Usefulness of double dose contrast-enhanced magnetic resonance imaging for clear delineation of gross tumor volume in stereotactic radiotherapy treatment planning of metastatic brain tumors: a dose comparison study

Subedi, Kalloo Sharma; Takahashi, Tetsuya; Yamano, Takafumi; Saitoh, Jun‐ichi; Nishimura, Keiichiro; Suzuki, Yoshiyuki; Ohno, Tatsuya; Nakano, Takashi

doi:10.1093/jrr/rrs053

Cited by 15 publications

(7 citation statements)

References 18 publications

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“…5). This is in line with several studies demonstrating a higher sensitivity for detecting small metastases using double or triple doses of GBCA 43–46 . Similar contrast (tumor-to-brain) was observed for gadoquatrane at a less than 75% of the Gd dose (more than 90% less for molecule dose) compared with the standard dose of gadoterate meglumine (0.1 mmol Gd/kg bw) (Fig.…”

Section: Discussionsupporting

confidence: 91%

Preclinical Profile of Gadoquatrane

Lohrke¹,

Berger

Frenzel³

et al. 2022

Invest Radiol

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Objectives The aim of this report was to characterize the key physicochemical, pharmacokinetic (PK), and magnetic resonance imaging (MRI) properties of gadoquatrane (BAY 1747846), a newly designed tetrameric, macrocyclic, extracellular gadolinium-based contrast agent (GBCA) with high relaxivity and stability. Materials and Methods The r1-relaxivities of the tetrameric gadoquatrane at 1.41 and 3.0 T were determined in human plasma and the nuclear magnetic relaxation dispersion profiles in water and plasma. The complex stability was analyzed in human serum over 21 days at pH 7.4 at 37°C and was compared with the linear GBCA gadodiamide and the macrocyclic GBCA (mGBCA) gadobutrol. In addition, zinc transmetallation assay was performed to investigate the kinetic inertness. Protein binding and the blood-to-plasma ratio were determined in vitro using rat and human plasma. The PK profile was evaluated in rats (up to 7 days postinjection). Magnetic resonance imaging properties were investigated using a glioblastoma (GS9L) rat model. Results The new chemical entity gadoquatrane is a macrocyclic tetrameric Gd complex with one inner sphere water molecule per Gd ( q = 1). Gadoquatrane showed high solubility in buffer (1.43 mol Gd/L, 10 mM Tris-HCl, pH 7.4), high hydrophilicity (logP −4.32 in 1-butanol/water), and negligible protein binding. The r1-relaxivity of gadoquatrane in human plasma per Gd of 11.8 mM −1 ·s −1 (corresponding to 47.2 mM −1 ·s −1 per molecule at 1.41 T at 37°C, pH 7.4) was more than 2-fold (8-fold per molecule) higher compared with established mGBCAs. Nuclear magnetic relaxation dispersion profiles confirmed the more than 2-fold higher r1-relaxivity in human plasma for the clinically relevant magnetic field strengths from 0.47 to 3.0 T. The complex stability of gadoquatrane at physiological conditions was very high. The observed Gd release after 21 days at 37°C in human serum was below the lower limit of quantification. Gadoquatrane showed no Gd 3+ release in the presence of zinc in the transmetallation assay. The PK profile (plasma elimination, biodistribution, recovery) was comparable to that of gadobutrol. In MRI, the quantitative evaluation of the tumor-to-brain contrast in the rat glioblastoma model showed significantly improved contrast enhancement using gadoquatrane compared with gadobutrol at the same Gd dose administered (0.1 mmol Gd/kg body weight). In comparison to gadoterate meglumine, similar contrast enhancement was reached with gadoquatrane with 75% less Gd dose. In terms of the molecule dose, this was reduced by 90% when compared with gadoterate meglumine. Because of its tetrameric structure and hence lower number of molecules per volume, all prepared formulations of gadoquatrane were iso-osmolar to blood. Conclusions The tetrameric...

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Section: Discussionsupporting

confidence: 91%

Preclinical Profile of Gadoquatrane

Lohrke¹,

Berger

Frenzel³

et al. 2022

Invest Radiol

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“…4 One obvious way of dealing with this issue is to increase the longitudinal relaxivity of GBCAs to increase the contrast between the lesion and background healthy parenchyma with the classic dose of 0.1 mmol Gd/kg. 25,26 A sufficient relaxivity increase could even enable reduction of the Gd dose without lowering the current efficacy associated with extracellular and nonspecific GBCAs. 4 All extracellular GBCAs currently on the market have roughly similar relaxivity properties, 27 and their use at higher doses is limited due to potential safety concerns.…”

mentioning

confidence: 99%

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol

et al. 2019

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Objectives We aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging. Methods We described the molecular structure of gadopiclenol and measured the r 1 and r 2 relaxivity properties at fields of 0.47 and 1.41 T in water and human serum. Nuclear magnetic relaxation dispersion profile measurements were performed from 0.24 mT to 7 T. Protonation and complexation constants were determined using pH-metric measurements, and we investigated the acid-assisted dissociation of gadopiclenol, gadodiamide, gadobutrol, and gadoterate at 37°C and pH 1.2. Applying the relaxometry technique (37°C, 0.47 T), we investigated the risk of dechelation of gadopiclenol, gadoterate, and gadodiamide in the presence of ZnCl 2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled 153 Gd-gadopiclenol were performed in Beagle dogs, and protein binding was measured in rats, dogs, and humans plasma and red blood cells. Results Gadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid); registry number 933983-75-6] is based on a pyclen macrocyclic structure. Gadopiclenol exhibited a very high relaxivity in water (r 1 = 12.2 mM −1 ·s −1 at 1.41 T), and the r 1 value in human serum at 37°C did not markedly change with increasing field (r 1 = 12.8 mM −1 ·s −1 at 1.41 T and 11.6 mM −1 ·s −1 at 3 T). The relaxivity data in human serum did not indicate protein binding. The nuclear magnetic relaxation dispersion profile of gadopiclenol exhibited a high and stable relaxivity in a strong magnetic field. Gadopiclenol showed high kinetic inertness under acidic conditions, with a dissociation half-life of 20 ± 3 days compared with 4 ± 0.5 days for gadoterate, 18 hours for gadobutrol, and less than 5 seconds for gadodiamide and gadopentetate. The pharmacokinetic profile in dogs was typical of extracellular nonspecific GBCAs, showing distribution in the extracellular compartment and no metabolism. No protein binding was found in rats, dogs, and humans. Conclusions Gadopiclenol is a new extracellular and macrocyclic Gd chelate that exhibited high relaxivity, no protein binding, and high kinetic inertness. Its pharmacokinetic profile in dogs was similar to that of other extracellular nonspecific GBCAs.

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“…At the same time, it has been known for a long time that the detection of small contrast-enhancing lesions is strongly dependent on the contrast dose, leading to the partial use of double-dose protocols in brain MRI to increase sensitivity. [33][34][35] In this regard, a study by Haubold et al 10 aimed to compare 2 reduction levels of intravenous ICM dose (100% dose corresponds to 1.5 mL/kg iopromide 300 mg I/mL [Ultravist 300; Bayer Vital GmbH, Leverkusen, Germany]) in CT using GANs. The authors reported that a 50% reduction in ICM dose could be achieved while maintaining image quality and consistency in the visualization of pathologies, whereas an 80% reduction negatively affected the consistency of the visualization of pathologies in CT imaging despite similar results of the quantitative image similarity evaluation.…”

Section: New Frontiers In Contrast Agent Dose Reductionmentioning

confidence: 99%

“…One example is the search for brain metastases, where it has long been known that doubling the dose can significantly increase the sensitivity in detecting metastases. 33,34 In this regard, recent studies have shown that such approaches may increase the sensitivity of radiologists in the detection of cerebral metastases. 2 Table 1 shows the publications in the 3 frontiers of AI in contrast media research.…”

Section: New Applicationsmentioning

confidence: 99%

AI as a New Frontier in Contrast Media Research

Haubold,

Hosch,

Jost

et al. 2023

Invest Radiol

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Artificial intelligence (AI) techniques are currently harnessed to revolutionize the domain of medical imaging. This review investigates 3 major AI-driven approaches for contrast agent management: new frontiers in contrast agent dose reduction, the contrast-free question, and new applications. By examining recent studies that use AI as a new frontier in contrast media research, we synthesize the current state of the field and provide a comprehensive understanding of the potential and limitations of AI in this context. In doing so, we show the dose limits of reducing the amount of contrast agents and demonstrate why it might not be possible to completely eliminate contrast agents in the future. In addition, we highlight potential new applications to further increase the radiologist's sensitivity at normal doses. At the same time, this review shows which network architectures provide promising approaches and reveals possible artifacts of a paired image-to-image conversion. Furthermore, current US Food and Drug Administration regulatory guidelines regarding AI/machine learning–enabled medical devices are highlighted.

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Usefulness of double dose contrast-enhanced magnetic resonance imaging for clear delineation of gross tumor volume in stereotactic radiotherapy treatment planning of metastatic brain tumors: a dose comparison study

Cited by 15 publications

References 18 publications

Preclinical Profile of Gadoquatrane

Preclinical Profile of Gadoquatrane

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol

AI as a New Frontier in Contrast Media Research

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