Indication-related dosing for magnetic resonance contrast media.

This presentation reviews the issue of contrast media dosing and imaging protocols for the optimal MR imaging detection and characterization of pathology. The cumulative clinical experience gained in performing contrast-enhanced MR examinations with gadolinium chelates indicates that a dose of 0.1 mmol/kg body weight provides safe and effective enhancement of most CNS pathology. Doses lower than 0.1 mmol/kg have been shown to be inadequate for delineating all but selected types of CNS pathology, such as masses with a high lesion to background ratio on post-contrast images (acoustic neuromas) or lesions located in areas in which the normal tissue very rapidly takes up contrast agent (e. g. microadenomas in the pituitary gland). Recent clinical studies have suggested a role for high dose gadolinium administration (up to 0.3 mmol/kg) for the optimal detection and delineation of cerebral metastases or other small or poorly enhancing lesions. Differences in the histopathologic characteristics (capillary permeability, vascularity, location, size) of specific diseased tissues may require varying doses or even a different contrast agent to be used for optimal imaging results. As new MR contrast agents and new scanning techniques are introduced, the specific diagnostic question posed will likely determine the choice of pulse sequence, contrast agent and dose used.

Magnetic resonance imaging of perilymphatic fistula.

Perilymphatic fistula (PLF) is considered to be a most challenging otologic issue. There are no currently agreed upon objective tests for the diagnosis of PLF. In an effort to improve diagnostic accuracy in patients with suspected PLF, a novel diagnostic test involving magnetic resonance (MR) contrast imaging was designed. An experimental PLF was created in the cochlear round window membrane of healthy adult cats. Since cochlear perilymph is thought to be an ultrafiltrate of cerebral spinal fluid, gadodiamide (gadolinium-diethylenetriamine penta-acetic acid [DTPA] bismethylamide), a nonionic paramagnetic contrast agent, was injected intrathecally in an attempt to enhance imaging of the created fistula. Post-contrast images of the fistualized cochlea demonstrate a significant increase in the signal intensity of the cochlear perilymph with pooling of enhanced perilymph observed in the ipsilateral mastoid bulla. Magnetic resonance contrast imaging may prove to be a valuable technique in human studies involving perilymphatic fistula.

Phase II clinical trial of gadoteridol injection, a low-osmolal magnetic resonance imaging contrast agent.

RATIONALE AND OBJECTIVES: The safety and efficacy of a new, low-osmolal magnetic resonance imaging contrast medium, gadoteridol injection, were evaluated in a phase II, open-label study at doses ranging from 0.05 to 0.30 mmol/kg. METHODS: Eighty-six patients with a diagnosis of intracranial tumor received gadoteridol injection followed by magnetic resonance imaging. RESULTS: Two adverse events (headache, taste disturbance) in 2 of 86 (2.3%) patients were reported. Both were of mild intensity and resolved without treatment and without residual effects. In 4 of 86 (4.7%) patients, 5 laboratory changes were reported by the investigators as possibly related to gadoteridol injection. Efficacy evaluation was conducted in 80 of the 86 patients who received gadoteridol injection. In these patients, a total of 119 lesions was identified, and each was evaluated at four time points after contrast administration, yielding a total of 476 lesion studies. Marked enhancement was demonstrated in 402 of 476 (84%) lesions, whereas slight enhancement was demonstrated in 62 of 476 (13%) lesions. The difference in both the incidence and degree of enhancement of pathology between the predose and postdose images was highly significant (P less than .001). CONCLUSIONS: Overall, enhanced images provided more diagnostic information and facilitated detection of more lesions than precontrast images. Gadoteridol injection at doses up to 0.3 mmol/kg is a safe and effective magnetic resonance imaging contrast agent for use in patients with intracranial tumors.

Fluorinated blood substitute retention in the rat measured by fluorine-19 magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Emulsions of perfluorocarbons (PFCs) have been tested as blood substitutes. However, evidence exists that there is long-term retention of some PFCs by the organs of the reticuloendothelial system (RES). The authors investigate organ retention of the blood substitute component, perfluorotripropylamine (FTPA), using fluorine-19 (19F) magnetic resonance imaging (MRI). METHODS: Various dosages of an emulsion of FTPA were administered to five rats. At intervals up to 86 weeks after infusion, 19F MRI was used to measure the amount of FTPA in liver and spleen. The data were fit to both linear and exponential elimination models, and organ retention half-lives were calculated. RESULTS: The exponential half-lives for combined liver and spleen FTPA ranged from 110 to 190 days. Linear half-lives ranged from 175 to 300 days. CONCLUSIONS: FTPA retained by the liver and spleen may be quantified by 19F MRI: The half-lives that were measured are longer than those reported previously for FTPA.

Efficacy of nonionic low-osmolar gadodiamide injection in animals with intracranial mass lesions.

Gadodiamide injection is a nonionic, low-osmolar formulation of a paramagnetic metal chelate complex consisting of gadodiamide and caldiamide sodium. The efficacy of gadodiamide injection as a magnetic resonance (MR) imaging enhancement medium was evaluated by imaging intracranial 9L-glioma lesions induced in rats and naturally occurring lesions in dogs. T1- and T2-weighted spin-echo images were obtained before and after administration of gadodiamide injection at doses of 0.1 and 0.2 mmol/kg. On the precontrast T1-weighted images, the intracranial lesions were not well seen, appearing isointense to normal brain parenchyma. Although the presence of disease was shown unequivocally on the T2-weighted images, the margins of the masses could not be delineated. Postcontrast T1-weighted images were characterized by marked enhancement of the tumor, with no change in signal intensity in the surrounding edematous brain tissue. Gadodiamide injection was efficacious in identifying areas of blood-brain barrier breakdown associated with intracranial masses.

Clinical safety and efficacy of gadoteridol: a study in 411 patients with suspected intracranial and spinal disease.

In this phase III study, 411 adult patients with suspected intracranial or spinal disease underwent magnetic resonance (MR) imaging before and after intravenous injection of 0.1 mmol/kg gadoteridol (gadolinium 1,4,7-tris [carboxymethyl]-10-[2'-hydroxypropyl]-1,4,7,10-tetraazacyclododecane+ ++). MR images were evaluated by a single unblinded reader at each of 27 sites; the diagnosis was confirmed with one of nine imaging or surgical procedures within 8 weeks before or after MR imaging. After injection, no clinically significant changes were noted in laboratory values, physical examination, or vital signs. Adverse clinical events possibly or probably associated with injection of gadoteridol were seen in 18 of 411 patients (4.4%); the most common were dysgeusia and mild nausea, and all abated without residual effects. MR images enhanced with gadoteridol in patients with confirmed disease provided more diagnostic information than unenhanced images in 128 of 175 brain examinations (73.1%) and 93 of 137 spinal examinations (67.9%). A change in diagnosis because of additional information from contrast-enhanced images was considered likely in 63 of 214 cranial and 54 of 161 spinal studies.

Gadolinium enhanced MR imaging of vascular stents.

The feasibility of obtaining in-plane magnetic resonance (MR) vascular images in the presence of a vascular stent and the value of infusing an MR contrast agent during imaging was assessed. Coronal and sagittal MR imaging at 1.5 T was performed on six dogs with tantalum aortic stents using single-section gradient echo (GRE) imaging and MR angiography techniques before and during intravenous infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). In-plane gradient echo (GRE) imaging and MR angiography clearly showed flow within the stented vessel as increased signal, with a minimum amount of stent-related artifact. Infusion of Gd-DTPA significantly increased the signal of flowing blood and allowed for better delineation of the stented aortic lumina. Our results demonstrate that in-plane GRE imaging and MR angiography can potentially be used as noninvasive methods for evaluating vascular patency in the presence of MR-compatible endovascular devices. In addition, Gd-DTPA infusion during MR vascular imaging clearly enhances the definition of flowing blood in the lumina of stented vessels.

Functional cardiovascular evaluation by magnetic resonance imaging.

The pursuit of capabilities for the evaluation of functional aspects of cardiovascular disease by MRI has resulted in the development and implementation of a number of interesting techniques that can be performed on a conventional scanner. Some currently available techniques emphasize the production of anatomically accurate images representing different phases of the cardiac cycle; others demonstrate physical changes within the acquired data that reflect motion, such as blood flow. Magnitude data from spin-echo and gradient-echo sequences can be used to produce dynamic images of the cardiovascular system. Phase data can be used to generate flow-based images reflecting the movement of blood protons. These techniques can be applied in the evaluation of ventricular function, valve function, or functional abnormalities in either congenital cardiovascular disease or great artery disease.

Evaluation of ferromagnetism and magnetic resonance imaging artifacts of the Strecker tantalum vascular stent.

A woven tantalum vascular stent (Strecker stent) was tested for ferromagnetism at 4.7 T and underwent magnetic resonance imaging (MRI) in vitro and in vivo at 1.5 T to evaluate the production of magnetic susceptibility artifacts. No ferromagnetism was detected. Spin-echo, phase reconstruction, and gradient echo images revealed a low level of susceptibility artifacts both in vitro and in vivo. Our findings demonstrate the feasibility of using MRI to evaluate blood vessels noninvasively following tantalum stent placement.

Gadolinium-DTPA enhanced dynamic MR imaging in the evaluation of cisplatinum nephrotoxicity.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) enhanced dynamic magnetic resonance (MR) imaging was used to monitor the nephrotoxic effects of cis-platinum (cis-diamminedichloroplatinum; CDDP), a chemotherapeutic agent that produces damage in the proximal convoluted tubule. Ten New Zealand white rabbits (NZWs) were divided into two groups and were evaluated at two clinically relevant doses of CDDP. Group 1 (four NZWs) received CDDP intravenously at 125 mg/m2 over 1 h. Rabbits in Group 2 (six NZWs) were infused with CDDP at 40 mg/m2 each day for 5 consecutive days. Dynamic MR images were performed in the axial plane at 1.5 T using a gradient recalled acquisition in the steady state sequence with an echo time of 11 ms, a repetition time of 20 ms, and a flip angle of 10 degrees after a bolus injection of Gd-DTPA 0.1 mmol/kg. Thirty-two sequential post Gd-DTPA images (5.12 s/image) were obtained over 2 min 45 s at a single location. All rabbits underwent baseline normal and serial post CDDP Gd-DTPA enhanced dynamic MR scans. Analysis of the alterations in the normal pattern of renal enhancement caused by CDDP was facilitated by using a stacked profile image and quantitative region of interest measurements of signal intensity. Normally, after the injection of Gd-DTPA, a dark band promptly appears in the outer cortex of the kidneys and migrates centripetally toward the papilla, reflecting the tubular concentration of Gd-DTPA. In Group 1 rabbits, nephrotoxicity due to CDDP was observed as early as 9 h after administration of the drug, with a complete disappearance of the dark band by 7 days. In Group 2 rabbits, the band disappeared gradually and reappeared 2-10 days after the completion of CDDP treatment, indicative of tubular damage and recovery with return of the concentrating ability of the kidney. These results illustrate the feasibility of using Gd-DTPA dynamic MR as a sensitive monitor of drug induced alterations of renal function.

Use of Gd-DTPA and fast gradient-echo and spin-echo MR imaging to demonstrate renal function in the rabbit.

The paramagnetic magnetic resonance (MR) imaging contrast agent gadolinium diethylenetriaminepentaacetic acid (DTPA) is freely filtered at the glomerulus and is neither secreted nor reabsorbed by the renal tubules. Fast MR imaging techniques, either gradient-echo or spin-echo, can be used to document the passage of Gd-DTPA through the renal tubules, as reflected by alteration in the MR signal intensity within the different anatomic regions of the kidney. Gradient-echo (repetition time of 35 msec, echo time of 7 msec, flip angles of 10 degrees-100 degrees) and spin-echo (repetition time of 35 msec, echo time of 8 msec) pulse sequences were used to acquire 20 consecutive images, one every 12 seconds, of the rabbit kidney. Both pulse sequences depicted the time course of Gd-DTPA distribution through the kidney but with distinctly different patterns of MR signal change. These dynamic MR images provide an MR nephrogram that directly demonstrates renal morphology and indirectly reflects the functional status of the renal vasculature, renal perfusion, and tubular concentrating ability.

Dynamic Gd-DTPA-enhanced MR imaging of the kidney: experimental results.

To determine the normal appearance of dynamic enhanced renal magnetic resonance (MR) images, 25 rabbits were injected with Gd-DTPA and 32 consecutive gradient-recalled images were acquired. Several rabbits were also imaged in dehydrated (five animals) and overhydrated (seven animals) states. A reproducible renal enhancement pattern is observed that can be divided into three phases. During the first phase, a peripheral dark band appears, probably representing arrival of Gd-DTPA within the arterioles and vasa recta. The second phase begins as a second dark band migrating centripetally toward the medulla; this likely represents the concentration of Gd-DTPA in the descending limb of the loop of Henle. The third phase is characterized by a gradual darkening in the papilla, probably caused by concentration of Gd-DTPA within the collecting ducts. Hydration status influences the duration of these phases. These observations can be explained by the anatomy and physiologic characteristics of the nephron, as well as the MR characteristics of Gd-DTPA at different concentrations.

Tantalum vascular stents: in vivo evaluation with MR imaging.

Magnetic resonance (MR) imaging at 1.5 T was performed on tantalum vascular stents placed in the aortas of six dogs. The stents produced no significant artifact and allowed for clear depiction of the aortic lumina as flow-void zones with spin-echo imaging and as high-signal areas with gradient-echo imaging. The MR findings correlated with the angiographic studies of the stented vessels. These results demonstrate the feasibility of MR imaging as a noninvasive means of evaluating vessel patency in the presence of tantalum vascular stents.

High-resolution MR of the spinal cord in humans and rats.

Human and rat cervical spinal cords were imaged with high-resolution spin-echo and inversion-recovery pulse sequences in an experimental 1.9-T MR system. The gross morphology of the cord was easily discernible in fresh and fixed specimens, including the white and gray commissures, dorsal and ventral horns, and lateral and posterior funiculi. The T1, T2, and spin-density values for gray and white matter were determined from these images and were found to be 914 msec, 114 msec, and 71% for white matter other than the dorsal columns, and 946 msec, 87 msec, and 80% for gray matter in human spinal cords. These values are reduced considerably after formalin fixation: T1 to 56% (white matter) and 54% (gray matter) of prefixation values, T2 to 52% (white matter) and 70% (gray matter) of fresh values, and spin density to 90% (white matter) and 96% (gray matter) of prefixation values. Interestingly, the central gray matter demonstrates higher signal intensity than the white matter on both short and long TR/TE images. This intensity difference was observed for both human and rat spinal cords, before and after fixation, and can be explained by the relatively small T1 differences between gray matter and white matter and the gray matter-white matter spin-density ratios: 1.127 for fresh and 1.203 for fixed specimens.

In vivo measurements of vascular oxygen tension in tumors using MRI of a fluorinated blood substitute.

The authors measured the level of blood oxygenation in vivo in a series of rats with implanted mammary adenocarcinoma. The technique used was 19F magnetic resonance imaging of a perfluorochemical blood substitute. The method is based on the effect of oxygen on the T1 relaxation time of the fluorochemical and allows the determination of mean vascular PO2 independent of the blood volume in the tissue. The PO2 levels in the liver, lung, and spleen also were determined and were consistent with previously reported results. When the rats breathed air, the tumor PO2 levels were somewhat lower than in the other organs and were in a range typical of venous blood. When the rat was given 100% oxygen to breathe, the tumor PO2 levels increased far less than the PO2 levels of the other organs. This may indicate a greatly diminished blood flow to this particular tumor.

Acute tubular necrosis: use of gadolinium-DTPA and fast MR imaging to evaluate renal function in the rabbit.

Sequential fast magnetic resonance (MR) images (repetition time = 33 ms, echo time = 7 ms, alpha = 22 degrees, one image every 12 s) were acquired using gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) (10 or 100 mumol/kg) to study perfusion and concentrating ability in normal rabbit kidneys and in kidneys with HgCl2-induced acute tubular necrosis (ATN). In normal rabbits receiving 100 mumol Gd-DTPA/kg a concentric region of decreased MR signal was observed. In sequential images the dark ring pattern migrated centripetally through the kidney moving from the corticomedullary junction to the inner medulla. The decrease in MR signal intensity occurred as a consequence of T2 relaxation (magnetic susceptibility) due to high concentration of Gd-DTPA within the tubules. This suggests that the dark ring pattern may serve as a qualitative feature indicative of the ability of the kidneys to concentrate. With the onset of HgCl2-induced ATN the pattern of enhancement due to Gd-DTPA administration changed markedly. Although the kidneys with ATN did continue to be perfused, the concentric dark ring pattern seen in normal kidneys receiving 100 mumol Gd-DTPA/kg was not observed. These results suggest that Gd-DTPA and fast imaging MR may provide a method of assessing perfusion and concentrating ability within the healthy or diseased kidney.

Hemorrhage and edema in acute spinal cord compression: demonstration by MR imaging.

Until the development of magnetic resonance (MR) imaging there was no nondestructive technique for monitoring the pathologic response to acute spinal cord trauma. The characteristic findings of hemorrhage, necrosis, and edema have been well described in animal models. We used a 1.4-T, animal imaging system to study acute cord contusions in rats. Contusions were induced by means of extradural aneurysm clip compression, and imaging was performed 3-5 hours after injury with short and long spin-echo (SE) sequences. Animals were killed immediately after imaging, and the gross anatomic and histologic findings were correlated with image appearances. On long SE sequences edema appeared as an area of high signal intensity that extended proximal and distal to the site of contusion. At the contusion site there was focal intraparenchymal hemorrhage which had low signal intensity on T2-weighted images, presumably owing to deoxyhemoglobin. MR imaging can be used to assess pathologic changes resulting from acute cord contusion and to aid in differentiating irreversible damage (hemorrhage) from potentially reversible edema.

The antitumor agent mitoxantrone binds cooperatively to DNA: evidence for heterogeneity in DNA conformation.

The equilibrium binding of the antitumor compound DHAQ, or mitoxantrone [1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10- anthracenedione], to various DNAs has been examined by optical titration and equilibrium dialysis methods. At low r (bound drug/DNA base pair) values, r less than 0.03, DHAQ binds, in a highly cooperative manner, to calf thymus and Micrococcus lysodeikticus DNAs. The binding isotherms for the interaction of DHAQ with Clostridium perfringens DNA and poly(dA-dT).poly(dA-dT) exhibit a small positive slope at low r values, suggestive of cooperative binding. In contrast, the binding of DHAQ to poly(dG-dC).poly(dG-dC) shows no evidence of cooperative binding even at very low r values. At higher r values (r greater than 0.05), the binding of DHAQ to all the DNAs studied is characterized by a neighbor-exclusion process. A model is proposed to account for the two modes of binding exhibited in the cooperative binding isotherms. The main feature of the proposed model is that local sequence and structural heterogeneity of the DNA give rise to sets of binding sites to which DHAQ binds in a highly cooperative manner, while the majority of the DNA sites bind DHAQ via a neighbor-exclusion process. This two-site model reproduces the observed binding isotherms and leads to the conclusion that DHAQ binds in clusters to selected regions of DNA. It is suggested that clustering may play a role in the physiological activity of drugs.