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Background: Magnetic resonance imaging (MRI) can be applied to visualize endolymphatic hydrops (EH)., Aims/objectives: To explore whether a 3-h time interval was feasible for clinical practice., Materials and Methods: We prospectively enrolled 15 patients with unilateral Meniere's disease, each of whom underwent delayed enhancement MRI scan of the inner ear after intravenous gadoteridol injection at a 3-h interval. The ears of these patients were divided into two groups (group A: the affected ears; group B: the unaffected ears). Among the two groups, the signal intensity in perilymphatic area of the basal turn of cochlea, the results of visual evaluations in the vestibule, cochlea and semicircular canal and the detection results of EH were compared., Results: Regarding the signal intensity, a difference was found between group A and group B ( p  = .016). Besides, no difference was found between the visual evaluations in the vestibule, cochlea and semicircular canal of the two groups. Regarding the detection results of EH, group A (6 vestibules were undiagnosable; 8 cochleae were undiagnosable); group B (9 vestibules were undiagnosable; 10 cochleae were undiagnosable)., Conclusions and Significance: In the clinical application of gadoteridol for the inner ear, 3-h delayed MR imaging may not be sufficient.

Background: Gd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs., Methods: Sprague-Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats (n = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment., Results: Plasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals (p < 0.001). Higher Gd levels after administration of gadobutrol or gadoterate versus gadoteridol were also determined in kidneys (p ≤ 0.002), cerebrum (p ≤ 0.001), cerebellum (p ≤ 0.003), skin (p ≥ 0.244), liver (p ≥ 0.053), and femur (p ≥ 0.271). At day 56, lower Gd levels were determined both in SN and healthy rats for all GBCAs and tissues, except the femur., Conclusions: Gd tissue levels were lower following gadoteridol exposure than following gadobutrol or gadoterate exposure., (© 2023. The Author(s).)

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect., Competing Interests: Declaration of interests M.S.F. is an employee of Asklepios BioPharmaceutical, Inc. (AskBio). C.L. reports honoraria for editorial work from Elsevier, Inc. The work submitted here was conducted in the course of employment for the National Institute of Neurological Disorders and Stroke, an agency of the US Government. K.S.B. is a consultant to AskBio, Aviado Bio, and Scribe Tx and a patent holder on relevant technologies utilized in this study. K.S.B. was a co-founder of Voyager Therapeutics, has not been associated with the company for over 3 years, and reports no current financial interests in that company., (Published by Elsevier Inc.)

Background: Normal background parenchymal enhancement (BPE) is a dynamic parameter affected by multiple factors., Purpose: To determine whether contrast agent injection rate affects the degree of BPE in women undergoing breast magnetic resonance imaging (MRI)., Material and Methods: A total of 85 patients included in our prospective study randomly received 0.1 mmol/kg gadoteridol at a rate of 3 mL/s (group A; n = 46) or 2 mL/s (group B; n = 39). Breast MRI was performed at 3T using a standard protocol including postcontrast axial 3D GRE T1-weighted sequences. Two expert breast radiologists, blinded to clinical and radiological information, independently quantified BPE on early postcontrast subtracted images, assigning a score of 1-4. Mean comparison and regression analysis were performed to assess the influence of injection rate on BPE., Results: Groups were homogeneous in terms of age and final BI-RADS score. The mean BPE score was significantly lower among patients in group A (mean of two readers: 1.36 vs. 1.90; P  < 0.01) with 70%-72% of patients assigned a BPE score of 1, compared with 36%-38% of patients in group B. Lower BPE scores were noted with the higher flow rate in subgroup analyses of both pre- and postmenopausal women, although the effect was more evident in premenopausal women. Regression analysis confirmed that the likelihood of a BPE 1 score was significantly increased with a higher flow rate ( P  < 0.01). The inter-reader agreement was excellent (0.83)., Conclusion: A higher contrast agent injection flow rate (3 mL/s) during breast MRI significantly reduces the degree of BPE, potentially allowing improved diagnostic accuracy by reducing false-positive and false-negative findings.

Purpose: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s., Methods: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists., Results: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values., Conclusion: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate safety and diagnostic accuracy of gadoteridol vs. other macrocyclic gadolinium-based contrast agents (GBCAs) in a large cohort of consecutive and non-selected patients referred for CE-MRI of the CNS., Material and Methods: Between November 2017 and March 2018, we prospectively enrolled a consecutive cohort of patients referred for neuroradiological CE-MRI (1.5T MRI). Image quality and adverse events were assessed. Diagnostic performance was determined for a subgroup of patients with truth standard findings available. Comparison was made between patients receiving gadoteridol and patients receiving other macrocyclic GBCAs. Inter-reader agreement (kappa) between two expert neuroradiologists was calculated for the diagnosis of malignancy., Results: Overall, 460 patients (220M/240F; mean age 54±16 years) were enrolled of which 230 received gadoteridol (Group 1) and 230 either gadoteric acid or gadobutrol [n=83 (36.1%) and n=147 (63.9%), respectively; Group 2]. Image quality was rated as good or excellent in both groups. The sensitivity, specificity and diagnostic accuracy for determination of malignancy was 88.2%, 96.5% and 95.4%, respectively, for Group 1 and 93.7%, 97.4% and 96.9%, respectively, for Group 2, with no significant differences between groups (P>0.75) for any determination. Inter-reader agreement for the identification of malignancy was excellent [K=0.877 (95%CI: 0.758-0.995) and K=0.818 (95%CI: 0.663-0.972) for groups 1 and 2, respectively; P=0.0913]. Adverse events occurred in 5 of 460 (1.09%) patients overall, with no significant difference (P=0.972) between groups., Conclusion: Gadoteridol was safe and guaranteed good image quality without significant differences when compared to gadobutrol and gadoteric acid in a wide range of CNS pathologies., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: Studies of gadolinium (Gd) clearance from animals in the first weeks after administration of gadolinium-based contrast agents (GBCAs) have previously looked at solitary timepoints only. However, this does not give information on differences between GBCAs and between organs in terms of Gd elimination kinetics., Purpose: To compare Gd levels in rat cerebellum, cerebrum, skin, and blood at 1, 2, 3, and 5 weeks after repeated administration of macrocyclic GBCAs., Study Type: Prospective., Animal Model: One hundred eighty male Sprague-Dawley rats randomized to three groups (n = 60/group), received intravenous administrations of gadoteridol, gadoterate meglumine, or gadobutrol (0.6 mmol/kg for each) four times/week for 5 consecutive weeks. Rats were sacrificed after washout periods of 1, 2, 3, or 5 weeks., Field Strength/sequence: Not applicable., Assessment: Cerebellum, cerebrum, skin, and blood were harvested for Gd determination by inductively coupled plasma-mass spectrometry (15 animals/group/all timepoints)., Statistical Tests: Anova and Dunnett's test (data with homogeneous variances and normal distribution). Kruskal-Wallis and Wilcoxon's rank sum tests (data showing nonhomogeneous variances or a non-normal distribution, significance levels: P < 0.05, P < 0.01, and P < 0.001)., Results: Gd levels in cerebellum, cerebrum, and skin were significantly lower after gadoteridol than after gadoterate and gadobutrol at all timepoints. Mean cerebellum Gd concentrations after gadoteridol, gadoterate, and gadobutrol decreased from 0.693, 0.878, and 1.011 nmol Gd/g at 1 week to 0.144, 0.282, and 0.297 nmol Gd/g at 5 weeks after injection. Similar findings were noted for cerebrum and skin. Conversely, significantly higher Gd levels were noted in blood after gadoteridol compared to gadobutrol at 1, 2, and 3 weeks and compared to gadoterate at all timepoints., Data Conclusion: Gadoteridol is eliminated more rapidly from rat cerebellum, cerebrum, and skin compared to gadoterate and gadobutrol in the first 5 weeks after administration, resulting in lower levels of retained Gd in these tissues., Evidence Level: 1 TECHNICAL EFFICACY: Stage 5., (© 2021 Bracco ImagingSpA. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Previous intraindividual comparative studies evaluating gadobutrol and gadoteridol for contrast-enhanced magnetic resonance imaging (MRI) of brain tumours have relied on subjective image assessment, potentially leading to misleading conclusions. We used artificial intelligence algorithms to objectively compare the enhancement achieved with these contrast agents in glioblastoma patients., Methods: Twenty-seven patients from a prior study who received identical doses of 0.1 mmol/kg gadobutrol and gadoteridol (with appropriate washout in between) were evaluated. Quantitative enhancement (QE) maps of the normalised enhancement of voxels, derived from computations based on the comparison of contrast-enhanced T1-weighted images relative to the harmonised intensity on unenhanced T1-weighted images, were compared. Bland-Altman analysis, linear regression analysis and Pearson correlation coefficient (r) determination were performed to compare net QE and per-region of interest (per-ROI) average QE (net QE divided by the number of voxels)., Results: No significant differences were observed for comparisons performed on net QE (mean difference -24.37 ± 620.8, p = 0.840, r = 0.989) or per-ROI average QE (0.0043 ± 0.0218, p = 0.313, r = 0.958). Bland-Altman analysis revealed better per-ROI average QE for gadoteridol-enhanced MRI in 19/27 (70.4%) patients although the mean difference (0.0043) was close to zero indicating high concordance and the absence of fixed bias., Conclusions: The enhancement of glioblastoma achieved with gadoteridol and gadobutrol at 0.1 mmol/kg bodyweight is similar indicating that these agents have similar contrast efficacy and can be used interchangeably, confirming the results of a prior double-blind, randomised, intraindividual, crossover study., (© 2021. The Author(s).)

Background: Intravenous gadoteridol injection can be applied to visualize endolymphatic hydrops (EH)., Aims/objectives: To explore whether 3.5-h time interval was feasible for clinical practice., Materials and Methods: We collected 70 unilateral Meniere's disease (MD) patients who were divided into two groups randomly (group A: 3.5-h time interval; group B: 4-h time interval). Among the two groups, the signal intensity (SI) in perilymphatic area of the basal turn of cochlea, the results of visual evaluations in the vestibule, cochlea and semicircular canal and the detection results of EH were compared., Results: Regarding the SI, no difference was found between A-affected ears and B-affected ears ( p =.499), and no difference was found between A-unaffected ears and B-unaffected ears ( p =.111). However, a difference was found between A-affected ears and A-unaffected ears ( p =.005), and a difference was found between B-affected ears and B-unaffected ears ( p =.012). Besides, no difference was found between the visual evaluations in the vestibule, cochlea, and semicircular canal of the two groups. Regarding the detection results of EH, no difference was found between the two groups (all p >.05)., Conclusions and Significance: In the clinical application of gadoteridol for the inner ear, 3.5-h delayed MR imaging is feasible.

Background: Neonates and young children require efficacious magnetic resonance imaging (MRI) examinations but are potentially more susceptible to the short- and long-term adverse effects of gadolinium-based contrast agents due to the immaturity of their body functions., Objective: To evaluate the acute safety and diagnostic efficacy of gadoteridol (ProHance) for contrast-enhanced MRI of the central nervous system (CNS) in children ≤2 years of age., Materials and Methods: One hundred twenty-five children ≤2 years old (including 57 children <6 months old) who underwent contrast-enhanced MRI of the CNS with gadoteridol at 0.1 mmol/kg body weight were retrospectively enrolled at five imaging centers. Safety data were assessed for acute/subacute adverse events in the 48 h following gadoteridol administration and, when available, vital signs, electrocardiogram (ECG) and clinical laboratory values obtained from blood samples taken from 48 h before until 48 h following the MRI exam. The efficacy of gadoteridol-enhanced MRI compared to unenhanced MRI for disease diagnosis was evaluated prospectively by three blinded, unaffiliated readers., Results: Thirteen changes of laboratory values (11 mild, 1 moderate, 1 unspecified) were reported as adverse events in 7 (5.6%) patients. A relationship to gadoteridol was deemed possible though doubtful for two of these adverse events in two patients (1.6%). There were no clinical adverse events, no serious adverse events and no clinically meaningful changes in vital signs or ECG recordings. Accurate differentiation of tumor from non-neoplastic disease, and exact matching of specific MRI-determined diagnoses with on-site final diagnoses, was achieved in significantly more patients by each reader following the evaluation of combined pre- and post-contrast images compared to pre-contrast images alone (84.6-88.0% vs. 70.9-76.9%; P≤0.006 and 67.5-79.5% vs. 47.0-66.7%; P≤0.011, respectively)., Conclusion: Gadoteridol at 0.1 mmol/kg body weight is safe, well tolerated and effective for contrast-enhanced MRI of the CNS in children ≤2 years of age., (© 2021. The Author(s).)

The article considers issues of pharmacoeconomics of applying gadolinium-containing contrast medium in diagnostic of multiple sclerosis in patients., Materials and Methods: The MS Excel calculator was applied to estimate costs and analyze impact on the budget under treatment of multiple sclerosis exacerbations, that were diagnosed using various gadolinium-containing contrast mediums. The direct medical costs for diagnostics with gadolinium-containing contrast medium and hospitalization due to exacerbation in accordance with mandatory medical insurance system were taken into account., The Results: At the expense of reducing number of multiple sclerosis exacerbations due to the use of single-molar gadolinium-containing contrast medium (gadobutrol) as compared with semi-polar gadolinium-containing contrast medium (gadodiamide, gadoteric acid and gadoteridol) in 1000 patients it is possible to reduce financial expenses from 1,968,642 to 7,175,520 RUB., Conclusion: The cost of magnetic resonance imaging diagnostics with contrast enhancement and treatment of multiple sclerosis exacerbations increases in the series: gadobutrol < gadodiamide (Jodas Expoim) < gadodiamide (GE Health Care) < gadoteridol < gadoteric acid.

Purpose: Whole-body magnetic resonance imaging (WB-MRI) is a radiation-free alternative to the 99m Tc-HDP bone scan (BS) for the detection of bone metastasis. The major drawback is the long examination time and application of gadolinium enhancer. The aim of this study is to analyze (i) the performance of WB-MRI versus the BS and (ii) the diagnostic benefit of gadolinium (WB-MRI + Gd) compared to a non-enhanced protocol (NE WB-MRI)., Methods and Materials: 1256 eligible WB-MRI scans were analyzed retrospectively with a single inclusion criterion, a clinical 12-month follow-up or a biopsy as ground truth. N = 285 patients received both a WB-MRI and a BS within 12 months. All the patients were imaged with a coronal T1w and a STIR, and n = 528 (42%) received an additional T1w-mDixon with gadoteridol (0.1 mmol Gd-DTPA/kg)., Results: From 1256 eligible patients, n = 884 (70%) had breast cancer as a primary disease, n = 101(8%) prostate cancer, and n = 77(6%) lung cancer. The sensitivity (Se) and negative predictive value (NPV) of the WB-MRI was 98/99%, significantly higher compared to BS with 82/89%, P < 0.001 Mc Nemar's test. The specificity (Spe) and positive predictive value (PPV) of the WB-MRI and BS was 85/82% and 91/86%, respectively. The interobserver agreement between WB-MRI and BS was 71%, Cohen's kappa 0.42. Analysis of the added diagnostic value of gadolinium revealed Se/Spe/PPV/NPV of 98/93/92/98% for the NE WB-MRI and 99/93/85/100% for the WM-MRI + Gd, P > 0.05 binary logistic regression with Fischer's exact test., Conclusion: WB-MRI exceeds the sensitivity of BS without compromising the specificity, even after omitting the gadolinium enhancer.

Background: The safety of gadolinium-based contrast agents is of fundamental importance., Purpose: To determine the frequency and severity of immediate-type adverse reactions to approved doses of gadoteridol in patients referred for routine gadoteridol-enhanced MRI in actual clinical practice settings., Study Type: Prospective, observational., Population: In all, 6163 subjects were enrolled (mean age: 56.7 ± 15.4 years; range: 6-93 years)., Field Strength/sequence: 1.5T and 3.0T., Assessment: Assessment was of immediate adverse reactions by the investigating radiologist using the MedDRA System Organ Class and preferred term., Statistical Tests: Summary statistics for continuous variables, descriptive statistics for demographic characteristics., Results: Overall, 19 adverse events occurred in 13 (0.21%) patients, of which 15 in 10 (0.16%) patients were considered related to gadoteridol administration. These events were evenly distributed between male and female subjects and all occurred in adults. Twelve of the 15 related events in eight (0.13%) patients were considered mild in intensity (rapidly self-resolving), while the remaining three events in two patients (0.03%) were considered moderate in intensity. None were of severe intensity and no serious adverse events occurred., Data Conclusion: The rate of immediate-type adverse events following exposure to approved doses of gadoteridol is extremely low, and mostly limited to transient and self-resolving symptoms., Level of Evidence: 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2020;51:861-868., (© 2019 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Afamin, which is a human blood plasma glycoprotein, a putative multifunctional transporter of hydrophobic molecules and a marker for metabolic syndrome, poses multiple challenges for crystallographic structure determination, both practically and in analysis of the models. Several hundred crystals were analysed, and an unusual variability in cell volume and difficulty in solving the structure despite an ∼34% sequence identity with nonglycosylated human serum albumin indicated that the molecule exhibits variable and context-sensitive packing, despite the simplified glycosylation in insect cell-expressed recombinant afamin. Controlled dehydration of the crystals was able to stabilize the orthorhombic crystal form, reducing the number of molecules in the asymmetric unit from the monoclinic form and changing the conformational state of the protein. An iterative strategy using fully automatic experiments available on MASSIF-1 was used to quickly determine the optimal protocol to achieve the phase transition, which should be readily applicable to many types of sample. The study also highlights the drawback of using a single crystallographic structure model for computational modelling purposes given that the conformational state of the binding sites and the electron density in the binding site, which is likely to result from PEGs, greatly varies between models. This also holds for the analysis of nonspecific low-affinity ligands, where often a variety of fragments with similar uncertainty can be modelled, inviting interpretative bias. As a promiscuous transporter, afamin also seems to bind gadoteridol, a magnetic resonance imaging contrast compound, in at least two sites. One pair of gadoteridol molecules is located near the human albumin Sudlow site, and a second gadoteridol molecule is located at an intermolecular site in proximity to domain IA. The data from the co-crystals support modern metrics of data quality in the context of the information that can be gleaned from data sets that would be abandoned on classical measures., (open access.)

Designing effective and safe tuberculosis (TB) subunit vaccines for inhalation requires identification of appropriate antigens and adjuvants and definition of the specific areas to target in the lungs. Magnetic resonance imaging (MRI) enables high spatial resolution, but real-time anatomical and functional MRI of lungs is challenging. Here, we describe the design of a novel gadoteridol-loaded cationic adjuvant formulation 01 (CAF01) for MRI-guided vaccine delivery of the clinically tested TB subunit vaccine candidate H56/CAF01. Gadoteridol-loaded CAF01 liposomes were engineered by using a quality-by-design approach to (i) increase the mechanistic understanding of formulation factors governing the loading of gadoteridol and (ii) maximize the loading of gadoteridol in CAF01, which was confirmed by cryotransmission electron microscopy. The encapsulation efficiency and loading of gadoteridol were highly dependent on the buffer pH due to strong attractive electrostatic interactions between gadoteridol and the cationic lipid component. Optimal gadoteridol loading of CAF01 liposomes showed good in vivo stability and safety upon intrapulmonary administration into mice while generating 1.5-fold MRI signal enhancement associated with approximately 30% T 1 relaxation change. This formulation principle and imaging approach can potentially be used for other mucosal nanoparticle-based formulations, species, and lung pathologies, which can readily be translated for clinical use.

The efficiency of MRI contrast agents depends on the relaxation rate enhancement that they can induce at imaging fields. It is well known that, at these fields, large relaxation rates are obtained by binding of gadolinium(III) ions to large molecules. By the same token, the interaction of the gadolinium(III) complexes with macromolecules that are found in biological tissues can be responsible for an increase of the relaxation rate with respect to the value observed in liquids. We investigate here the relaxation enhancement of gadoteridol (Gd-HP-DO3A) in crosslinked hyaluronic acid, taken as model tissue, using fast field-cycling relaxometry. The analysis of the relaxation profiles as a function of the magnetic fields indicates that a sizable increase in the relaxation rates is due to a modest interaction of the contrast agent with the hydrogel and to the slower mobility of the water molecules outside the first-coordination sphere of the gadolinium(III) ion., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gadolinium-based contrast agents (GBCAs) have been suggested as off-label alternatives to iodine-based contrast agents for fluoroscopic imaging during interventional pain procedures. We report a case of accidental intrathecal administration of a GBCA during a neuraxial interventional pain procedure leading to acute gadolinium neurotoxicity, which resulted in encephalopathy and ultimately death. To our knowledge, it is the first published case of fatal intrathecal gadolinium-induced encephalopathy and the first published case of intrathecal gadoteridol causing serious neurologic complications. In addition, the case presented here is placed in context with an associated comprehensive, evidence-based review of the use of gadolinium in interventional pain procedures, addressing gadolinium chemistry and pharmacologic properties, neurotoxicity and radiology. Physicians must be aware that gadolinium poses a significant risk of acute neurotoxicity even in small doses. Until further safety research is performed, GBCAs should not be considered a safe alternative for use in neuraxial interventional spine procedures when there is a risk of inadvertent intrathecal administration., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Gadobutrol is a gadolinium-based contrast material (GBCM) with a high concentration of gadolinium and high relaxivity. Our purpose was to evaluate the signal intensity profiles in brain tissue for the bolus width and degree of signal change after bolus injection using an echo planar dynamic susceptibility contrast (DSC) sequence. We compared gadobutrol to gadoteridol using various injection speeds and saline flush volumes., Methods: We studied 97 patients who underwent brain MRI. Datasets for perfusion studies were acquired using a 3T scanner with an echo planar imaging (EPI) sequence. The injection protocols were set up with combinations of injection speed and saline flush volume for both gadobutrol and gadoteridol. The full width at half maximum (FWHM) and the maximum signal change ratio (SCR max ) of the time intensity curves were measured., Results: The FWHM did not show a statistically significant difference according to injection speed, flush volume, or type of GBCM. The SCR max showed a greater change with a faster injection speed, larger saline flush, and gadobutrol administration. The difference between gadobutrol and gadoteridol became smaller with a faster injection speed and a larger saline flush., Conclusion: The maximum signal drop was larger with gadobutrol when the injection speed was slow and the saline flush was small. Thus, gadobutrol may be useful to obtain a better profile for DSC perfusion MRI in conditions requiring a slower injection speed and/or a smaller volume of saline flush.

Purpose: Delayed ferumoxytol enhancement on T 1 -weighted images appears visually similar to gadoteridol enhancement. The purpose of this study was to quantitatively compare ferumoxytol T 1 enhancement to gadoteridol enhancement with an objective, semi-automated method., Methods: 206 sets of post-gadoteridol and 24 h post-ferumoxytol T 1 -weighted scans from 58 high grade glioma patients were analyzed (9 pre-chemoradiation, 111 < 90 days post-chemoradiation, 21 > 90 days post-chemoradiation, 65 post-bevacizumab scans). Enhancement volumes and signal intensities normalized to normal appearing tissue proximal to enhancement were calculated with a semi-automated method. Enhancement cube root volumes (D) and signal intensities (SI) were compared between the 2 contrast agents, and relative difference of D and SI were compared in different treatment groups with multivariate analysis. Within patient differences in D and SI before and after treatment with bevacizumab or steroid were assessed in 26 patients in each treatment group., Results: When compared to gadoteridol, ferumoxytol D was 13.83% smaller and SI was 7.24% lower (P < 0.0001). The relative differences in D and SI between the 2 contrast agents were not significantly different between treatment groups (P > 0.05). Relative difference in D and SI did not change significantly in response to bevacizumab (P = 0.5234 and P = 0.2442, respectively) or to steroid (P = 0.3774, P = 0.0741) in the within patient comparison., Conclusion: The correlation between the 2 contrast agents' enhancement size and signal intensity and their similar behavior in response to therapy suggest that ferumoxytol can be used for revealing enhancement in high grade glioma patients. Magn Reson Med 80:224-230, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Objectives: X-ray iodinated contrast media have been shown to generate contrast in MR images when used with the chemical exchange saturation transfer (CEST) approach. The aim of this study is to compare contrast enhancement (CE) capabilities and perfusion estimates between radiographic molecules and a Gd-based contrast agent in two tumour murine models with different vascularization patterns., Methods: MRI-CEST and MRI-CE T 1w images were acquired in murine TS/A and 4 T1 breast tumours upon sequential i.v. injection of iodinated contrast media (iodixanol, iohexol, and iopamidol) and of gadoteridol. The signal enhancements observed in the two acquisition modalities were evaluated using Pearson's correlation, and the correspondence in the spatial distribution was assessed by a voxelwise comparison., Results: A significant, positive correlation was observed between iodinated contrast media and gadoteridol for tumour contrast enhancement and perfusion values for both tumour models (r = 0.51-0.62). High spatial correlations were observed in perfusion maps between iodinated molecules and gadoteridol (r = 0.68-0.86). Tumour parametric maps derived by iodinated contrast media and gadoteridol showed high spatial similarities., Conclusions: A good to strong spatial correlation between tumour perfusion parameters derived from MRI-CEST and MRI-CE modalities indicates that the two procedures provide similar information., Key Points: • Gd-based agents are the standard of reference for contrast-enhanced MRI. • Iodinated contrast media provides MRI-CEST contrast enhancement in animal tumour models. • Contrast enhancements were positively correlated between iodinated agents and gadoteridol. • Tumour perfusion map showed similar spatial distribution between iodinated agents and gadoteridol. • MRI-CEST with iodinated agents provide similar information to gadoteridol.

Conclusion: In the mouse, when a tympanic perforation is present, gadoteridol does not seem to cause ototoxicity. Gadodiamide may cause mild ototoxicity other than toxicity to the outer hair cells of the cochlea., Objectives: Endolymphatic hydrops have been visualized through intra-tympanic injection of gadolinium-based contrast agents (GBCAs) and three-dimensional fluid-attenuated inversion recovery (3-D FLAIR) magnetic resonance imaging. However, reports on the safety of GBCAs are limited. This study aimed to assess ototoxicity of gadoteridol and gadodiamide., Method: In a prospective, randomized, controlled trial, myringotomies in the left ear were performed in 20 male C57 BL/6 mice. After testing the baseline auditory brainstem response (ABR) (range = 8-32 kHz), the test solution (gadoteridol, gadodiamide, saline, or cisplatin) was injected into the left ear. ABR testing was repeated 14 days after test solution application. In morphological experiments, images of post-mortem surface preparations were assessed for cochlear hair cell status., Results: At 14 days following gadoteridol application, there was no significant change in ABR thresholds at 8, 16, or 32 kHz. Gadodiamide application caused a significant change in the ABR threshold at 8 kHz. Apparent cochlear hair cell loss was not observed in the surface preparation after gadoteridol or gadodiamide application.

Objective: The purpose of this study was to determine the incidence of nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD) and moderate-to-severe impairment of kidney function who had not previously been exposed to gadolinium-based contrast agents (GBCAs) or referred to undergo contrast-enhanced MRI with gadobenate dimeglumine or gadoteridol., Subjects and Methods: Two multicenter prospective cohort studies evaluated the incidence of unconfounded NSF in patients with stage 3 CKD (estimated glomerular filtration rate [eGFR] in cohort 1, 30-59 mL/min/1.73 m(2)) or stage 4 or 5 CKD (eGFR in cohort 2, < 30 mL/min/1.73 m(2)) after injection of gadobenate dimeglumine (study A) or gadoteridol (study B). A third study (study C) determined the incidence of NSF in patients with stage 4 or 5 CKD who had not received a GBCA in the 10 years before enrollment. Monitoring for signs and symptoms suggestive of NSF was performed via telephone at 1, 3, 6, and 18 months, with clinic visits occurring at 1 and 2 years., Results: For studies A and B, the populations evaluated for NSF comprised 363 and 171 patients, respectively, with 318 and 159 patients in cohort 1 of each study, respectively, and with 45 and 12 patients in cohort 2, respectively. No signs or symptoms of NSF were reported or detected during the 2 years of patient monitoring. Likewise, no cases of NSF were reported for any of the 405 subjects enrolled in study C., Conclusion: To our knowledge, and consistent with reports in the literature, no association of gadobenate dimeglumine or gadoteridol with unconfounded cases of NSF has yet been established. Study data confirm that both gadoteridol and gadobenate dimeglumine properly belong to the class of GBCAs considered to be associated with the lowest risk of NSF.

Purpose: Contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) with gadolinium-based contrast agents (GBCAs) is standard of care for CNS imaging and diagnosis because of the visualization of lesions that cause blood-brain barrier breakdown. Gadobutrol is a macrocyclic GBCA with high concentration and high relaxivity. The objective of this study was to compare the safety and efficacy of gadobutrol 1.0 M vs unenhanced imaging and vs the approved macrocyclic agent gadoteridol 0.5 M at a dose of 0.1 mmol/kg bodyweight., Materials and Methods: Prospective, multicenter, double-blind, crossover trial in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol. Three blinded readers assessed the magnetic resonance images. The primary efficacy variables included number of lesions detected, degree of lesion contrast-enhancement, lesion border delineation, and lesion internal morphology., Results: Of the 402 treated patients, 390 patients received study drugs. Lesion contrast-enhancement, lesion border delineation, and lesion internal morphology were superior for combined unenhanced/gadobutrol-enhanced imaging vs unenhanced imaging (P < 0.0001 for all). Compared with gadoteridol, gadobutrol was non-inferior for all primary variables and superior for lesion contrast-enhancement, as well as sensitivity and accuracy for detection of malignant disease. The percentage of patients with at least one drug-related adverse event was similar for gadobutrol (10.0%) and gadoteridol (9.7%)., Conclusion: Gadobutrol is an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS. Gadobutrol demonstrates greater contrast-enhancement and improved sensitivity and accuracy for detection of malignant disease than gadoteridol, likely because of its higher relaxivity.

Decreased nutrition has been proposed as a potential mechanism leading to intervertebral disc degeneration. A method to investigate it in vivo is the MRI evaluation of the transport of a paramagnetic contrast agent, which is assumed to diffuse through the endplate to the disc using the same mechanisms as the cell nutrients. However, previous numerical studies questioned the value of this method as a model to investigate disc nutrition. To assess its validity, a parametric osmoporoelastic finite element model of a lumbar intervertebral disc incorporating diffusion and convection of a solute (representing the contrast agent) was developed. A Taguchi sensitivity analysis was performed in order to assess the relevance of various parameters which influence the solute transport. Subsequently, a full-factorial sensitivity analysis was used to investigate specifically the diffusion coefficients of the contrast agent. The most important parameters in determining the results were the disc height, the diffusion coefficients and the pharmacokinetic of the contrast agent. However, diffusion coefficients values as measured in in vitro studies would lead to insubstantial enhancement of the MRI signal. Thus, transport mechanisms other than pure diffusion should be active in in vivo transport of the contrast agent. In conclusion, the study showed that post-contrast MRI may not be suited for a quantitative analysis, but only for a qualitative examination aimed for example to detect endplate lesions. Open questions remain on the use of post-contrast MRI for the investigation of the relevance of reduced nutrition as a trigger to disc degeneration., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this investigation was to compare magnetization-prepared rapid gradient echo (MP-RAGE) images with T1-weighted images (T1WI) and T2-weighted images (T1W2) of postmortem brain tissue fixed by admixtures of formalin and gadoteridol. We additionally sought to explore the feasibility of using fixed brain magnetic resonance imaging (MRIs) in forensic practices., Methods: Specimens included in the study were eight whole brains that had been removed during forensic autopsy. Brain specimens were randomly divided into three groups and MRIs were performed either (A) the day of autopsy (n=2) on unfixed tissue, (B) after immersion fixation in 20% formalin (n=3), or (C) after immersion fixation in 20% formalin mixed with 4 mL/L ProHance® (gadoteridol) (n=3). T1WI, T2WI, and MP-RAGE images of all group samples were acquired with a 3T clinical MR scanner. Gray and white matter contrasts of the cortex and basal nucleus in every fixation group and image sequence were then visually compared., Results: Gray/white matter contrasts of the cortex were good in all images obtained by MP-RAGE, and T1WIs of specimens fixed by formalin and gadoteridol-mixed formalin. Additionally, gray/white matter contrast in the basal nucleus was sufficient in the MP-RAGE sequence of specimens fixed by gadoteridol-mixed formalin., Conclusions: MRI of brains immersion-fixed in formalin and gadolinium could serve as a promising tool for neuropathological assessment in forensic practices., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of this study was to evaluate the potential interference of five gadolinium-based contrast agents (GBCAs), gadodiamide (Omniscan®), gadobenate dimeglumine (Multihance®), gadoxetate disodium (Primovist®), gadobutrol (Gadovist®), and gadoteridol (Prohance®), on three clinical laboratory widely used colorimetric calcium assays including the newly developed 5-nitro-5'methyl-l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (NM-BAPTA) method., Methods: Plasma was collected from healthy volunteers aged 23-52, and spiked with varying concentrations of the five GBCAs. Calcium determinations were performed in duplicates using the o-cresolphthalein complexone (OCP), arsenazo-III dye, and NM-BAPTA methods on the Roche Integra 400, Abbott Architect 16000, and Roche Modular P automated analyzers respectively., Results: Gadobenate dimeglumine, gadobutrol, and gadoteridol did not interfere with any of the assays. There was a small positive bias (8%, p<0.01) at a very high concentration (25mmol/L) of gadoxetate disodium when calcium was assayed using the arsenazo-III method. Gadodiamide at a very high concentration (50mmol/L) induced a significant positive bias (16%, p<0.01) on calcium when measured using the NM-BAPTA method; however a much larger bias (90%, p≪0.01) was observed when calcium was measured using the arsenazo-III method. Significant interferences in calcium measurements using the OCP method began at gadodiamide concentrations as low as 0.5mmol/L (-9%, p<0.01). This negative bias was more pronounced at higher gadodiamide concentrations., Conclusions: Of all 5 GBCAs tested, only gadodiamide showed significant interference on the OCP calcium assay at clinically relevant concentrations. The NM-BAPTA assay showed minimum interference with the five GBCAs and demonstrated equal or better performance than the OCP and the arsenazo-III methods in terms of interference with GBCAs., (Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)