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Supplemental digital content is available in the text., Objective Multiple clinical and preclinical studies have reported a signal intensity increase and the presence of gadolinium (Gd) in the brain after repeated administration of Gd-based contrast agents (GBCAs). This bioanalytical study in rat brain tissue was initiated to investigate whether the residual Gd is present as intact GBCA or in other chemical forms by using tissue fractionation and chromatography. Materials and Methods Rats were divided randomly in 6 groups of 10 animals each. They received 10 daily injections of 2.5 mmol/kg bodyweight of 1 of 5 different GBCAs: linear GBCAs such as gadodiamide (Omniscan; GE Healthcare), gadopentetate dimeglumine (Gd-DTPA, Magnevist; Bayer), or gadobenate dimeglumine (Multihance; Bracco) and macrocyclic GBCAs such as gadobutrol (Gadovist; Bayer) and gadoterate meglumine (Gd-DOTA, Dotarem; Guerbet) or saline. On days 3 and 24 after the last injection (p.i.), 5 randomly chosen animals of each group were killed by exsanguination, and their brains were excised and divided into cerebrum, pons, and cerebellum. The brain sections were homogenized by sonication in ice-cold buffer at pH 7.4. Soluble and insoluble fractions were separated by centrifugation, and the soluble fractions were further separated by gel permeation chromatography (GPC). The Gd concentration in all tissue fractions and in the GPC eluate was measured by inductively coupled plasma–mass spectrometry. In a recovery control experiment, all GBCAs were spiked to blank brain tissue and more than 94% recovery of Gd in the tissue fractions was demonstrated. Results Only traces of the administered Gd were found in the rat brain tissue on day 3 and day 24 p.i. In the animals treated with macrocyclic GBCAs, Gd was found only in the soluble brain fraction and was present solely as low molecular weight molecules, most likely the intact GBCA. In the animals treated with linear GBCAs Gd was found to a large extent in the insoluble tissue fraction. The Gd concentration in the soluble fraction was comparable to the macrocyclic agents. According to GPC, a smaller portion of the Gd in the soluble fraction of the linear GBCAs groups was bound to macromolecules larger than 250 to 300 kDa. The nature of the Gd-containing macromolecules and the insoluble species were not determined, but they appeared to be saturable with Gd. The excretion of the soluble Gd species in the linear and macrocyclic GBCA groups was still ongoing between days 3 and 24 p.i. This was also observed for the macromolecular Gd species in the linear GBCA groups, but at a slower rate. Conclusions The residual Gd found in the rat brain after repeated administration of all 3 linear GBCAs was present in at least 3 distinctive forms—soluble small molecules, including the intact GBCA, soluble macromolecules, and to a large extent in insoluble form. The latter 2 are most likely responsible for the prolonged signal intensity enhancement in brain structures observed in magnetic resonance imaging. No relevant differences between the 3 linear GBCAs were observed. The Gd concentrations in the brain after administration of macrocyclic GBCAs are lower, and the Gd is only present in soluble small molecules, which were slowly excreted. This underlines the crucial importance of the kinetic inertness of macrocyclic agents in the prevention of potential retention of Gd in the brain compared with the 3 linear, kinetically less restricted GBCAs.

OBJECTIVE:: To evaluate the diagnostic efficacy (accuracy, sensitivity, specificity) of 1.0 M gadobutrol versus 0.5 M gadopentetate for the classification of lesions as either benign or malignant in patients with known or suspected liver lesions. METHODS AND MATERIALS:: A multicenter, phase-III, randomized, interindividually controlled comparison study with blinded reader evaluation was performed to investigate the diagnostic efficacy of a bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentetate at a dose of 0.1 mmol Gd/kg BW.The imaging protocol included a dynamic 3D-evaluation, static conventional, and fat saturated T1-weighted sequences. MR datasets were evaluated by 3 independent radiologists. The standard of reference was defined by an independent truth panel (radiologist or hepatologist).The safety evaluation included adverse events, vital signs, and physical examination. RESULTS:: A total of 497 of 572 patients were eligible for the final efficacy analysis. Noninferiority of gadobutrol-enhanced magnetic resonance imaging (MRI) for the classification of liver lesions was demonstrated on the basis of diagnostic accuracy determined by the on-site investigators (-0.098, 0.021) as well as for the average reader of the blinded evaluation (-0.096, 0.014) (95% confidence interval), compared with the predefined standard of reference. Very similar increases in sensitivity (ranging from approximately 10% to approximately 55%) and specificity (ranging from approximately 1%- approximately 18%) compared with precontrast MRI were also observed for the 2 contrast agent groups, with maximum differences of 4%.Very similar, low rates of adverse events were recorded for each of the 2 groups. No clinically relevant changes in vital signs or the results of the physical examination were observed in any patient. CONCLUSION:: This study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol (0.1 mmol/kg body weight) to 0.5 M gadopentetate (0.1 mmol/kg body weight) in the diagnostic assessment of liver lesions with contrast-enhanced MRI. The known excellent safety profile of gadobutrol was confirmed in this clinical trial and is similar to that of gadopentetate.

Ziel: 1. Evaluierung des superparamagnetischen Eisenoxidpräparates Feruglose (Clariscan™) für die Detektion und Differenzierung von benignen und malignen Mamma-Tumoren mit dynamischer Magnetresonanztomographie (MRT). 2. Vergleich des neuen makromolekularen Magnetresonanzkontrastmittels (MRKM) Feruglose (Molekulargewicht = 100 kDa) und des Standard–MRKM Gd-DTPA (Molekulargewicht = 0,5 kDa) in Bezug auf ihre Fähigkeit benigne und maligne Brust-Läsionen zu differenzieren. Methode: 25 Patientinnen mit Verdacht auf eine Mamma–Läsion, diagnostiziert mittels Palpation, konventioneller Röntgen-Mammographie und Sonographie, wurden vor und nach Feruglose-Injektion MR-tomographisch untersucht. Das Untersuchungsprotokoll beinhaltete eine axiale T2-gewichtete (TR/TE/FA: 4000/150/90°) Turbo-Spinecho (TSE)-Sequenz und eine transversale repetitive dynamische T1-gewichtete (TR/TE/FA: 14/1/30°) Fast Field Echo (FFE)-Sequenz. Die MRT-Daten wurden qualitativ und quantitativ (eine Computer–gesteuerte Messung der Signalintensitäten vor und nach KM–Gabe) ausgewertet. Die Differenz der gemessenen Signalintensitäten (Δ SI) vor und nach KM–Injektion wurde anhand der Formel: Δ SI = (SI post – SI prä)/ SI prä quantifiziert. Mittels kinetischer Analysen der Δ SI–Daten erfolgte die Quantifizierung der Tumormikrozirkulationsparameter: Kapillarpermeabilität (KPS) und fraktionales Plasmavolumens (fPV). Diese quantitativen Daten (KPS, fPV) wurden mit der Histologie der Tumoren, dem Scarrf–Bloom-Richardson (SBR)-Score und der Mikrogefäßdichte (microvessel density, MVD) korreliert. Bei 14 Patientinnen wurde außer der Feruglose–verstärkten Studien–MRT eine vergleichende Standard–Untersuchung mit Gd–DTPA unter Einsatz von einer axialen T2–gewichteten (TR/TE/FA: 4000/150/90°) TSE–Sequenz und einer axialen repetitiven dynamischen T1–gewichteten (TR/TE/FA: 9.1/4.6/30°) FFE–Sequenz durchgeführt. Ergebnisse: Die KPS korrelierte hoch signifikant mit dem Tumorgrading, quantifiziert nach dem SBR-Score. Bei zehn der elf benignen Mamma-Läsionen betrug der endotheliale Transfer–Koeffizient 0 und bei allen Karzinomen war der Kapillarpermeabilitätswert höher als 0. Sämtliche Läsionen zeigten nach Gd-DTPA-Gabe ein signifikant höheres max. KM-Enhancement als nach Feruglose-Gabe (p0.05). Auch die Verteilung der KM-Anreicherungscharakteristika war für die Feruglose-Daten signifikant unterschiedlich zwischen benignen und malignen Tumoren (χ² =9.017, p0.05). Schlussfolgerung: Mit der Feruglose-verstärkten dynamischen MRT kann die Dignität von Mamma-Tumoren nicht invasiv in vivo eingeschätzt werden. Die Feruglose-verstärkte dynamische MRT bietet eine verbesserte Spezifität für die Detektion von benignen und malignen Mamma-Tumoren aber eine schlechtere Sensitivität im Vergleich zu der Gd-DTPA-verstärkten dynamischen MRT. Purpose: 1. To define the value of the superparamagnetic iron oxide contrast agent feruglose (Clariscan™) in detection and differentiation of benign and malignant breast tumors with dynamic magnetic resonance tomography (MRT). 2. To compare the new macromolecular contrast agent feruglose (molecular weight, MW = 100 kDa) and the standard small molecular contrast agent gadopentetate (MW = 0,5 kDa) in their abilities to differentiate benign and malignant breast lesions. Materials and methods: 25 women with suspiscious breast lesions, diagnosed by clinical examination, conventional mammography and ultrasound, underwent feruglose–enhanced magnetic resonance mammography (MRM). The MR imaging was performed using an axial T2–weighted (TR/TE/FA: 4000/150/90°) 2D TSE sequence and axial T1–weighted (TR/TE/FA: 14/1/30°) dynamic 3D spoiled fast field echo (FFE) sequence. Images were qualitatively and quantitatively (average signal intensities, SI, precontrast and postcontrast) analyzed. Delta signal intensities were calculated according to the formula: Δ SI = (SI post – SI prä)/ SI prä. By kinetic analysis of dynamic magnetic resonance imaging were estimated microvascular characteristics: transendothelial permeability (KPS) and fractional plasma volume (fPV). These MRI–derived parameters (KPS and fPV) were correlated with histopathologic tumor grade (SBR–score) and microvessel density (MVD). In 14 patients, in addition to the feruglose–study, a standard gadopentetate–enhanced MRI was performed using an axial T2–weighted (TR/TE/FA: 4000/150/90°) 2D TSE sequence and an axial dynamic T1–weighted (TR/TE/FA: 9.1/4.6/30°) 3D FFE sequence. Results: KPS values were zero for all but one lesion and above zero in all carcinomas. A highly positive correlation was observed between MRI–derived KPS values and SBR–tumor grade (r²=0.64, p≤0.05). All breast lesions showed a substantially higher mean tumor peak enhancement data after administration of gadopentetate as compared to feruglose (p0.05). Conclusion: Feruglose–enhanced MRI is capable to characterize and grade breast tumors non–invasively in vivo. Feruglose provides a substantially lower enhancement of breast lesions as compared to gadopentetate, but an improved specificity for lesion characterization.