Cerebral neoplastic enhancing lesions: multicenter, randomized, crossover intraindividual comparison between gadobutrol (1.0M) and gadoterate meglumine (0.5M) at 0.1 mmol Gd/kg body weight in a clinical setting.

OBJECTIVE: Two macrocyclic extracellular contrast agents, one-molar neutral gadobutrol and ionic gadoterate meglumine, were compared to determine the overall preference for one or the other in a clinical setting. MATERIALS AND METHODS: Multicenter, randomized, single-blind, intra-individually controlled, comparison study with a corresponding blinded read. Efficacy analysis was based on 136 patients who underwent identical MRI examinations: group A first received 1.0M gadobutrol followed by 0.5M gadoterate meglumine 48 h to 7 days later; group B had a reversed administration order. Three independent blinded readers assessed off-site their overall diagnostic preference (primary efficacy parameter) based on a matched pairs approach. RESULTS: Superiority of gadobutrol over gadoterate meglumine was demonstrated for the qualitative assessment of overall preference across all readers by a statistically significant difference between both contrast agents for this primary endpoint. Preferences in lesion enhancement (secondary endpoint) were also found significantly in favor of gadobutrol. For preference in lesion delineation from surrounding tissue/edema and for internal structure only a trend towards a higher proportion for gadobutrol was found (except for internal structure reported by one reader, which showed a result of statistical significance). Lesion contrast and relative lesion enhancement (quantitative parameters) were statistically significantly higher for gadobutrol compared to gadoterate meglumine. CONCLUSION: Contrast-enhanced MRI of neoplastic brain lesions at a dose of 0.1 mmol Gd/kg body weight, assessed in a standardized off-site blinded reading, results in a significantly higher qualitative and quantitative preference for gadobutrol compared to gadoterate meglumine.

Safety of gadobutrol, a new generation of contrast agents: experience from clinical trials and postmarketing surveillance.

OBJECTIVE: To assess the clinical safety and tolerability of the macrocyclic contrast agent gadobutrol (Gadovist/Gadavist) overall and in specific patient populations based on clinical trials and postmarketing experience. MATERIALS AND METHODS: In total, 5545 patients enrolled in 34 prospective clinical studies were evaluated in an integrated analysis of safety. Of all enrolled patients, 4549 received gadobutrol at a dose of ≤ 0.09 mmol/kg body weight to a maximum of 0.51 mmol/kg body weight, with most patients (53.5%) receiving the recommended dose of >0.09 to 0.11 mmol/kg body weight. Data include comparisons with other extracellular contrast agents and subgroup analyses in pediatric patients, and patients with allergic disposition, renal impairment, hepatic impairment, or cardiovascular disease. Furthermore, worldwide postmarketing safety surveillance results, including nephrogenic systemic fibrosis reports, based on more than 5.7 million estimated applications are described. RESULTS: One or more adverse events (AEs) assessed as related to the administration of gadobutrol were reported by 182 (4.0%) of the 4549 patients who participated in clinical trials. This is comparable to the incidence observed with the comparator contrast agents (74/1844 patients, 4.0%). The most common AEs, independent of drug relationship, were headache, nausea, feeling hot, and dysgeusia. The favorable safety profile of gadobutrol was also demonstrated in the following specific subpopulations in whom similar incidence rates were seen: pediatric patients aged 2 to 17 years (8/138 patients, 5.8%), patients with severe or moderate renal impairment (9/366 patients, 2.5%), patients with severe or moderate hepatic impairment (9/214 patients, 4.2%), and patients with cardiovascular disorders (42/1506 patients, 2.8%). Having been established in controlled clinical trials, this safety profile was also confirmed by postmarketing surveillance data. With more than 5.7 million estimated administrations of gadobutrol, a total of 1175 (0.02%) suspected adverse drug reactions have been reported. The most serious adverse reactions seen in postmarketing surveillance included rare reports of cardiac arrest, respiratory arrest, anaphylactoid shock, and nephrogenic systemic fibrosis. Incidence and type of AEs from postmarketing surveillance were consistent with the established safety profile. CONCLUSION: The comprehensive analysis of safety data obtained from 34 clinical studies demonstrates that gadobutrol has an excellent safety profile and a positive benefit risk profile when used in patients in need of contrast-enhanced magnetic resonance imaging. Gadobutrol was well tolerated by adults, by children, by patients with impaired liver or kidney function, and by patients with cardiovascular disease. The favorable safety profile is confirmed by the available postmarketing surveillance data and is compared with that of other gadolinium-based contrast agents.

Human brain tumor imaging with a protein-binding MR contrast agent: initial experience.

Gadofosveset is a Gd-based protein-binding blood pool agent with increased relaxivities and blood half-life compared with conventional Gd-based contrast agents (GBCAs). No experience exists about the use of gadofosveset as an extracellular agent. In this report we present the first clinical experience with gadofosveset in enhancing intracranial tumors. Ten patients with different intracranial tumors were examined with a standard dose (0.03 mmol/kg) of gadofosveset compared with a standard dose (0.1 mmol/kg) of conventional GBCA. As a result of its significantly higher relaxivity, gadofosveset could, despite its low dose, achieve a sufficient contrast enhancement. The visual rating of the intensity of enhancement and the contrast to noise ratios were comparable to conventional agents. The detection and delineation of more complex lesions was rated equal. In one nonenhancing low grade astrocytoma an enhancing nodule became visible only 5 h after gadofosvesest injection. As shown in this initial report, contrast-enhanced intracranial tumor imaging is possible with the protein-binding blood pool agent gadofosveset. The agent gives a significant tumor contrast in early postcontrast imaging comparable with conventional agents. As a result of its unique longer lasting contrast, the use of gadofosveset might enable a new approach to imaging mild or nonenhancing tumors.

Peripheral magnetic resonance angiography with continuous table movement in combination with high spatial and temporal resolution time-resolved MRA With a total single dose (0.1 mmol/kg) of gadobutrol at 3.0 T.

PURPOSE: To prove the concept of peripheral continuous table movement (CTM) MR-angiography (MRA) in combination with high spatial and temporal resolution time-resolved TWIST-MRA in a single MR-examination at 3.0 T with a single dose (0.1 mmol/kg) of gadobutrol in total. MATERIALS AND METHODS: We included 22 consecutive patients (15 m/7 f, mean age: 64 years) referred for peripheral MRA with clinical symptoms of peripheral arterial occlusive disease Fontaine stages II-IV. All of them underwent both CTM-MRA (TR: 2.4 ms/TE: 1.0 ms/flip angle: 21 degree) of the entire run-off vessels and TWIST-MRA (TR: 2.8 ms/TE: 1.1 ms/flip angle: 20 degree) of the calf station during a single MR-examination. All examinations were performed on a 3.0 T MR system (Tim Trio). Spatial resolution of the CTM-MRA datasets was technically limited to an acquired resolution of 1.2 x 1.2 x 1.96 mm3 reconstructed to 1.2 mm isotropic. The TWIST-MRA was acquired with 1.1 x 1.1 x 1.35 mm3 and reconstructed to 1.1 mm isotropic with a temporal resolution of 5.5 seconds in the calf station. A total of 0.1 mmol/kg BW gadobutrol diluted 1:1 with saline was injected at a flow rate of 1.5 mL/s of which 0.07 mmol/kg was administered for the CTM-MRA and 0.03 mmol/kg for the TWIST-MRA. CTM-MRA run off datasets were qualitatively assessed using a 4 point scale (4 = excellent, 1 = nondiagnostic) followed by TWIST-MRA datasets for the calf using the same scale. Additional relevant findings only visible in the TWIST-MRA were documented. RESULTS: All datasets could be evaluated with a total of 397 assessable segments. CTM-MRA was diagnostic in 99% (393/397 segments) with image quality judged as excellent in 54% (213/397 segments), good in 42% (14/397), and moderate in 4% (14/397) of analyzed segments respectively. Nondiagnostic image quality was seen in 1% (4/397 segments). Venous overlay in the calf station was found in 27% (6/22 patients). TWIST-MRA was diagnostic in 100% (115/115 segments), throughout with good or excellent image quality. In 14 of 22 patients additional relevant findings were detected by TWIST-MRA. CONCLUSION: Single-dose gadobutrol CTM-MRA in combination with a high spatial and temporal resolution TWIST-MRA at 3.0 T is a reliable technique with good image quality. Despite the use of single dose contrast agent large field of view coverage and dynamic images can be acquired. Because of its robustness, this imaging approach of the vasculature has great potential for a broad clinical use.

Biphasic blood pool contrast agent-enhanced whole-body MR angiography for treatment planning in patients with significant arterial stenosis.

OBJECTIVE: To prospectively evaluate diagnostic accuracy of first pass and combined first pass and steady state high-spatial-resolution whole-body magnetic resonance (MR) angiography with a blood pool contrast agent for quantification of arterial stenosis in different vascular territories. MATERIALS AND METHODS: After Institutional Review Board approval and informed consent, 50 patients with known 50% or greater stenosis in at least one vascular territory; as shown by the standard-of-reference (14 digital subtraction angiographies, 4 computed tomographies, 32 ultrasound examinations), were included. The patients underwent MR angiography at 1.5 Tesla, using a standardized nonbody-weight-adapted i.v. bolus injection of 11 mL gadofosveset trisodium. First pass imaging with 4 different table positions in a whole-body MR scanner (MAGNETOM Avanto, Siemens Healthcare), using individual circulation time determined by a test bolus, was performed. Steady state imaging was performed using an isometric spatial resolution of 1.0 mm. Image quality was rated. Each vascular segment in MR angiography was evaluated by 2 independent and blinded reviewers and the stenosis degree was compared with the preferred standard-of-reference, using a 5-point scale. Differences between first pass and combined MR angiography were assessed with a 95% confidence interval (CI) by applying the adjusted modified chi(2) test. Changes in therapy based on the whole-body examination strategy were evaluated. RESULTS: The number of nondiagnostic territories was 24 of 197 (12.2%) for first pass MR angiography and decreased to 3 of 197 (1.5%) after addition of steady state MR angiography. The diagnostic accuracy for quantification of arterial stenosis in combined MR angiography (94.7%; 95% CI: 92.4-97.1) was superior to first pass MR angiography (81.7%; 95% CI: 73.7-89.8; statistically significant). Patient management was changed in 12 of 49 patients, in 7 of 12 patients the change was applied to an additional lesion detected by the whole-body examination strategy. CONCLUSION: The quantification and detection of arterial stenosis is improved by the steady state high-resolution gadofosveset trisodium-enhanced MR angiography. Additional lesions detected by whole-body examination strategy or differences in stenosis quantification may lead to changes in therapy.

Dicentric chromosomes and gamma-H2AX foci formation in lymphocytes of human blood samples exposed to a CT scanner: a direct comparison of dose response relationships.

Experiments using the induction of dicentric chromosomes (dicentrics) as well as the gamma-H2AX foci formation in lymphocytes of blood samples from a healthy donor were performed to directly evaluate the radiation sensitivity of both biological endpoints. For computed tomography scans at dose levels from 0.025 to 1 Gy, a linear-quadratic dose-response relationship for dicentrics and a linear dose-response relationship for gamma-H2AX foci were obtained. The coefficients of the dose-response relationship for dicentrics are alpha = (3.76 +/- 0.29) x 10(-2) Gy(-1) and beta = (5.54 +/- 0.45) x 10(-2) Gy(-2), the linear coefficient for gamma-H2AX foci is (7.38 +/- 0.11) Gy(-1). The findings indicate that scoring of dicentrics as well as microscopic analysis of gamma-H2AX foci are sensitive methods to quantify a radiation-induced biological damage at low doses. However, since gamma-H2AX foci can be partially repaired within a few hours, biological damages present for days or even months, which constitute the clinically relevant endpoints, can only be quantified reliably by scoring of chromosome aberrations. Thus currently the quantification of dicentrics or reciprocal translocations remains the recommended method for estimating the effect of exposures to low dose levels of radiation ('biological dosimetry'). However, owing to the high radiation sensitivity of the gamma-H2AX foci assay observed in the present study, further investigations on the effectiveness of low-linear energy transfer radiation qualities in producing gamma-H2AX foci in lymphocytes from healthy donors should be performed.

Absolute quantification of regional renal blood flow in swine by dynamic contrast-enhanced magnetic resonance imaging using a blood pool contrast agent.

AIM: To evaluate for the first time in an animal model the possibility of absolute regional quantification of renal medullary and cortical perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a blood pool contrast agent. MATERIAL AND METHODS: A total of 18 adult female pigs (age, 16-22 weeks; body weight, 45-65 kg; no dietary restrictions) were investigated by DCE-MRI. Absolute renal blood flow (RBF) measured by an ultrasound transit time flow probe around the renal vein was used as the standard of reference. An inflatable stainless cuff placed around the renal artery near its origin from the abdominal aorta was used to reduce RBF to 60%, 40%, and 20% of the baseline flow. The last measurement was performed with the cuff fully reopened. Absolute RBF values during these 4 perfusion states were compared with the results of DCE-MRI performed on a 1.5-T scanner with an 8-channel phased-array surface coil. All scans were acquired in breath-hold technique in the coronal plane using a field of view of 460 mm.Each dynamic scan commenced with a set of five 3D T1-weighted gradient echo sequences with different flip angles (alpha = 2 degrees, 5 degrees, 10 degrees, 20 degrees, 30 degrees): TE, 0.88 milliseconds; TR, 2.65 milliseconds; slice thickness, 8.8 mm for 4 slices; acquisition matrix, 128 x 128; and acquisitions, 4. These data served to calculate 3D intrinsic longitudinal relaxation rate maps (R10) and magnetization (M0). Immediately after these images, the dynamic 3D T1-weighted gradient echo images were acquired with the same parameters and a constant alpha = 30 degrees, half Fourier, 1 acquisition, 64 frames, a time interval of 1.65 seconds between each frame, and a total duration of 105.6. Three milliliters of an albumin-binding blood pool contrast agent (0.25 mmol/mL gadofosveset trisodium, Vasovist, Bayer Schering Pharma AG, Berlin, Germany) was injected at a rate of 3 mL/s. Perfusion was calculated using the arterial input function from the aorta, which was extracted from the dynamic relaxation rate change maps and perfusion images were calculated on a voxel-by-voxel basis using a singular value decomposition. RESULTS: In 11 pigs, 4 different perfusion states were investigated sequentially. The reduced kidney perfusion measured by ultrasound highly correlated with total renal blood flow determined by DCE-MRI, P < 0.001. The correlation coefficient between both measurements was 0.843. Regional cortical and medullary renal flow was also highly correlated (r = 0.77/0.78, P < 0.001) with the degree of flow reduction. Perfusion values smaller than 50 mL/min/100 cm were overestimated by MRI, high perfusion values slightly underestimated. CONCLUSION: DCE-MRI using a blood pool contrast agent allows absolute quantification of total kidney perfusion as well as separate determination of cortical and medullary flow. The results show that our technique has sufficient accuracy and reproducibility to be transferred to the clinical setting.

Intravascular contrast agent T1 shortening: fast T1 relaxometry in a carotid volunteer study.

OBJECTIVE: To measure the T1 times in blood after the administration of the intravascular contrast agent gadofosveset trisodium in humans. MATERIALS AND METHODS: In a pilot study for parameter optimization, the T1-shortening induced by the injection of a single dose (0.03 mmol/kg body weight) of the MR contrast agent Vasovist (Bayer Schering Pharma AG) was measured at B0=1.5 T as a function of time. In four sessions, T1 measurements were performed in the carotid vein of 9 volunteers up to 30 min after injection. T1 times were measured using a segmented saturation recovery turboFLASH (SSRTFL) pulse sequence with 7 different saturation recovery delay times in a total acquisition time of 20 s. RESULTS: The SSRTFL measurements showed T1 times of about 100 ms immediately after injection, which gradually increased to 175 ms at 30 min. The time curve of the R1=1/T1 averaged over all volunteers could be described with an exponential decay with a time constant T=330+/-65 s and an amplitude DeltaR1=4.1+/-0.3 s(-1), and a constant offset of R1(0)=5.7+/-0.2 s(-1). Mean relaxation values are in excellent agreement with theoretical predictions. CONCLUSION: An analytical expression for the initial T1-shortening of Vasovist was derived which can now be used for optimization of the pulse sequence parameters in clinical studies.

First-pass whole-body magnetic resonance angiography (MRA) using the blood-pool contrast medium gadofosveset trisodium: comparison to gadopentetate dimeglumine.

OBJECTIVES: To evaluate gadofosveset trisodium for first-pass magnetic resonance angiography (MRA) in the setting of whole-body MRA (WB-MRA). MATERIALS AND METHODS: Forty patients were examined using either 10 mL gadofosveset trisodium (n = 20) or 30 mL gadopentetate dimeglumine (n = 20), followed by arterial-phase imaging of 4 consecutive anatomic regions. Signal intensity was measured in 2 vessels per region. Relative contrast values (RC) were calculated. Arterial contrast, venous overlay, and image quality were rated by 2 radiologists. The Mann-Whitney U test was used to test for significance. RESULTS: Compared with gadopentetate dimeglumine, gadofosveset trisodium enhanced imaging revealed higher RC values in 2 vessel regions, with the differences being significant in 3 of 4 vessel segments. Gadofosveset trisodium revealed lower RC values in 2 regions with significant differences in 2 segments. Qualitative evaluation revealed higher ratings for gadofosveset trisodium regarding all 3 criteria with significant differences in 2 regions. CONCLUSIONS: Gadofosveset trisodium serves well for first-pass imaging in WB-MRA.

Treatment with granulocyte colony-stimulating factor for mobilization of bone marrow cells in patients with acute myocardial infarction.

BACKGROUND: This study was undertaken to evaluate the hypothesis that treatment with granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow cells (BMCs) is feasible and safe and promotes neovascularization and myocardial function in patients with acute myocardial infarction. METHODS: Fourteen patients in the treatment group and 9 patients in the control group were enrolled in this prospective, nonrandomized, open-label study. Forty-eight hours after successful recanalization and stent implantation, the patients of the treatment group received 10 microg/kg body weight per day G-CSF subcutaneously for mean treatment duration of 7.0 +/- 1.0 days. Nine patients fulfilled the entry criteria but refused participation and served therefore as control group. In both groups, regional wall motion and perfusion was evaluated with electrocardiogram-gated sestamibi single-photon emission computed tomography imaging and ejection fraction with radionuclidventriculography before discharge and after 3 months. RESULTS: No severe side effects of G-CSF treatment were observed. There was a significant improvement of the regional wall motion and perfusion within the treatment group (P < .0001) and between the treatment and control group (P < .05 and P < .01, respectively). Ejection fraction in the treatment group increased from 0.40 +/- 0.11 to 0.48 +/- 0.13 (P < .01), whereas in the control group, ejection fraction increased from 0.40 +/- 0.13 to 0.43 +/- 0.13 (P = .049). A control angiography of the treatment group after 12.4 +/- 6.6 months showed an in-stent restenosis in 1 patient. CONCLUSION: In patients with acute myocardial infarction, treatment with G-CSF to mobilize BMCs is feasible and safe and seems to be effective under clinical conditions. The therapeutic effect might be attributed to BMC-associated promotion of myocardial regeneration and neovascularization.