Investigative Radiology

Comparison of the Relaxivities of Macrocyclic Gadolinium-Based Contrast Agents in Human Plasma at 1.5, 3, and 7 T, and Blood at 3 T Purpose The relaxivities of 3 macrocyclic gadolinium-based contrast agents (GBCAs) were determined in human plasma and blood under standardized and clinically relevant laboratory conditions. Methods The T1 relaxivity, r1, was determined in human plasma at 1.5, 3, and 7 T, and in human blood at 3 T at 37°C in phantoms containing 4 different concentrations of the macrocyclic GBCAs gadobutrol, gadoteridol, and gadoterate. An inversion recovery turbo spin echo sequence was used to generate images with several inversion times. The T1-times were obtained by fitting the signal intensities to the signal equation. r1 was obtained by a 1/y-weighted regression of the T1-rates over the concentration of the GBCAs. Results For gadobutrol, the obtained r1 [L/(mmol·s)] in human plasma at 1.5 T, 3 T, and 7 T, and in human blood at 3 T was 4.78 ± 0.12, 4.97 ± 0.59, 3.83 ± 0.24, and 3.47 ± 0.16. For gadoteridol, r1 was 3.80 ± 0.10, 3.28 ± 0.09, 3.21 ± 0.07, and 2.61 ± 0.16, and for gadoterate, 3.32 ± 0.13, 3.00 ± 0.13, 2.84 ± 0.09, and 2.72 ± 0.17. Conclusions The relaxivity of gadobutrol is significantly higher than that of gadoteridol and gadoterate at all magnetic field strengths and in plasma as well as in blood, whereas that of gadoteridol was higher than gadoterate only in plasma at 1.5 and 7 T. This is in accordance with results from 3 previous studies obtained in different media. Received for publication January 31, 2019; and accepted for publication, after revision, April 6, 2019. Conflicts of interest and sources of funding: The authors P.S., I.M.N.-H., and S.T. declare no conflicts of interest. The authors M.R., T.F., G.J., J.E. and H.P. are employees of Bayer AG. This study was funded by the Vienna Science and Technology Fund (WWTF-LS11-018), Austrian Science Fund (FWF KLI541-B30), and Slovak Grant Agency (APVV-15-0029). Financial support to the Medical University of Vienna was also provided by Bayer AG. Correspondence to: Siegfried Trattnig, MD, MR Centre-Highfield MR, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waerhringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: siegfried.trattnig@meduniwien.ac.at. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

AcidoCEST-UTE MRI for the Assessment of Extracellular pH of Joint Tissues at 3 T Objectives The goal of this study was to demonstrate feasibility of measuring extracellular pH in cartilage and meniscus using acidoCEST technique with a 3-dimensional ultrashort echo time readout (acidoCEST-UTE) magnetic resonance imaging (MRI). Materials and Methods Magnetization transfer ratio asymmetry, radiofrequency (RF) power mismatch, and relative saturation transfer were evaluated in liquid phantoms for iopromide, iopamidol, and iohexol over a pH range of 6.2 to 7.8, at various agent concentrations, temperatures, and buffer concentrations. Tissue phantoms containing cartilage and meniscus were evaluated with the same considerations for iopamidol and iohexol. Phantoms were imaged with the acidoCEST-UTE MRI sequence at 3 T. Correlation coefficients and coefficients of variations were calculated. Paired Wilcoxon rank-sum tests were used to evaluate for statistically significant differences. Results The RF power mismatch and relative saturation transfer analyses of liquid phantoms showed iopamidol and iohexol to be the most promising agents for this study. Both these agents appeared to be concentration independent and feasible for use with or without buffer and at physiologic temperature over a pH range of 6.2 to 7.8. Ultimately, RF power mismatch fitting of iohexol showed the strongest correlation coefficients between cartilage, meniscus, and fluid. In addition, ratiometric values for iohexol are similar among liquid as well as different tissue types. Conclusions Measuring extracellular pH in cartilage and meniscus using acidoCEST-UTE MRI is feasible. Received for publication January 31, 2019; and accepted for publication, after revision, April 3, 2019. Drs Ya-Jun Ma and Rachel High contributed equally to this work. Conflicts of interest and sources of funding: The authors gratefully acknowledge grant support from the VA Rehabilitation Research and Development Service (Merit Award I01RX002604), VA Clinical Science Research and Development Service (Merit Award I01CX001388), and National Institutes of Health (2R01AR062581, 1R01AR068987, and 1R21AR073496). The authors declare no conflicts of interest. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Correspondence to: Eric Y. Chang, MD, Radiology Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, MC 114, San Diego, CA 92161. E-mail: ericchangmd@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Imaging Features of Hepatocellular Carcinoma: Quantitative and Qualitative Comparison Between MRI-Enhanced With Gd-EOB-DTPA and Gd-DTPA Objectives The aim of this study was to compare the major imaging features of hepatocellular carcinoma (HCC) on magnetic resonance imaging (MRI) scans with Gd-EOB-DTPA (EOB) and extracellular agent (ECA; Gd-DTPA) contrast media. Materials and Methods Among 184 surgically proven HCCs in 169 patients who underwent a liver MRI with either EOB (n = 120) or ECA (n = 49), 55 HCCs were matched according to tumor size, Edmonson grade (major and worst), and gross type for each of the 2 contrast media. For the qualitative analysis, 2 board-certified radiologists independently reviewed arterial phase hyperenhancement, hypointensity on portal venous phase, hypointensity on delayed or transitional phase (DP/TP, 120–150 seconds), and capsule appearance. For the quantitative analysis, a third radiologist measured the signal intensity at each phase by placing the region of interest for tumor and normal liver parenchyma. The lesion-to-liver contrast (LLC) and lesion-to-liver contrast enhancement ratio (LLCER) were calculated. Results On qualitative analysis, hypointensity on DP/TP was seen more frequently with EOB (91% in reader 1, 89% in reader 2) than with ECA (73% in reader 1, 75% in reader 2; P = 0.026). Capsule appearance was seen less frequently with EOB (31% in reader 1, 44% in reader 2) than with ECA (73% in reader 1, 78% in reader 2; P < 0.001). On quantitative analysis, the LLC on arterial phase (AP) was better with ECA (P = 0.003), whereas LLC on DP was better with EOB (P < 0.001). The LLCER from precontrast to AP was higher with ECA (P = 0.022), whereas the LLCER from portal venous phase to DP was higher with EOB (P < 0.001). Conclusions ECA-MRI revealed better LLC on AP and detection rate of capsule appearance than EOB-MRI. EOB-MRI showed superior LLC on TP. Received for publication December 27, 2018; and accepted for publication, after revision, February 18, 2019. Jinwoo Son and Shin Hye Hwang contributed equally to this study. Conflicts of interest and sources of funding: none declared. Correspondence to: Mi-Suk Park, MD, PhD, Department of Radiology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonse-ro, Seodaemun-gu, Seoul 03722, South Korea. E-mail: radpms@yuhs.ac. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent Objectives This preclinical study was devised to investigate potential cellular toxicity in human neurons induced by gadolinium-based contrast agents (GBCAs) used for contrast-enhanced magnetic resonance imaging (MRI). Neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is 1 of 2 brain regions that displays the greatest T1-dependent signal hyperintensity changes. Methods Eight GBCAs were tested. Dopaminergic neurons modeling a subset of those in the basal ganglia were differentiated from an established human neuroblastoma cell line and exposed to increasing concentrations of each agent for 7 days. The tested dosages ranged from clinically relevant concentrations measured in some autopsy patients who had received repeated injections of contrast for MRI, to higher concentrations to reveal dose-dependent toxicity trends. Cell death, mitochondrial membrane potential, mitochondrial oxidative capacity, and mitochondrial function measured by oxygen consumption were quantified in cells treated with each GBCA or the osmolality control mannitol and compared to untreated cells which served as a negative control. Results Mannitol caused no change from negative controls in any of the tests, at any concentration tested. For all GBCAs, cell death increased with exposure dose, with toxicity at clinically relevant doses for agents with lower kinetic stability. Reduction of mitochondrial membrane potential and oxidative respiratory function also generally mirrored the agents' structural kinetic stabilities, with greater impairment at lower concentration for the less stable agents. Conclusions In human neurons modeling a subset of those in the basal ganglia, these results demonstrate a toxic effect of gadolinium-containing MRI contrast agents on mitochondrial respiratory function and cell viability. Toxicity increases as agent concentration increases and as the kinetic stability of the agent decreases. Received for publication January 8, 2019; and accepted for publication, after revision, March 1, 2019. Johannes T. Heverhagen and Val M. Runge share the senior authorship. Author contributions: D.V.B. and V.M.R. conceived of the overall project. D.V.B. conceived the experimental plans, designed the protocols, conducted the experiments, analyzed the data, and produced the final figures. J.K.R. validated reproducibility of quantifications as a second reader. D.V.B. wrote and revised the manuscript. H.v.T.K. and J.T.H. financed and oversaw the project. All authors discussed the results and approved the final manuscript. This work was performed in the laboratory for Experimental Radiology, Inselspital, University Hospital of Bern, located in the Department for BioMedical Research (DBMR), University of Bern. Imaging was conducted at the Live Cell Imaging Core Facility of the Microscopy Imaging Center at the University of Bern. The experiments measuring oxygen consumption and acidification were performed in the laboratory of Stefan Freigang in the Institute of Pathology at the University of Bern. This study was funded by the Department of Diagnostic, Interventional, and Pediatric Radiology, Inselspital, University Hospital of Bern, University of Bern, Bern, Switzerland. The authors declare no conflicts of interest. Correspondence to: Danielle V. Bower, MD, PhD, Department of Diagnostic, Interventional, and Pediatric Radiology, Inselspital, University Hospital of Bern, University of Bern, Freiburgstrasse 10, 3010 Bern, Switzerland. E-mail: danielle.bower@insel.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Computer-Aided Diagnosis of Pulmonary Fibrosis Using Deep Learning and CT Images Objectives The objective of this study is to assess the performance of a computer-aided diagnosis (CAD) system (INTACT system) for the automatic classification of high-resolution computed tomography images into 4 radiological diagnostic categories and to compare this with the performance of radiologists on the same task. Materials and Methods For the comparison, a total of 105 cases of pulmonary fibrosis were studied (54 cases of nonspecific interstitial pneumonia and 51 cases of usual interstitial pneumonia). All diagnoses were interstitial lung disease board consensus diagnoses (radiologically or histologically proven cases) and were retrospectively selected from our database. Two subspecialized chest radiologists made a consensual ground truth radiological diagnosis, according to the Fleischner Society recommendations. A comparison analysis was performed between the INTACT system and 2 other radiologists with different years of experience (readers 1 and 2). The INTACT system consists of a sequential pipeline in which first the anatomical structures of the lung are segmented, then the various types of pathological lung tissue are identified and characterized, and this information is then fed to a random forest classifier able to recommend a radiological diagnosis. Results Reader 1, reader 2, and INTACT achieved similar accuracy for classifying pulmonary fibrosis into the original 4 categories: 0.6, 0.54, and 0.56, respectively, with P > 0.45. The INTACT system achieved an F-score (harmonic mean for precision and recall) of 0.56, whereas the 2 readers, on average, achieved 0.57 (P = 0.991). For the pooled classification (2 groups, with and without the need for biopsy), reader 1, reader 2, and CAD had similar accuracies of 0.81, 0.70, and 0.81, respectively. The F-score was again similar for the CAD system and the radiologists. The CAD system and the average reader reached F-scores of 0.80 and 0.79 (P = 0.898). Conclusions We found that a computer-aided detection algorithm based on machine learning was able to classify idiopathic pulmonary fibrosis with similar accuracy to a human reader. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Received for publication February 15, 2019; and accepted for publication, after revision, March 19, 2019. Conflicts of interest and sources of funding: This study was funded by the Swiss National Science Foundation, Roche Pharma Ltd, and the Lindenhof Foundation. The authors declare no conflicts of interest. Correspondence to: Andreas Christe, MD, Department of Diagnostic, Interventional, and Pediatric Radiology, Inselspital, Bern University Hospital, Freiburgstrasse 10, 3010 Bern, Switzerland. E-mail: andreas.christe@insel.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Super-Resolution Contrast-Enhanced Ultrasound Methodology for the Identification of In Vivo Vascular Dynamics in 2D Objectives The aim of this study was to provide an ultrasound-based super-resolution methodology that can be implemented using clinical 2-dimensional ultrasound equipment and standard contrast-enhanced ultrasound modes. In addition, the aim is to achieve this for true-to-life patient imaging conditions, including realistic examination times of a few minutes and adequate image penetration depths that can be used to scan entire organs without sacrificing current super-resolution ultrasound imaging performance. Methods Standard contrast-enhanced ultrasound was used along with bolus or infusion injections of SonoVue (Bracco, Geneva, Switzerland) microbubble (MB) suspensions. An image analysis methodology, translated from light microscopy algorithms, was developed for use with ultrasound contrast imaging video data. New features that are tailored for ultrasound contrast image data were developed for MB detection and segmentation, so that the algorithm can deal with single and overlapping MBs. The method was tested initially on synthetic data, then with a simple microvessel phantom, and then with in vivo ultrasound contrast video loops from sheep ovaries. Tracks detailing the vascular structure and corresponding velocity map of the sheep ovary were reconstructed. Images acquired from light microscopy, optical projection tomography, and optical coherence tomography were compared with the vasculature network that was revealed in the ultrasound contrast data. The final method was applied to clinical prostate data as a proof of principle. Results Features of the ovary identified in optical modalities mentioned previously were also identified in the ultrasound super-resolution density maps. Follicular areas, follicle wall, vessel diameter, and tissue dimensions were very similar. An approximately 8.5-fold resolution gain was demonstrated in vessel width, as vessels of width down to 60 μm were detected and verified (λ = 514 μm). Best agreement was found between ultrasound measurements and optical coherence tomography with 10% difference in the measured vessel widths, whereas ex vivo microscopy measurements were significantly lower by 43% on average. The results were mostly achieved using video loops of under 2-minute duration that included respiratory motion. A feasibility study on a human prostate showed good agreement between density and velocity ultrasound maps with the histological evaluation of the location of a tumor. Conclusions The feasibility of a 2-dimensional contrast-enhanced ultrasound-based super-resolution method was demonstrated using in vitro, synthetic and in vivo animal data. The method reduces the examination times to a few minutes using state-of-the-art ultrasound equipment and can provide super-resolution maps for an entire prostate with similar resolution to that achieved in other studies. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received for publication December 18, 2018; and accepted for publication, after revision, February 20, 2019. Conflicts of interest and sources of funding: The authors would like to thank the following funding agencies: Science and Technology Facilities Council (ST/M007804/1), Medical Research Council UK (MRC/CIC3/027 and G0800896), British Heart Foundation (PG/10/021/28254), Engineering and Physical Sciences Research Council (EP/N015320/1), and BK Medical Ltd (Herlev, Denmark) for their support. Correspondence to: Vassilis Sboros, PhD, Institute of Biochemistry, Biological Physics, and Bio Engineering, Engineering and Physical Sciences, Heriot-Watt University, Riccarton, EH14 4AS United Kingdom. E-mail: V.Sboros@hw.ac.uk. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prophylaxis in High-Risk Patients With eGFR < 30 mL/min/1.73 m2: Get the Balance Right Objectives Clinical guidelines recommend prophylactic intravenous fluids for patients with estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 to prevent adverse postcontrast outcomes. These patients represent a small minority of the population receiving intravascular iodinated contrast material, and data are not readily available. The current study aim is to gain insight into positive and negative effects of prophylaxis by comparing postcontrast outcomes in high-risk patients who did and did not receive prophylaxis. Materials and Methods Observational data were gathered over 4 years. Inclusion criteria were age 18 years or older, eGFR less than 30 mL/min/1.73 m2, and elective intravascular iodinated contrast administration. Exclusion criteria were dialysis and nonstandard periprocedural prophylaxis. Primary outcome was postcontrast acute kidney injury (>25% or >44 μmol/L serum creatinine increase within 2–5 days). Secondary outcomes were change in eGFR, 5 mL/min/1.73 m2 or greater eGFR decline, dialysis, and mortality at 1 month postcontrast including primary cause, as well as complications of prophylaxis. Results were stratified by contrast procedure type and corrected for potential confounders. Results Of all 55,474 elective procedures with intravascular contrast administration, 362 patients met the inclusion criteria: 281 (78%) received standard 0.9% NaCl prophylaxis and 81 (22%) received no prophylaxis. Prophylaxis versus no prophylaxis adjusted odds ratios were nonsignificant and less than 1 for postcontrast renal outcomes (postcontrast acute kidney injury, eGFR decline, dialysis), indicating a trend toward a protective effect of prophylaxis. For mortality, adjusted odds ratios were nonsignificant and greater than 1, indicating a trend toward higher mortality risk after prophylaxis. Of the primary causes of death analyzed in prophylaxis patients, 24% (5/21) were related to prophylaxis. Among 281 prophylaxis patients, 18 (6.4%) complications of prophylaxis occurred: 15 heart failures and 3 arrhythmias. Conclusions Based on this study, no standard recommendation with regard to giving or withholding prophylaxis can be given. Prophylactic fluids may confer some protection against postcontrast renal adverse events but may also contribute toward increased risk of short-term death. In this setting, benefits and risks of prophylaxis must be carefully weighed and cardiac parameters assessed for each individual patient. Received for publication February 8, 2019; and accepted for publication, after revision, March 14, 2019. Conflicts of interest and sources of funding: The authors declare no conflicts of interest. The study was funded by Stichting de Weijerhorst. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Correspondence to: Estelle C. Nijssen, MSc, Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, the Netherlands. E-mail: estelle.nijssen@mumc.nl. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Increased Retention of Gadolinium in the Inflamed Brain After Repeated Administration of Gadopentetate Dimeglumine: A Proof-of-Concept Study in Mice Combining ICP-MS and Micro– and Nano–SR-XRF Objectives The aim of this study was to determine in vivo if brain inflammation leads to increased gadolinium (Gd) retention in brain tissue after repeated applications of Gd-based contrast agents (GBCAs). Materials and Methods Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice (n = 6). Experimental autoimmune encephalomyelitis and healthy control mice (n = 4) received 2.5 mmol/kg Gd-DTPA over 10 days (8 injections, cumulated dose of 20 mmol/kg), starting at day 14 post immunization when EAE mice reached the maximal clinical disability. In a group of mice, T1-weighted 2-dimensional RARE images were acquired before the first GBCA injection and 1 day after the last injection. Mice were killed either 1 day or 10 days after the last Gd application. From each single animal, a brain hemisphere was used for Gd detection using inductively coupled plasma mass spectrometry, whereas the other hemisphere was processed for histology and synchrotron x-ray fluorescence spectroscopy (SR-XRF) analysis. Results Gadolinium deposition in inflamed brains was mapped by SR-XRF 1 day after the last Gd-DTPA injections, although only mild signal hyperintensity was found on unenhanced T1-weighted images. In addition, using inductively coupled plasma mass spectrometry, we detected and quantified Gd in both healthy and EAE brains up to 10 days after the last injections. However, EAE mouse brains showed higher levels of Gd (mean ± SD, 5.3 ± 1.8 μg/g; range, 4.45–8.03 μg/g) with respect to healthy controls (mean ± SD, 2.4 ± 0.6 μg/g; range, 1.8–3.2 μg/g). By means of micro–SR-XRF, we identified submicrometric Gd hotspots in all investigated samples containing up to 5893 μg Gd/g tissue. Nano–SR-XRF further indicated that Gd small hotspots had an average size of ~160 nm diameter and were located in areas of high inflammatory activity. Conclusions After repeated administrations of Gd-DTPA, ongoing inflammation may facilitate the retention of Gd in the brain tissue. Thus, neuroinflammation should be considered as a risk factor in the recommendation on use of linear GBCA-enhanced MRI. Received for publication December 14, 2018; and accepted for publication, after revision, March 11, 2019. Shuangqing Wang and Bernhard Hesse contributed equally to this article. Conflicts of interest and sources of funding: There are no conflicts of interest to declare. This work was supported by the European Synchrotron Radiation Facility and the German Research Foundation (Deutsche Forschungsgemeinschaft; SFB1340-1/B05, IN156/4-1, and GRK2260 [BIOQIC]). Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Correspondence to: Carmen Infante-Duarte, PhD, Experimental Neuroimmunology, Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: carmen.infante@charite.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Preventive Effect of Changing Contrast Media in Patients With A Prior Mild Immediate Hypersensitivity Reaction to Gadolinium-Based Contrast Agent Objectives Currently, the prevention of recurrent immediate hypersensitivity reactions (HSRs) to contrast media (CM) requests premedication and changing the culprit contrast agent. However, strategies for the prevention of immediate HSRs to gadolinium-based magnetic resonance contrast agents (GBCAs) have not yet been established. This study aimed to evaluate the effectiveness of changing the contrast agent and single-dose premedication for HSR recurrence prevention in patients with a history of mild immediate HSR to GBCA. Materials and Methods The outcomes of patients with mild immediate HSR to GBCA who subsequently underwent enhanced magnetic resonance imaging between October 2012 and July 2017 were analyzed. The institutional CM monitoring system was retrospectively reviewed, and data on the application of premedication and choice of CM were obtained. Gadolinium-based magnetic resonance contrast agents were classified into 3 classes according to their molecular structure (macrocyclic ionic, macrocyclic nonionic, and linear ionic). Intravenous chlorpheniramine 4 mg, 30 minutes before the GBCA administration, or intravenous methylprednisolone sodium succinate 40 mg plus chlorpheniramine 4 mg, 1 hour before the GBCA administration, was administrated as premedication regimen. Recurrence rates of immediate HSR were compared according to prevention strategies. Results A total of 185 patients with a history of mild immediate HSR to GBCA were re-exposed to GBCA 397 times during the study period. The overall recurrence rate was 19.6% (78/397). Changing the culprit GBCA significantly reduced the recurrence rate, compared with reusing the culprit GBCA (6.9%, 9/130 and 25.8%, 69/267; P < 0.001). The recurrence rate was lowest when the GBCA was changed to a different molecular structure class from the culprit agent, followed by changing to CM with the same molecular structure and reusing the culprit GBCA (6.2%, 7/113 vs 11.8%, 2/17 vs 25.8%, 69/267; P < 0.001 with χ2 test for trend). Single-dose premedication demonstrated no significant prophylactic effect on recurrence (20.4%, 17/98 vs 17.3%, 61/299 with and without premedication, respectively; P = 0.509). Premedication in addition to changing CM also showed no additional prophylactic effect (7.2%, 7/97 and 6.1%, 2/33, respectively; P = 0.821). Conclusions Changing the CM from the culprit agent could reduce the chance of HSR recurrence in patients with prior mild immediate HSR to GBCA, especially when the CM was changed to one of a different molecular structure class. However, single-dose premedication administration did not show significant HSR recurrence rate difference. Received for publication January 29, 2019; and accepted for publication, after revision, March 20, 2019. The authors report no conflicts of interest. Correspondence to: Young Hun Choi, MD, Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, South Korea. E-mail: iater@snu.ac.kr. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Evaluation of Gadopiclenol and P846, 2 High-Relaxivity Macrocyclic Magnetic Resonance Contrast Agents Without Protein Binding, in a Rodent Model of Hepatic Metastases: Potential Solutions for Improved Enhancement at Ultrahigh Field Strength Purpose The aim of this study was to evaluate in vitro and in vivo the enhancement properties of experimental gadolinium (Gd)-based contrast agents (GBCAs) with different molecular weights and hydration numbers (P846 and gadopiclenol) compared with clinically approved low-molecular, extracellular agents (gadopentetate and gadoterate) at 9.4 T and to discuss influencing factors on r1 relaxivities. Methods and Materials All experiments were performed with a 9.4 T animal scanner (Bruker, Germany). We performed relaxometry measurements for all contrast agents in human plasma at 37°C using an IR-RARE sequence. In addition, we compared P846 with gadopentetate and gadopiclenol with gadoterate intraindividually in rats with hepatic colorectal cancer metastases (n = 10 each) acquiring T1-weighted FLASH sequences before and at 10 consecutive time points during 20 minutes. After intravenous contrast agent application, signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs), and lesion enhancement (LE) for liver parenchyma and tumors were calculated based on region of interest measurements. Results Longitudinal relaxivities (r1) of the low-molecular agents were lower as compared with the experimental compounds. However, r1 of gadopentetate and gadoterate demonstrated only a moderate decrease of r1 at 9.4 T as compared with known data at lower field strengths (gadopentetate: r1 [at 9.4 T], 3.4 mM−1 s−1/r1 [at 1.5 T], 4.1 mM−1 s−1/gadoterate: r1 [at 9.4 T], 3.1 mM−1 s−1/r1 [at 1.5 T], 3.6 mM−1 s−1). In contrast, r1 of P846 showed a marked reduction at 9.4 T compared with 1.5 T (P846: r1 [at 9.4 T], 6.4 mM−1 s−1/r1 [at 1.5 T], 32 mM−1 s−1). Gadopiclenol provided the highest r1 in this study at 9.4 T and the drop of r1 as compared with lower field strength is less apparent (gadopiclenol: r1 [at 9.4 T], 8.7 mM−1 s−1/r1 [at 1.5 T], 12.7 mM−1 s−1). In vivo, P846 and gadopiclenol showed significantly higher SNR, CNR, and LE as compared with the low-molecular control agents (mean ± SD; SNRliver [gadopentetate, 18.1 ± 1.2; P846, 27.2 ± 1.5; P < 0.001]; SNRtumor [gadopentetate, 22.6 ± 1.9; P846, 40.1 ± 1.9; P < 0.001]; CNR [gadopentetate, 4.6 ± 1.0; P846, 12.9 ± 0.9; P < 0.001]; LE [gadopentetate, 7.2 ± 1.9; P846, 14.9 ± 1.9; P < 0.001]/SNRliver [gadoterate, 8.8 ± 0.5; gadopiclenol, 12.6 ± 1.3; P < 0.001]; SNRtumor [gadoterate, 11.3 ± 1.2; gadopiclenol, 20.9 ± 2.9; P < 0.001]; CNR [gadoterate, 2.5 ± 0.7; gadopiclenol, 8.3 ± 1.7; P < 0.001]; LE [gadoterate, 4.4 ± 1.2; gadopiclenol, 13.0 ± 2.9; P < 0.001]). Thus, for equal Gd doses, gadopiclenol and P846 increase the CNR of liver metastases by a factor of 2.5 to 3 at 9.4 T compared with gadoterate and gadopentetate. Conclusions P846 and gadopiclenol provide superior enhancement at 9.4 T as compared with gadopentetate and gadoterate. However, the macromolecular agent P846 shows a marked decrease of r1 from 1.5 T to 9.4 T. This effect is less apparent for the low-molecular agents gadopiclenol, gadopentetate, and gadoterate. Yet, based on the higher hydration number, r1 of P846 and gadopiclenol are markedly higher as compared with the reference contrast agents. Thus, building compounds with moderately increased molecular size and hydration number, as implemented in gadopiclenol, seems to be a promising way to develop highly effective GBCAs. Advantages for gadopiclenol include a strong enhancement regardless of the external magnetic field strength, pharmacokinetics comparable to those of clinically approved extracellular GBCAs, and the potential to either improve sensitivity in diagnostic magnetic resonance imaging by improving lesion conspicuity or to perform studies with significantly reduced Gd-dose while at the same time providing comparable diagnostic accuracy. However, all this needs to be proven in clinical studies. Received for publication February 17, 2019; and accepted for publication, after revision, March 19, 2019. Conflicts of interest and sources of funding: This project was in part supported by research grant no. 0314101 from the BMBF (German Ministry of Education and Research). The authors report no conflicts of interest. Correspondence to: Peter Fries, MD, Clinic for Diagnosis and Interventional Radiology, Saarland University Medical Center, Bldg 50.1, Kirrberger Strasse 66421 Homburg, Germany. E-mail: drpeterfries@googlemail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.