particle size (59 nm), RES-directed agents were compared for liver enhancement after radiation-induced liver injury. A single x-irradiation exposure varying from 10 to 60 Gy was delivered to one side of the liver. T2-weighted spinecho magnetic resonance imaging was performed 3 days after x-irradiation at 30 minutes post-contrast. Using the RES-directed PION, the normal, non-irradiated portion of the liver decreased in signal intensity with a maximum negative enhancement of -66%, while the irradiated portion of the liver decreased in signal intensity by -24% (60 Gy). The signal intensity decline of irradiated liver tissue using PION was dose dependent, but was found at all radiation dose levels (10-60 Gy). The difference in signal intensity between irradiated (-63%) and non-irradiated (-82%) portions was also statistically different using DDM128 at 60 Gy. However, lower irradiation doses (10 and 30 Gy) failed to produce a statistically significantly different enhancement in the irradiated and non-irradiated portion of the liver. Sensitivity of liver enhancement with RES-directed agents is size dependent. The smaller particle (PION) is more sensitive for detection of radiation-induced hepatitis than the larger particle (DDM128). The relative insensitivity of DDM128 enhancement for diffuse liver injury will be clinically advantageous for detecting focal lesions in the presence of diffuse hepatic injury.

Tumor blood volume (BV), subject to both morphologic and physiologic influences, can be measured using contrast-enhanced magnetic resonance imaging (MRI). The aims of this study were to determine whether MRI enhanced with a macromolecular contrast medium (MMCM) could resolve differences in BV between different tumor types, between different regions within tumors, and within the same tumor in life and after death. Tumor BV estimates were based on the MRI signal intensity responses in the tumors and in reference venous blood following enhancement with a blood pool MMCM using two mammary adenocarcinoma models. Estimates of BV were made before and immediately following death. An in vitro measurement of tumor gadolinium concentration following death was correlated with MRI enhancement. Statistically significant differences (P0.05) were observed in MRI-estimated tumor BV between tumor subtypes, between in vivo and postmortem measurements, and between the tumor periphery and tumor centers. MRI assays enhanced with a macromolecular contrast agent can resolve blood volume differences between tumor types, between regions within the same tumor, and between vital and postmortem states.

A new macromolecular contrast agent, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)-24-cascade-polymer, was compared with Gd-DTPA for time-dependent delineation of acute myocardial ischemia. Acute myocardial ischemia was produced in 12 rats by occluding the anterior branch of the left coronary artery for 20-40 minutes. Dynamic spin-echo magnetic resonance imaging (MRI) was performed for 30 minutes after injection of Gd-DTPA (n = 6) or the cascade polymer (n = 6) using equimolar doses (0.1 mmol of Gd/kg). The contrast agent-induced changes in signal intensity (deltaSI) in normal and ischemic myocardium were observed. In normal myocardium, both contrast agents caused a sharp increase in deltaSI, followed by a decline to baseline values over the 30-minute period. Enhancement in the ischemic myocardium was attenuated. Gd-DTPA showed greater deltaSI in ischemic myocardium than the cascade polymer, which gave rise to virtually no enhancement. Significant differences (P0.05) in signal enhancement between normal and ischemic myocardium persisted for only 6 minutes using Gd-DTPA but for 18 minutes with the cascade polymer. Use of Gd-DTPA-24-cascade-polymer extends the temporal window of dynamic contrast-enhanced MRI for the differentiation of ischemic and normal myocardium. Identification of the ischemic zone is easier with the cascade polymer, which demonstrates virtually no signal enhancement in this territory.

We present three cases of adrenocortical carcinoma, a rare tumor in children, with extension into the inferior vena cava and the right atrium. The diagnosis is facilitated by use of ultrasonography, computed tomography and magnetic resonance imaging.

Magnetic resonance imaging (MRI) enhanced with contrast media has the potential to measure the level of angiogenesis in cancers and to monitor the immediate effects of drugs intended to inhibit angiogenesis. To appreciate the significance of such potential, it is necessary to first understand what is angiogenesis and why it is receiving so much attention.

The ideal radiological contrast medium (RCM) should produce no adverse reaction (AR) and the patient should be unaware that he has received an injection, either intravenous or intraarterial. No RCM yet developed has achieved this ideal performance but with the low osmolar contrast media (LOCM) major gains have been made in this respect for both intravenous and intraarterial injection.

Causes for airways obstruction in infants and children vary considerably from those encountered in adult populations. The recent dissemination of rapid CT scan (helical and electron beam) has changed the diagnostic imaging approach in children with suspected airways obstruction. Fast CT scan not only detects the location of obstruction with high sensitivity but also frequently provides clues to specific pathologic diagnoses.

The value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of "blood-pool"-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed.

The potential to define liver tumors at magnetic resonance (MR) imaging was compared with a positive and a negative contrast agent (gadoxetic acid disodium, or gadolinium EOB-DTPA [a hepatocyte-directed agent], and ferumoxides, or superpara-magnetic iron oxide particles [a Kupffer cell-directed agent], respectively) in normal rats and in rats with induced acute hepatitis, fatty liver, or cirrhosis.Rats with implanted liver adenocarcinomas were divided into four groups: no diffuse liver disease ("normal" [n = 6]) and diffuse liver diseases (induced acute hepatitis [n = 6], fatty liver [n = 6], or cirrhosis [n = 6]). Rats first received gadoxetic acid disodium (50 mumol/kg) and then, 45 minutes later, ferumoxides (10 mumol/kg). Liver signal intensity enhancement and tumor-to-liver contrast-to-noise ratio (C/N) were measured in each group.Mean liver signal intensity enhancement values with gadoxetic acid disodium and ferumoxides were excellent in the normal liver model (176% and -62%, respectively; P.01) but were significantly reduced in the acute hepatitis model (82% and -36%, respectively). In the fatty livers compared with the normal livers, enhancement with gadoxetic acid disodium was reduced (57%) but with ferumoxides was excellent (-55%). In the cirrhotic livers compared with the normal livers, enhancement with gadoxetic acid disodium (174%) was virtually the same but was impaired with ferumoxides (-43%).Hepatic enhancement and tumor-to-liver C/N with either positive or negative liver-enhancing agents can be impaired by the presence of underlying liver disease. Prior knowledge of the type of diffuse liver disease may influence the choice of contrast agent for tumor detection.

An automated method for two-dimensional spatial depiction (mapping) of quantitative physiological tissue characteristics derived from contrast-enhanced MRI was applied to a model of inflammatory disease represented by antigen-induced arthritis of the temporomandibular joint in the rabbit. Specifically, an established two-compartment kinetic model of unidirectional mass transport was implemented on a pixel-by-pixel basis to generate maps of tissue permeability surface area product (PS) and fractional blood volume (BV) based on dynamic MRI intensity data after administration of albumin-(Gd-DTPA)30, a prototype macromolecular contrast medium designed for blood pool enhancement. Maps of PS and BV in a disease model of induced arthritis clearly depicted zones of increased permeability (up to approximately 200 microliters/cc/h-compared to 25 microliters/cc/h in normal tissues).

To determine the relationship between capillary density, a recognized surrogate of tumor angiogenesis, and magnetic resonance (MR) imaging-derived estimates of plasma volume (PV) and microvascular permeability in two mammary carcinoma models.Dynamic spin-echo imaging was performed by using albumin-(gadolinium-diethylenetriaminepentaacetic acid)34, a prototype blood-pool contrast medium, in 14 rats with a subcutaneously implanted slow- or fast-growing subtype of R3230 mammary carcinoma. Data were fitted to an established two-compartment kinetic model to estimate PV and permeability.MR imaging-derived tumor PVs and permeabilities increased exponentially with increasing capillary density. MR imaging-derived microvascular characteristics correlated strongly with histologic capillary density, with an r2 of .85.Contrast medium-enhanced MR imaging may prove useful in estimating angiogenic activity in carcinomas. MR imaging may be superior to histologic assay because it is noninvasive, can be used to "sample" the entire tumor, and reflects both anatomic and physiologic characteristics.

Das ideale RKM sollte keine Nebenwirkungen hervorrufen, und der Patient sollte nicht merken, das eine i.v.- oder i.a.-Injektion verabreicht wurde. Kein bisher entwickeltes KM hat dieses Ziel erreicht, aber die niederosmolaren KM haben sowohl fur i.v.- als auch i.a.-Injektionen in dieser Beziehung deutliche Fortschritte gemacht.

Doses of gadopentetate dimeglumine of 0.1-0.5 mmol/kg cause cardiodepressive effects when injected as a rapid central bolus into the left jugular vein. This study evaluated the hemodynamic effects of this magnetic resonance imaging contrast medium with and without calcium supplementation in a rat model. Also, the potential of gadopentetate dimeglumine to bind ionized serum calcium was investigated in vitro. Addition of calcium ions resulted in dose-dependent attenuation of the hemodynamic depression induced by gadopentetate dimeglumine alone. The cardiodepressive response was negated for a 0.1-mmol/kg dose of the contrast agent by addition of 6 mumol/kg of calcium, for a 0.3-mmol/kg dose by addition of 12 mumol/kg of calcium, and for a 0.5-mmol/kg dose by addition of 18 mumol/kg of calcium. Concentrations of 2 and 4 mmol/L of gadopentetate dimeglumine were found to bind 5.1% and 10.1% of the ionized calcium in rat serum under in vitro conditions, respectively.

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.

The effect of a new intravascular magnetic resonance (MR) contrast medium (gadolinium diethylenetriaminepentaacetic acid [DTPA] polylysine) was evaluated in acute, subacute, and chronic myocardial infarctions in rats. Signal intensity (SI) was measured before and after intravenous administration of Gd-DTPA polylysine. Before administration of contrast material, chronic infarctions had lower SI than normal myocardium. With Gd-DTPA polylysine, three zones were identified in acute and subacute stages of myocardial infarction, but in the chronic stage, images demonstrated two zones. In acute and subacute infarctions, Gd-DTPA polylysine produced greater enhancement (over 60 minutes) in the peri-infarction zone than in the normal or infarcted myocardium. In chronic infarctions, Gd-DTPA polylysine had no discernible effect on the SI of the central infarction zone. Overall, it caused no significant hemodynamic effects. MR imaging with Gd-DTPA polylysine produced differential tissue enhancement in myocardial infarctions, which varied according to the age of the infarction.

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.

Paramagnetic macromolecules like Gd-DTPA labeled albumin offer certain beneficial features that distinguish them from smaller molecular paramagnetic contrast media, such as Gd-DTPA dimeglumine, which generally distribute in the extracellular fluid space. By joining multiple paramagnets to one large carrier molecule, the molar dose of the agent necessary for image enhancement is reduced, the proton relaxation effectiveness of such macromolecular agents is increased and they may even serve as markers of perfusion and abnormal vascular permeability. The accumulated experimental results with albumin labeled with Gd-DTPA are described.

A method is provided for obtaining in vivo diferentiation of tissues in an animal by nuclear magnetic resonance imaging comprising the steps of introducing into the animal a complex comprising a paramagnetic ferric ion and a chelator. Particular contrast agents, Fe(HBED) and Fe(EHPG), are excretable by a hepatobiliary pathway.

Two nitroxide spin labels (NSL) were compared for in vitro relaxivity and in normal rats for efficiency of urographic enhancement. One of the NSL, PCA, a pyrrolidinyl agent, was ionic and one, NAT, was a non-ionic pyrrolidinyl NSL with multiple hydroxyl substituents for water solubility. Using both NSLs the renal medulla and papilla were noted to show greater contrast enhancement than the cortex, with a maximum enhancing effect between 5 and 15 minutes. Using doses of 1.0 and 2.5 mmol/kg, more than 100 per cent increases in spin echo intensities above the baseline were observed. The lowest tested dose of 0.1 mmol/kg showed an easily detectable enhancing effect for NAT. The good contrast enhancing properties of NAT, considered together with its better acute tolerance, justifies further investigation of this non-ionic compound.

This is a report of ten infants and small children with congenital obstructive lesions of the distal trachea and main bronchi. Four were successfully resected. One with a distal segment stenosis required tracheal resection at age 6 wk, another with stenosis of the distal half of the trachea at age 18 mo, and 2 (1 with distal stenosis and 1 with tracheal hamartoma) at age 4 yr. All 4 are presently free of symptoms and their anastomoses have grown without stricture. A child with coil-spring mucosal stenosis of the left main bronchus developed an excellent airway following bronchoscopic removal of the folds, and a baby with tracheomalacia was successfully treated with a rib splint on a segment of distal tracheomalacia, but she died later of associated cyanotic congenital heart disease. Four babies died with airway obstruction in the newborn period. Two with critical distal stenoses died before tracheal reconstruction could be performed. Two died following emergency resections in which all of the congenital stenosis could not be removed. In both, stenotic trachea remained despite operation. All of these infants had complete cartilage rings the entire length of the trachea. Congenital lesions of the distal trachea may become suddenly life-threatening at birth or during the onset of a respiratory infection. An abrupt or insidious onset of airway symptoms requires an expeditious diagnostic evaluation to define the tracheobronchial anatomy, and the operating team has to be prepared for emergency tracheal reconstruction.

Changes in contrast due to paramagnetic substances depend on many factors, such as the properties and concentration of the substance, the external pulse and time parameters and the inherent relaxation time of the tissues. The physical background for contrast enhancement by paramagnetic substances is reviewed and the various groups of magneto-pharmaceuticals which have been used experimentally and clinically are described. The effect on signal intensity due to changes in dose, pulse sequence, repetition and echo times have been simulated and measured on phantoms and the effect of various tissue relaxation times on contrast has been investigated.

The angiographic and pathologic features of an endodermal sinus tumor (EST) arising from the retroperitoneum in a 19-month-old boy are presented. Although rare instances of extragonadal origin of EST have been reported, this is the first detailed description of the angiographic abnormalities. The angiographic appearance was that of a primarily retroperitoneal tumor with parasitized feeding arteries from the liver and right kidney, early filling venous radicles, sinusoidal pooling of contrast material, and inferior vena caval obstruction.

Two dilute oral iron solutions, made from commonly available nonprescription dietary supplements, were found to enhance the gastrointestinal tract in nuclear magnetic resonance imaging of live rats and one human volunteer. The paramagnetic and pharmacologic properties of ferric ammonium citrate were more favorable than those of ferrous sulfate heptahydrate. The paramagnetic iron solutions shorten T1 and T2 relaxation times of water protons in the contrast media-filled gastrointestinal tract, producing easily observable change in NMR intensity. Because these iron solutions are available commercially and are known to be well tolerated, the clinical use of iron-containing NMR contrast agents for the gastrointestinal tract is feasible.

Frontal chest radiographs can be misleading in the evaluation of central venous catheter placement. Lateral chest radiographs were obtained, in addition to the standard frontal radiographs, in 25 young children. In five (20%) of the children, the catheters were found to be malpositioned, and the frontal radiograph showed evidence of the abnormality in all five. The lateral radiographs also showed evidence of the abnormality in all five children; however, in three of the five, the lateral radiographs provided additional, more specific, diagnostic information. The lateral chest radiographs also demonstrated satisfactory catheter positioning in three other children in whom the frontal radiographs suggested abnormal positioning. Accurate assessment of catheter position was possible in all patients using both frontal and lateral chest radiographs. Injection of contrast material was not necessary to locate malpositioned cathethers. Lateral radiographs are recommended whenever an abnormal catheter position is suspected clinically or from findings on the routine frontal radiograph.

The study aim was to define potential differences and advantages in magnetic resonance (MR) patterns of tumoral contrast enhancement using either a small molecular, extracellular fluid contrast enhancer [Gd-DTPA] or a macromolecular agent [albumin-(Gd-DTPA)20], designed for primary intravascular biodistribution. MR images of 25 mice with implanted fibrosarcomas were obtained before and repeatedly for up to 120 minutes after injection of either Gd-DTPA [0.2 mmol/kg, n = 11] or albumin-(Gd-DTPA) [0.0029 mmol/kg, n = 14]. Histologically, this hypovascular tumor contained zones of viable tissue and non-viable, necrotic tissue. Using either type of contrast media, the viable portions enhanced strongly, up to 152% and the necrotic portions enhanced poorly, less than 31%. However, the time-course of enhancement differed between contrast agents. Gd-DTPA tended to provide maximal enhancement soon after administration with no significant changes over two hours. Enhancement from albumin-(Gd-DTPA) was weak initially, corresponding to tumor hypovascularity, but over two hours the signal of the viable tumor zones progressively increased in intensity. This gradual tumoral accumulation of the macromolecular agent within the tumor was considered to reflect abnormal capillary permeability, associated with neovascularity. Thus, the increasing intensity within the neoplastic tissues over time, reflecting abnormal capillary permeability for macromolecules, may serve as a useful, albeit indirect, marker of neoplasia.

The utility of a macromolecular, intravascular contrast agent, albumin-gadolinium diethylenetriaminepentaacetic acid (DTPA), for the differentiation of acutely ischemic and reperfused myocardium on magnetic resonance (MR) images was investigated. Regional, reversible myocardial ischemia was produced in rats and confirmed. After reperfusion, flow to the compromised myocardial segment returned to baseline. Normal myocardium could not be differentiated from ischemic myocardium on nonenhanced MR images (n = 12). After 5 minutes of myocardial ischemia and after administration of albumin-Gd-DTPA, the ischemic zone involving the free wall of the left ventricle was characterized by the absence of significant enhancement. Normal myocardium appeared homogeneously enhanced (by 145%). This pattern persisted for up to 1 hour of myocardial ischemia. In six rats that underwent myocardial reperfusion after 5 minutes of ischemia, the normal and reperfused myocardium became isointense. Radiotracer studies with albumin-Gd-153-DTPA confirmed the decreased distribution of contrast agent to the ischemic myocardium, possibly due to decreased blood pool or a blocked primary delivery system in the ischemic myocardium.

Gadolinium-DTPA (Gd-DTPA) enhancement of magnetic resonance (MR) imaging was tested for diagnostic utility in evaluating carcinoma. Human breast carcinoma implanted in ten nude mice was studied before and after injection of Gd-DTPA at two different doses (0.2 and 0.5 mmol/kg body weight). Before injection, all tumors appeared homogeneous in intensity on spin-echo images; after injection, it was possible to distinguish areas of strong enhancement from areas of weak enhancement. Histologic correlations showed that the strongly enhanced areas corresponded to richly vascularized connective tissue and apparently viable tumoral tissues, while the weakly enhanced areas corresponded to nonvascularized necrotic tissue. The results indicate that intravenously administered paramagnetic agents such as Gd-DTPA may improve the specificity and diagnostic accuracy of MR imaging by permitting better differentiation of tumor elements.

Hydropneumothorax may be diagnosed on a supine radiograph by recognition of a pleural line with increased density lateral to it in the pleural space. Recognition of this condition may have implications for therapeutic chest tube placement.

A newborn infant with agenesis of the left lung and critical distal tracheal stenosis required tracheal resection and reanastomosis. This case illustrates the combined use of flow-volume curves, radiology and endoscopy in the diagnosis and management of airway obstruction in infants. It also establishes the feasibility of complete tracheal reconstruction in small babies.

Recent advances in technology have made direct radiographic magnification of the newborn infant clinically feasible. A microfocus radiographic tube and a rare-earth, high-speed recording system were combined to obtain more than 2,000 radiographs at magnifications of 2-2.5. Special positioning devices permitted imaging of even those infants confined to incubators and connected to life-supporting systems. When quantitatively compared with three conventional contact radiographic systems with respect to resolution, contrast, and noise, magnification radiography showed overall superiority of image characteristics. Definition of subtle abnormalities and anatomically small structures permitted diagnoses which could not be made from conventional images. Furthermore, infant radiation exposure was markedly less (15 mR [3.9 mC/kg] maximum skin exposure) as compared with conventional contact radiographic systems (24 mR [6.1 mC/kg] to 45 mR [11.6 mC/kg]).

The experience from 123 pediatric MRI examinations disclosed several different types of artifacts and age-related variants that could have caused pitfalls in MRI interpretation. Artifacts were caused by metallic objects, patient touching the RF coil, and patient motion. The potential pitfalls are caused by the MRI variant appearances of anatomical structures specific to the growing body. Recommendations concerning preparation and immobilization of children prior to and during MRI examinations to minimize artifacts are given.