Miles A. Kirchin

Safety, tolerance, biodistribution, and MR imaging enhancement of the liver with gadobenate dimeglumine: Results of clinical pharmacologic and pilot imaging studies in nonpatient and patient volunteers

PURPOSE The purpose of this study was to assess safety, tolerance, biodistribution, and magnetic resonance (MR) imaging enhancement of the liver with gadobenate dimeglumine. MATERIALS AND METHODS Phase I single-blind studies were performed in 53 healthy volunteers, of whom 39 received gadobenate dimeglumine and 14 placebo. Another 106 patients with focal liver disease received gadobenate dimeglumine in parallel-group, open-label, phase II studies. The imaging potential of gadobenate dimeglumine was assessed in all 106 patients plus 11 healthy volunteers, whereas pharmacokinetics were determined for 42 healthy volunteers. Safety was assessed for all subjects enrolled in the study. Imaging protocols for healthy volunteers were similar to those for patients and comprised predose T2-weighted sequences and pre- and postinjection T1-weighted spin-echo and gradient-echo sequences. RESULTS Gadobenate dimeglumine was safe and well tolerated in healthy volunteers and patients, with pharmacokinetics described adequately as a distribution phase and an elimination phase. Most of the injected dose of gadobenate was excreted unchanged in urine within 24 hours, although a fraction corresponding to 0.6%-4.0% of the injected dose was eliminated with the bile and recovered in the feces. The gadobenate dimeglumine-enhanced signal intensity of liver parenchyma was dose-related and constant for 120 minutes. Gadobenate dimeglumine-enhanced MR imaging was superior to nonenhanced MR imaging in more than 50% of patient studies, with more lesions seen in 26%-38% of patients and smaller lesions in 21%-33% of patients. In general, image sets acquired 40-180 minutes after administration of a dose were preferred, whereas images acquired during the dynamic phase after administration were typical of those obtained with extracellular fluid contrast agents. CONCLUSION Gadobenate dimeglumine is a safe and efficacious MR imaging contrast agent suitable for both delayed and dynamic imaging of the liver.

Contrast‐enhanced MR angiography of the run‐off vasculature: Intraindividual comparison of gadobenate dimeglumine with gadopentetate dimeglumine

To compare intraindividually gadobenate dimeglumine (Gd‐BOPTA) with gadopentetate dimeglumine (Gd‐DTPA) for multi‐station MR Angiography of the run‐off vessels.

Hepatocellular Carcinoma: Correlation Between Gadobenate Dimeglumine–enhanced Mri and Pathologic Findings

RATIONALE AND OBJECTIVES To correlate the appearance of hepatocellular carcinoma on delayed (60 minutes) postcontrast T1-weighted gradient echo images with the mode of action of gadobenate dimeglumine (Gd-BOPTA) and the anatomic and pathologic characteristics of the lesions. METHODS A total of 34 patients with hepatocellular carcinoma and varying degrees of diffuse liver disease were studied. T2-weighted spin echo and T1-weighted spin echo and gradient echo images were acquired before and 60 minutes after the intravenous administration of 0.1 mmol/kg Gd-BOPTA. Qualitative and quantitative evaluations of the images were performed and correlated with histologic findings. The quantitative evaluation, performed on T1-weighted gradient echo images, looked at the percentage increase of liver enhancement after Gd-BOPTA administration, the lesion-to-liver contrast/noise (C/N) ratio before and after Gd-BOPTA administration, and the C/N variation after Gd-BOPTA administration. Qualitative assessment considered the morphologic features of the lesions as well as the visual variation of contrast before and after Gd-BOPTA administration. Finally, a histologic evaluation was made of the degree of differentiation of the lesions and of the presence of fatty metaplasia, necrosis, bile, or intratumoral peliosis. RESULTS Among the parameters affecting lesion identification were the extent of liver function, degree of vascularization, residual functionality of the tumor cells, and characteristics of the neoplastic tissue. Positive correlations (Spearman coefficients = 0.359 and 0.393, respectively) were observed precontrast between the degree of liver failure and the amount of contrast noise, and postcontrast between the amount of intralesional fatty metaplasia and the extent to which lesion conspicuity worsened after Gd-BOPTA administration. An inverse correlation (Spearman coefficient = -0.330) was observed between the degree of lesion differentiation and the visible appearance after Gd-BOPTA administration, with well-differentiated lesions tending toward worsened conspicuity postcontrast. A statistically significant difference (P = 0.001) was observed in the mean precontrast C/N ratio for lesions later showing unchanged conspicuity and worse conspicuity on postcontrast images, respectively. Marked variation (P = 0.019) was also observed between Child A and B cirrhotic patients for the degree of hepatic enhancement on postcontrast images. CONCLUSIONS The results suggest that liver parenchyma signal intensity is influenced by the extent to which liver function is compromised, that residual hepatocytic functionality permits Gd-BOPTA uptake by certain lesions and that this uptake might subsequently impair the observed C/N ratio on delayed images, and that the worsening of lesion conspicuity on postcontrast images is influenced also by high quantities of intralesional fatty metaplasia.

Safety assessment of gadobenate dimeglumine (MultiHance): extended clinical experience from phase I studies to post-marketing surveillance.

Clinical trials completed by September 2000 on gadobenate dimeglumine (Gd‐BOPTA; MultiHance®) included 2540 adult and pediatric subjects that were administered this agent. For adult patient volunteers, the overall incidence of adverse events (AEs) was 19.8%, although marked study‐ and indication‐related differences were apparent. Events potentially related to Gd‐BOPTA administration were reported for 15.1% of adult patients. The vast majority of AEs were non‐serious, mild, transient, and self‐resolving. Headache, injection site reaction, nausea, taste perversion, and vasodilation were the most common AEs, reported with a frequency of between 1.0% and 2.6%. Serious AEs potentially related to Gd‐BOPTA were reported for five (0.2%) patients overall. Controlled studies revealed no differences between Gd‐BOPTA and other gadolinium chelates or placebo in the incidence and type of AEs. Similarly, no differences with respect to adult patients and/or comparator were noted in studies on pediatric subjects and subjects with renal or liver insufficiency. Post‐marketing surveillance of approximately 100000 doses revealed an overall AE incidence of < 0.03% with serious AEs reported for < 0.005% of patients. J. Magn. Reson. Imaging 2001;14:281–294.

16-MDCT Angiography of Aortoiliac and Lower Extremity Arteries: Comparison with Digital Subtraction Angiography

OBJECTIVE The objective of our study was to prospectively compare CT angiography (CTA) performed on a 16-MDCT scanner and digital subtraction angiography (DSA) in patients with peripheral arterial disease. SUBJECTS AND METHODS CTA and DSA were compared in 50 patients. CTA was independently evaluated by two blinded observers. DSA was evaluated by two additional blinded observers in consensus. Consensus DSA served as the reference standard for comparisons with CTA in terms of diagnostic quality, grading of stenoocclusive lesions, visualization of collaterals, impact on patient management, and time required for analysis. RESULTS No significant differences in diagnostic quality were observed between CTA and DSA above the ankle; both CTA observers noted significantly better visualization of pedal arteries (70 and 72 segments, respectively) than on DSA (57 segments). Of 958 stenoocclusive lesions on DSA, CTA observers 1 and 2 detected 933 and 929 lesions, respectively. Sensitivity and specificity for the detection of hemodynamically relevant (> 50%) lesions was 93.3% and 96.5% for observer 1 and 90.1% and 95.6% for observer 2. Collaterals were seen at 150 arterial levels on DSA compared with 97 and 92 levels on CTA (p < 0.05, both observers). Patient management decisions based on CTA were equivalent to those based on DSA in 49 of the 50 patients. CONCLUSION CTA is an effective noninvasive alternative to DSA for the evaluation of peripheral arterial disease.

Clinical Value of MDCT in the Diagnosis of Coronary Artery Disease in Patients with a Low Pretest Likelihood of Significant Disease

OBJECTIVE The aim of this study was to evaluate the clinical value of MDCT in the diagnosis of coronary artery disease in a population having a low pretest likelihood of significant disease. SUBJECTS AND METHODS Sixty-four patients with suspected coronary artery disease and a low pretest likelihood of significant disease according to the criteria of the American Heart Association underwent both MDCT of the heart and quantitative conventional coronary angiography (QCA). MDCT examinations were performed on a 16-MDCT scanner. CT data sets were evaluated on a per-patient basis and a per-segment basis and were classified as indicating no disease, nonsignificant disease (stenoses </= 50%), or significant disease (stenoses > 50%). Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 16-MDCT in the detection or exclusion of significant and nonsignificant coronary artery disease were evaluated on both per-patient and per-segment bases. RESULTS Regarding the success rate of 16-MDCT, 94% (60/64) of patients and 92% (388/420) of vessel segments were of sufficient quality for diagnosis. In the remaining 60 patients evaluated, QCA revealed significant coronary artery disease, nonsignificant disease, and no disease in 8.3% (5/60), 75.0% (45/60), and 16.7% (10/60) of cases, respectively, on a per-patient basis, and in 1.3% (5/388), 23.2% (90/388), and 75.5% (293/388) of cases, respectively, on a per-segment basis. The sensitivity, specificity, NPV, and PPV of 16-MDCT for the detection of significant coronary artery disease were 80.0%, 94.5%, 98.1%, and 57.1%, respectively, on a per-patient basis, and 80.0%, 99.2%, 99.7%, and 57.1% on a per-segment basis. CONCLUSION In a population having a low pretest likelihood of significant coronary artery disease, 16-MDCT shows a moderate to high sensitivity and high NPV for the detection or exclusion of significant disease, but has a somewhat reduced PPV compared with QCA.

Contrast bolus optimization for cardiac 16-slice computed tomography : Comparison of contrast medium formulations containing 300 and 400 milligrams of iodine per milliliter

Objectives:The aims of our study were to compare contrast injection protocols with contrast media containing 300 and 400 mg iodine per milliliter for optimal contrast enhancement in cardiac multidector row computed tomography (CT) and to evaluate the correlation of test bolus curve parameters with the final contrast density of the main bolus. Materials and Methods:Sixty patients with known or suspected coronary artery disease were included in a prospective double-blind study. Patients were randomized to 2 groups. Group 1 received 83 mL of a contrast medium (CM) containing 300 mg of iodine (Iomeron 300, Bracco Imaging SpA, Milan, Italy) at a flow rate of 3.3 mL/s, whereas group 2 received 63 mL of the same agent containing 400 mg of iodine (Iomeron 400) at a flow rate of 2.5 mL/s. The test bolus volumes were 20 mL and 15 mL, respectively. Imaging was performed using a 16-slice CT system (16DCT; Somatom Sensation 16, Siemens Medical Solutions, Forchheim, Germany). Contrast densities (Hounsfield Units [HU]) were determined in the cardiac chambers and in the main coronary arteries. The peak density and area under the curve of the test bolus were calculated for each patient. Results:The mean contrast densities of the coronary arteries were 259.1 ± 46.7 HU for group 1 and 251.6 ± 51.0 HU, for group 2. No noteworthy differences between groups were noted for density measurements in the cardiac chambers or for the ratio of right-to-left ventricle density. Whereas a positive correlation was noted for both groups between the area under the curve of the test bolus and the mean density of the main bolus, a positive correlation between peak density of the test bolus and mean density of the main bolus was noted only for group 1. Conclusion:Equivalent homogenous enhancement of the ventricular cavities and coronary arteries to that obtained using a CM with standard iodine concentration (Iomeron 300) can be achieved with lower overall volumes of administered CM and reduced injection flow rates when a CM with high iodine concentration (Iomeron 400) is used.

Solid hypervascular liver lesions: accurate identification of true benign lesions on enhanced dynamic and hepatobiliary phase magnetic resonance imaging after gadobenate dimeglumine administration.

Purpose:To evaluate hepatobiliary phase magnetic resonance imaging with gadobenate dimeglumine for differentiation of benign hypervascular liver lesions from malignant or high-risk lesions. Methods and Materials:Retrospective assessment was performed of 550 patients with 910 hypervascular lesions (302 focal nodular hyperplasia [FNH], 82 nodular regenerative hyperplasia [NRH], 59 hepatic adenoma or liver adenomatosis [HA/LA], 329 hepatocellular carcinomas [HCC], 12 fibrolamellar-HCC [FL-HCC], 21 peripheral cholangiocarcinomas [PCC], 105 metastases). Imaging was performed before and during the arterial, portal-venous, equilibrium, and hepatobiliary phases after gadobenate dimeglumine administration (0.05 mmol/kg). Histologic confirmation was available for ≥1 lesion per patient, except for patients with suspected FNH (diagnosis based on characteristic enhancement/follow-up). Lesion differentiation (benign/malignant) on the basis of contrast washout and lesion enhancement (hypo-/iso-/hyperintensity) was assessed (sensitivity, specificity, accuracy, PPV, and NPV) relative to histology or final diagnosis. Results:On portal-venous or equilibrium phase images, washout was not seen for 208 of 526 (39.5%) malignant (HCC, FL-HCC, PCC, metastases) and high-risk (HA/LA) lesions. Conversely, only 5 of 384 (1.3%) true benign lesions (FNH/NRH) showed washout. Taking washout as indicating malignancy, the sensitivity, specificity, and accuracy for malignant lesion identification during these phases was 61.8%, 98.7%, and 77.4%. On hepatobiliary phase images, 289 of 302 FNH, 82 of 82 NRH, 1 of 59 HA or LA, 62 of 341 HCC or FL-HCC, and 2 of 105 metastases were hyperintense or isointense. Taking iso- or hyperintensity as an indication for lesion benignity, the sensitivity, specificity, accuracy, PPV, and NPV for benign lesion identification was 96.6%, 87.6%, 91.4%, 85.1%, and 97.3%, respectively. Conclusions:Hepatobiliary phase imaging with gadobenate dimeglumine is accurate for distinguishing benign lesions from malignant or high-risk lesions. Biopsy should be considered for hypointense lesions on hepatobiliary phase images after gadobenate dimeglumine.

Follow-Up of Coiled Cerebral Aneurysms at 3T: Comparison of 3D Time-of-Flight MR Angiography and Contrast-Enhanced MR Angiography

BACKGROUND AND PURPOSE: Our aim was to compare contrast-enhanced MR angiography (CE-MRA) and 3D time-of-flight (TOF) MRA at 3T for follow-up of coiled cerebral aneurysms. MATERIALS AND METHODS: Fifty-two patients treated with Guglielmi detachable coils for 54 cerebral aneurysms were evaluated at 3T MRA. 3D TOF MRA (TR/TE = 23/3.5; SENSE factor = 2.5) and CE-MRA by using a 3D ultrafast gradient-echo sequence (TR/TE = 5.9/1.8; SENSE factor = 3) enhanced with 0.1-mmol/kg gadobenate dimeglumine were performed in the same session. Source images, 3D maximum intensity projection, 3D shaded surface display, and/or 3D volume-rendered reconstructions were evaluated in terms of aneurysm occlusion/patency and artifact presence. RESULTS: In terms of clinical classification, the 2 MRA sequences were equivalent for 53 of the 54 treated aneurysms: 21 were considered fully occluded, whereas 16 were considered to have a residual neck and 16 were considered residually patent at follow-up MRA. The remaining aneurysm appeared fully occluded at TOF MRA but had a residual patent neck at CE-MRA. Visualization of residual aneurysm patency was significantly (P = .001) better with CE-MRA compared with TOF MRA for 10 (31.3%) of the 32 treated aneurysms considered residually patent with both sequences. Coil artifacts were present in 5 cases at TOF MRA but in none at CE-MRA. No relationship was apparent between the visualization of patency and either the size of the aneurysm or the interval between embolization and follow-up. CONCLUSION: At follow-up MRA at 3T, unenhanced TOF and CE-MRA sequences are similarly effective at classifying coiled aneurysms as occluded or residually patent. However, CE-MRA is superior to TOF MRA for visualization of residual patency and is associated with fewer artifacts.

Renal Artery Stenosis Evaluation: Diagnostic Performance of Gadobenate Dimeglumine–enhanced MR Angiography—Comparison with DSA

PURPOSE To prospectively determine diagnostic performance and safety of contrast material-enhanced (CE) magnetic resonance (MR) angiography with 0.1 mmol per kilogram of body weight gadobenate dimeglumine for depiction of significant steno-occlusive disease (> or =51% stenosis) of renal arteries, with digital subtraction angiography (DSA) as reference standard. MATERIALS AND METHODS This multicenter study was approved by local institutional review boards; all patients provided written informed consent. Patient enrollment and examination at centers in the United States complied with HIPAA. Two hundred ninety-three patients (154 men, 139 women; mean age, 61.0 years) with severe hypertension (82.2%), progressive renal failure (11.3%), and suspected renal artery stenosis (6.5%) underwent CE MR angiography with three-dimensional spoiled gradient-echo sequences after administration of 0.1 mmol/kg gadobenate dimeglumine at 2 mL/sec. Anteroposterior and oblique DSA was performed in 268 (91.5%) patients. Three independent blinded reviewers evaluated CE MR angiographic images. Sensitivity, specificity, and accuracy of CE MR angiography for detection of significant steno-occlusive disease (> or =51% vessel lumen narrowing) were determined at segment (main renal artery) and patient levels. Positive and negative predictive values and positive and negative likelihood ratios were determined. Interobserver agreement was analyzed with generalized kappa statistics. A safety evaluation (clinical examination, electrocardiogram, blood and urine analysis, monitoring for adverse events) was performed. RESULTS Of 268 patients, 178 who were evaluated with MR angiography and DSA had significant steno-occlusive disease of renal arteries at DSA. Sensitivity, specificity, and accuracy of CE MR angiography for detection of 51% or greater stenosis or occlusion were 60.1%-84.1%, 89.4%-94.7%, and 80.4%-86.9%, respectively, at segment level. Similar values were obtained for predictive values and for patient-level analyses. Few CE MR angiographic examinations (1.9%-2.8%) were technically inadequate. Interobserver agreement for detection of significant steno-occlusive disease was good (79.9% agreement; kappa = 0.69). No safety concerns were noted. CONCLUSION CE MR angiography performed with 0.1 mmol/kg gadobenate dimeglumine, compared with DSA, is safe and provides good sensitivity, specificity, and accuracy for detection of significant renal artery steno-occlusive disease.