Investigative Radiology

Advanced Diffusion-Weighted Abdominal Imaging: Qualitative and Quantitative Comparison of High and Ultra-High: b: -Values for Lesion Detection and Image Quality Introduction Magnetic resonance imaging (MRI) of the abdomen increasingly incorporates diffusion-weighted imaging (DWI) sequences. Whereas DWI can substantially aid in detecting and characterizing suspicious findings, it remains unclear to what extent the use of ultra-high b-value DWI might further be of aid for the radiologist especially when using DWI sequences with advanced processing. The target of this study was therefore to compare high and ultra-high b-value DWI in abdominal MRI examinations. Methods This institutional review board–approved, prospective study included abdominal MRI examinations of 70 oncologic patients (mean age, 58 years; range, 21-90 years) examined with a clinical 1.5 T MRI scanner (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany) with an advanced echo planar DWI sequence (b = 0, 50, 900, and 1500 s/mm2) after ex vivo phantom and in vivo volunteer investigations. High b900 and ultra-high b1500 DWIs were compared by a qualitative reading for image quality and lesion conspicuity using a 5-point Likert scale with 2 radiologists as readers. The ratios of apparent signal intensities of suspicious lesions/normal tissue of the same organ (LNTRs) were calculated. Appropriate methods were used for statistical analysis, including Wilcoxon signed-rank test and κ statistic for interreader agreement analysis (P < 0.05/0.0125/0.005 after Bonferroni correction). Results Image quality was significantly increased with b900 as compared with b1500 DWI (P < 0.001) despite using an advanced DWI sequence. A total of 153 suspicious lesions were analyzed. Overall reader confidence for characterization/detection of malignant lesions and, correspondingly, the LNTR (mean, 2.7 ± 1.8 vs 2.4 ± 1.6) were significantly higher with b900 than with b1500 DWI (P < 0.001 and P < 0.001). The increased confidence of lesion recognition and LNTR in the b900 DWI remained significant qualitatively in lymphatic and hepatic lesions and quantitatively in lymphatic, pulmonal, and osseous lesions. Conclusions Using high b-value DWI (900 s/mm2) provided an improved image quality and also lesion conspicuity as compared with ultra-high b-value DWI (1500 s/mm2) in oncologic abdominal examinations despite using advanced processing. Consequently, the value for additional ultra-high b-value DWI in oncologic examinations should be critically evaluated in future studies. Received for publication September 8, 2019; and accepted for publication, after revision, October 22, 2019. S. Bickelhaupt: speaker's fee from Siemens, (pending) patents in DWI. T.A. Kuder: cofounder of HQ Imaging GmbH, (pending) patents in DWI. F.B. Laun: cofounder of HQ Imaging GmbH. T. Benkert T and R. Strecker: employees of Siemens Healthcare. Conflicts of interest and sources of funding: none declared. Correspondence to: Constantin Dreher, MD, Department of Radiation Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor Kutzer-Ufer 1-3, 68167 Mannheim; and Division of Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. E-mail: constantin.dreher@umm.de. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Assessment of Low-Grade Focal Cartilage Lesions in the Knee With Sodium MRI at 7 T: Reproducibility and Short-Term, 6-Month Follow-up Data Objectives Several articles have investigated potential of sodium (23Na) magnetic resonance imaging (MRI) for the in vivo evaluation of cartilage health, but so far no study tested its feasibility for the evaluation of focal cartilage lesions of grade 1 or 2 as defined by the International Cartilage Repair Society. The aims of this study were to evaluate the ability of 23Na-MRI to differentiate between early focal lesions and normal-appearing cartilage, to evaluate within-subject reproducibility of 23Na-MRI, and to monitor longitudinal changes in participants with low-grade, focal chondral lesions. Materials and Methods Thirteen participants (mean age, 50.1 ± 10.9 years; 7 women, 6 men) with low-grade, focal cartilage lesions in the weight-bearing region of femoral cartilage were included in this prospective cohort study. Participants were assessed at baseline, 1 week, 3 months, and 6 months using morphological MRI at 3 T and 7 T, compositional 23Na-MRI at 7 T, and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. 23Na signal intensities corrected for coil sensitivity and partial volume effect (23Na-cSI) were calculated in the lesion, and in weight-bearing and non–weight-bearing regions of healthy femoral cartilage. Coefficients of variation, repeated measures analysis of covariance models, and Pearson correlation coefficients were calculated to evaluate within-subject reproducibility as well as cross-sectional and longitudinal changes in 23Na-cSI values. Results The mean coefficients of variation of 23Na-cSI values between the baseline and 1-week follow-up were 5.1% or less in all cartilage regions. Significantly lower 23Na-cSI values were observed in lesion than in weight-bearing and non–weight-bearing regions at all time points (all P values ≤ 0.002). Although a significant decrease from baseline 23Na-cSI values in lesion was found at 3-month visit (P = 0.015), no substantial change was observed at 6 months. KOOS scores have improved in all subscales at 3 months and 6 months visit, with a significant increase observed only in the quality of life subscale (P = 0.004). Conclusions In vivo 23Na-MRI is a robust and reproducible method that allows to differentiate between low-grade, focal cartilage lesions and normal-appearing articular cartilage, which supports the concept that compositional cartilage changes can be found early, before the development of advanced morphological changes visible at clinical 3-T MRI. Received for publication November 25, 2019; and accepted for publication, after revision, December 18, 2019. Conflicts of interest and sources of funding: This work was supported by the Novartis Pharma AG PJMR0062112, Austrian Science Fund (FWF) KLI541-B30, Jane and Aatos Erkko Foundation, and Slovak Grant Agency APVV-15-0029. Correspondence to: Štefan Zbýň, PhD, Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, 2021 6th St SE, Minneapolis, MN 55455. E-mail: szbyn@umn.edu. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Ultrasound Time-Harmonic Elastography of the Pancreas: Reference Values and Clinical Feasibility Objectives Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a very low 5-year survival rate of 8%. The aims of this study are to determine reference values and physiologic confounders in healthy pancreas and to assess the diagnostic accuracy of ultrasound time-harmonic elastography (THE) in the detection of PDAC. Materials and Methods From March 2017 through May 2019, a total of 54 study participants with healthy pancreas (n = 33, CTR) or PDAC (n = 21) were prospectively enrolled. Repeatability of THE was tested in a CTR subgroup (n = 5) undergoing repeat measurement on 4 different days. Interobserver variability was analyzed in 10 healthy volunteers. Age-matched and sex-matched subgroups of CTR (n = 13) and PDAC (n = 13) were compared. In participants with histopathologically proven PDAC, measurements were performed separately in tumorous (PDAC-T) and nontumorous pancreatic tissue (PDAC-NT). Diagnostic performance of pancreatic THE was assessed by receiver operating characteristic curve analysis. Results Time-harmonic elastography was highly repeatable (intraclass correlation coefficient, 0.99), and interobserver agreement was excellent (intraclass correlation coefficient, 0.97). Shear wave speed (SWS) of PDAC-T (mean [95% confidence interval] in meters per second, 1.88 ± 0.07 [1.84–1.92]) was higher than SWS of CTR (1.63 ± 0.04 [1.60–1.66], P < 0.001) and PDAC-NT (1.59 ± 0.03 [1.57–1.61], P < 0.001). The exploratory diagnostic performance of THE in separating PDAC-T was excellent (area under the receiver operating characteristic curve, 1.0). Tumorous pancreatic ductal adenocarcinoma was distinguished from CTR and PDAC-NT with cutoff values of 1.73 m/s and 1.70 m/s, respectively. Conclusions Pancreatic ultrasound THE has high repeatability and provides excellent imaging contrast based on SWS, allowing detection of PDAC without overlap to nontumorous pancreatic tissue. Received for publication August 18, 2019; and accepted for publication, after revision, October 15, 2019. Conflicts of interest and sources of funding: This study was supported by the German Federal Ministry of Education and Research (LiSyM 031 L0057 to I.S.) and the German Research Foundation (SFB 1340 to B.H., I.S. and J.B.; BIOQIC GRK 2260 to I.S.). Correspondence to: Stephan Rodrigo Marticorena Garcia, MD, Department of Radiology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany. E-mail: stephan.marticorena-garcia@charite.de. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

HLA-DRB1*15: 02 Is Associated With Iodinated Contrast Media–Related Anaphylaxis Background The incidence of severe reaction induced by iodinated contrast media (ICM) has increased over the years with an increasing use of imaging modalities. Although ICM anaphylaxis is rare, it can be life-threatening, but currently, there is no biomarker that can identify individuals at risk of ICM anaphylaxis. Objective The aim of this study is to investigate the genetic susceptibility of ICM anaphylaxis. Methods Patients who had ICM anaphylaxis were enrolled in the study, and their blood samples were collected for genotyping of human leukocyte antigen (HLA)-A, -B, -C, and -DR. The results were compared with those of healthy Korean general population. MRGPRX2 gene in ICM anaphylaxis group was also sequenced and compared with the Korean standard database of genetic polymorphism. Results The frequencies of 3 HLA alleles (B*52:01, C*12:02, and DRB1*15:02) were significantly higher in 47 patients with ICM anaphylaxis. In particular, HLA-DRB1*15:02 was 5 times more frequent in the ICM anaphylaxis group than the Korean general population (34.0% vs 6.6%; odds ratio, 7.306; 95% confidence interval, 3.622–14.740), and this difference was most pronounced in subjects with iohexol-induced anaphylaxis (odds ratio, 16.516; 95% CI, 5.241–52.047; P < 0.0001). Eight single nucleotide polymorphisms were identified in MRGPRX2 gene, but their frequencies were not different in those with ICM anaphylaxis compared with the general Korean population. Conclusions HLA-DRB1*15:02 is associated with ICM anaphylaxis in the Korean population. Received for publication September 10, 2019; and accepted for publication, after revision, November 6, 2019. Soo Jie Chung and Dong Yoon Kang contributed equally to this manuscript. This research was supported by a grant (17172MFDS158) from Ministry of Food and Drug Safety of Korea in 2017 and a grant from Ministry of Food and Drug Safety to the regional pharmacovigilance center in 2018. Conflicts of interest and sources of funding: none declared. 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: Hye-Ryun Kang, MD, PhD, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, South Korea. E-mail: helenmed@snu.ac.kr. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Signal Enhancement and Enhancement Kinetics of Gadobutrol, Gadoteridol, and Gadoterate Meglumine in Various Body Regions: A Comparative Animal Study Objectives The signal enhancement (SE) and enhancement kinetics of gadolinium-based contrast agents (GBCAs) in T1-weighted magnetic resonance (MR) images depend on the relaxivity of the GBCA and its pharmacokinetic profile. This in vivo study systematically compared the SE (technical efficacy) and the enhancement kinetics of the 3 macrocyclic GBCAs gadobutrol, gadoteridol, and gadoterate meglumine in various body regions. Materials and Methods A total of 15 healthy male white New Zealand rabbits were randomly divided into 3 groups (n = 5/group). The GBCAs were injected intravenously (0.1 mmol/kg body weight) and signal intensities from multiphase T1-weighted MR images (1.5 T; volumetric interpolated breath-hold examination (VIBE); repetition time/echo time/α: 4.74 milliseconds/2.38 milliseconds/10°) before and up to approximately 23 minutes after contrast injection were determined in the brain, tongue, submandibular gland, liver, spleen, prostate, muscle, and blood/aorta). Thirty minutes after injection, the animals were sacrificed and Gadolinium (Gd) concentrations were determined in the above-mentioned tissue samples by inductively coupled plasma optical emission spectrometry. Gadolinium tissue concentrations were correlated with the respective SE measurements in each tissue. Results The time course of SE, representing the pharmacokinetic profile of the GBCA, was similar for all 3 agents in all tissues. The magnitude of SE was, however, tissue dependent and consistently higher for gadobutrol (P < 0.05 in all tissues but brain). No significant difference in the magnitude of SE was found between gadoteridol and gadoterate meglumine. The inductively coupled plasma optical emission spectrometry analysis revealed no differences in Gd-tissue concentrations between the GBCAs. A linear correlation was observed between SE and the respective Gd concentrations for all 3 GBCAs. A significantly higher enhancement efficacy, that is, SE per Gd concentration, was observed for gadobutrol. Conclusions Gadobutrol-enhanced MR imaging showed greater SE compared with gadoteridol and gadoterate meglumine, whereas the SE kinetics were similar among the 3 GBCAs. For all 3 GBCAs, the SE was independent of the body region. Received for publication September 25, 2019; and accepted for publication, after revision, November 30, 2019. Conflicts of interest and sources of funding: G.K., T.F., H.P., and G.J., are employees of Bayer AG, Berlin, Germany. This study was initiated and funded by Bayer AG, Berlin, Germany. 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: Gesine Knobloch, MD, Radiology R&D (Medical and Clinical Affairs), Bayer AG, Muellerstr. 178, 13353 Berlin, Germany. E-mail: gesine.knobloch@bayer.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Impact of Software Parameter Settings on Image Quality of Virtual Grid Processed Radiography Images: A Contrast-Detail Phantom Study Objectives Mobile radiography systems are commonly used in the intensive care unit. The use of a physical antiscatter grid with these systems is uncommon because of drawbacks. In 2015, Virtual Grid (Fujifilm, Tokyo, Japan) became available for chest and abdomen examinations. In this study, we compared image quality (IQ) with a contrast-detail phantom (CDRAD 2.0; Artinis Medical Systems, Zetten, the Netherlands) of digital radiographs acquired without any grid (gridless) with those corrected for scatter by either software (SW)-based scatter correction (Virtual Grid) or a physical grid (grid). Furthermore, we determined the optimal Virtual Grid settings that lead to the best contrast-detail IQ score (inverse IQ figure). Materials and Methods Images were obtained with a cassette spot film device with an inserted portable flat-panel detector (Fujifilm, Tokyo, Japan). The CDRAD phantom was sandwiched between polymethylmethacrylate (PMMA) with total thicknesses of 12, 16, 21, and 26 cm to simulate patient attenuation and scatter. Tube voltages of 81, 90, 109, and 125 kVp were used to make the radiographs. In total, 12 different Virtual Grid settings (grid ratio, line pairs (lp)/cm, and type of interstitial material) were applied for every phantom thickness and tube voltage. Results An average increase of 32% in IQ was obtained when Virtual Grid images with a SW grid ratio 10:1 were compared with gridless images (P < 0.001). Increasing the SW grid ratio to 20:1 resulted in a further increased IQ. With a phantom thickness of 12 cm PMMA, Virtual Grid outperformed the removable physical grid presented in the cassette spot film device. The linear mixed-effects model showed that IQ is mainly affected by PMMA, tube voltage, and the SW grid ratio. Conclusions Virtual Grid improves images obtained without physical grid for a wide range of experimental conditions. Despite the different possible settings of the Virtual Grid SW, the most important parameter affecting IQ is the SW grid ratio. Received for publication September 16, 2019; and accepted for publication, after revision, December 2, 2019. Conflicts of interest and sources of funding: none declared. This research has benefitted from a statistical consult with Ghent University FIRE (Fostering Innovative Research based on Evidence). Correspondence to: Tim Gossye, MSc, Department of Human Structure and Repair, Ghent University, Proeftuinstraat 86, B-9000 Ghent, Belgium. E-mail: tim.gossye@ugent.be. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Quantitative Knee Arthrography in a Large Animal Model of Osteoarthritis Using Photon-Counting Detector CT Objective The aim of this study was to grade cartilage damage in a swine model of osteoarthritis using a whole-body photon-counting detector (PCD) CT. Materials and Methods A multienergy phantom containing gadolinium (Gd) (2, 4, 8, and 16 mg/mL) and hydroxyapatite (200 and 400 mg/cc) was scanned using a PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs, D50 reconstruction kernel) to serve as calibration for material decomposition and to assess quantification accuracy. Osteoarthritis was induced in Yucatan miniswine (n = 8) using 1.2 mg monoiodoacetate (MIA) injected into a randomized knee, whereas the contralateral control knee received saline. Twenty-one days later, a contrast bolus (gadoterate meglumine, 4 mL/knee) was intra-articularly administered into both knees. The knees were simultaneously scanned on the PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs). Multienergy images were reconstructed with a sharp “V71” kernel and a quantitative “D50” kernel. Image denoising was applied to the V71 images before grading cartilage damage, and an iterative material decomposition technique was applied to D50 images to generate the Gd maps. Two radiologists blinded to the knee injection status graded the cartilage integrity based on a modified International Cartilage Repair Society scoring system. Histology was performed on excised cartilage using methylene blue/basic fuchsin. Statistical analysis of grade distribution was performed using an exact test of omnibus symmetry with P < 0.05 considered significant. Results Material decomposed images from the multienergy phantom scan showed delineation and quantification of Gd and hydroxyapatite with a root-mean-squared error of 0.3 mg/mL and 18.4 mg/cc, respectively. In the animal cohort, the radiologists reported chondromalacia in the MIA knees with International Cartilage Repair Society scores ranging from grade 1 (cartilage heterogeneity, n = 4 knees) to grade 3 (up to 100% cartilage loss, n = 4 knees). Grade 1 was characterized by cartilage heterogeneity and increased joint space in the patellofemoral compartment, whereas grade 3 was characterized by cartilage erosion and bone-on-bone articulation in the patellofemoral compartment. All control knees were scored as grade 0 (normal cartilage). Significant difference (P = 0.004) was observed in the grade distribution between the MIA and control knees. Gross examination of the excised knees showed cartilage lesions in the grade 3 MIA knees. The Gd maps from material decomposition showed lower contrast levels in the joint space of the MIA knee compared with the contralateral control knee due to joint effusion. Histology revealed chondrocyte loss in the MIA knee cartilage confirming the chondrotoxic effects of MIA on cartilage matrix. Conclusions We demonstrated a high-resolution and quantitative PCD-CT arthrography technique for grading cartilage damage in a large animal model of osteoarthritis. Photon-counting detector CT offers simultaneous high-resolution and multienergy imaging capabilities that allowed morphological assessment of cartilage loss and quantification of contrast levels in the joint as a marker of joint disease. Cartilage damage in the MIA knees was graded using PCD-CT images, and the image-based findings were further confirmed using histology and gross examination of the excised knees. Received for publication October 22, 2019; and accepted for publication, after revision, November 27, 2019. Conflicts of interest and source of funding: This study was funded by the Imaging Biomarker Discovery Program, Mayo Clinic–Center for Individualized Medicine, and partially supported by the National Institutes of Health under award numbers R01 EB016966 and C06 RR018898. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The device described is a research scanner and not commercially available. Dr McCollough receives industry funding from Siemens Healthcare. For the remaining authors, none were declared. Correspondence to: Kishore Rajendran, PhD, Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: rajendran.kishore@mayo.edu. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Temperature-Sensitive Frozen-Tissue Imaging for Cryoablation Monitoring Using STIR-UTE MRI Purpose The aim of this study was to develop a method to delineate the lethally frozen-tissue region (temperature less than −40°C) arising from interventional cryoablation procedures using a short tau inversion-recovery ultrashort echo-time (STIR-UTE) magnetic resonance (MR) imaging sequence. This method could serve as an intraprocedural validation of the completion of tumor ablation, reducing the number of local recurrences after cryoablation procedures. Materials and Methods The method relies on the short T1 and T2* relaxation times of frozen soft tissue. Pointwise Encoding Time with Radial Acquisition, a 3-dimensional UTE sequence with TE = 70 microseconds, was optimized with STIR to null tissues with a T1 of approximately 271 milliseconds, the threshold T1. Because the T1 relaxation time of frozen tissue in the temperature range of −40°C < temperature < −8°C is shorter than the threshold T1 at the 3-tesla magnetic field, tissues in this range should appear hyperintense. The sequence was evaluated in ex vivo frozen tissue, where image intensity and actual tissue temperatures, measured by thermocouples, were correlated. Thereafter, the sequence was evaluated clinically in 12 MR-guided prostate cancer cryoablations, where MR-compatible cryoprobes were used to destroy cancerous tissue and preserve surrounding normal tissue. Results The ex vivo experiment using a bovine muscle demonstrated that STIR-UTE images showed regions approximately between −40°C and −8°C as hyperintense, with tissues at lower and higher temperatures appearing dark, making it possible to identify the region likely to be above the lethal temperature inside the frozen tissue. In the clinical cases, the STIR-UTE images showed a dark volume centered on the cryoprobe shaft, Vinner, where the temperature is likely below −40°C, surrounded by a doughnut-shaped hyperintense volume, where the temperature is likely between −40°C and −8°C. The hyperintense region was itself surrounded by a dark volume, where the temperature is likely above −8°C, permitting calculation of Vouter. The STIR-UTE frozen-tissue volumes, Vinner and Vouter, appeared significantly smaller than signal voids on turbo spin echo images (P < 1.0 × 10−6), which are currently used to quantify the frozen-tissue volume (“the iceball”). The ratios of the Vinner and Vouter volumes to the iceball were 0.92 ± 0.08 and 0.29 ± 0.07, respectively. In a single postablation follow-up case, a strong correlation was seen between Vinner and the necrotic volume. Conclusions Short tau inversion-recovery ultrashort echo-time MR imaging successfully delineated the area approximately between −40°C and −8°C isotherms in the frozen tissue, demonstrating its potential to monitor the lethal ablation volume during MR-guided cryoablation. Received for publication September 17, 2019; and accepted for publication, after revision, November 10, 2019. Conflicts of interest and sources of funding: The study was funded in part by the National Institutes of Health (P41EB015898, R01EB020667, R01CA235134). The content of the material is solely the responsibility of the authors and does not necessarily represent the official views of these agencies. The PETRA sequence was provided by Siemens Healthineers as a work-in-progress package. J.T. has received research funding from Siemens Healthineers for an unrelated study. Q.W. received a scholarship from the China Scholarship Council and a stipend from the Chinese PLA General Hospital. R.T.S. is an employee of Siemens Healthineers. J.T. received grant support through the institution provided by Siemens Healthineers for an unrelated study. K.T. received grant support through the institution provided by Canon USA for an unrelated study. J.T. and K.T.'s interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. Correspondence to: Junichi Tokuda, PhD, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, ASB-I, L1-050, Boston, MA 02115. E-mail: tokuda@bwh.harvard.edu. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Safety Analysis of Iobitridol as a Nonionic Contrast Medium: A Postmarketing Multicenter Surveillance Study With 94,960 Patients Almost 20 Years After Introduction Objectives Our study sought to reevaluate the safety and diagnostic efficacy of iobitridol as a nonionic contrast medium after almost 20 years of use. Materials and methods This noninterventional postmarketing surveillance noncontrolled, multicenter (168 centers in Germany) study enrolled 94,960 patients receiving intravenous or intra-arterial iobitridol. The majority of the adjusted population (n = 92,550, 98.2%) underwent either computed tomography examination (n = 46,502, 49.3%) or intravenous urography (n = 46,048, 48.8%). A standardized questionnaire was used to ascertain patient's information, known risk factors, renal function status, premedication, type of examination, injection of contrast agent, imaging quality, diagnostic value, and safety. Results A total of 469 patients (0.49%) experienced an adverse event (AE), and 24 patients (0.025%) reported a serious AE (SAE). All patients recovered and no fatal event occurred. The prevalence of AE was significantly higher in patients with at least one risk factor, with premedication, with a history of AE, in female and patients younger than 60 years old (P < 0.05). Presence of at least one risk factor is the only predictive factor for the prevalence of SAE (P = 0.042). In patients with a history of AE, premedication did not significantly lower the AE rate (P = 0.737). No statistically significant difference in the prevalence of AE between the different combination of cortisone and/or antihistamines as pretreatment was found. Conclusions Iobitridol is a safe contrast medium with a high tolerability and efficacy. Presence of risk factors such as cardiovascular diseases, allergies, or asthma was the only significant predictive factor for an AE and an SAE. Premedication did not significantly lower the occurrence of an AE and an SAE. Received for publication July 13, 2019; and accepted for publication, after revision, August 13, 2019. Conflicts of interest and sources of funding: B.G. received no personal payment, payment to the institution from Guerbet. O.H. is a Guerbet employee. M.W. is the owner of Michael Wolf Information Systems. F.C. received grants from Berlin Institute of Health, grants from German-Israeli Foundation for Scientific Research, grants from Boston Scientific, nonfinancial support from PharmaCept, nonfinancial support from C.R. Bard, nonfinancial support from Siemens Healthcare, nonfinancial support from Angiodynamics, personal fees from Guerbet, personal fees from PharmaCept, personal fees from Abbott, personal fees from Siemens Healthcare, personal fees from Bayer Healthcare, outside the submitted work. B.H. received grant money from the following companies or nonprofit organizations to the Department of Radiology: Abbott, AbbVie, Ablative Solutions, Accovion, Achaogen Inc, Actelion Pharmaceuticals, ADIR, Aesculap, AGO, Arbeitsgemeinschaft industrieller Forschungsvereinigungen, Arbeitsgemeinschaft Internistische Onkologie, Alexion Pharmaceuticals, Amgen, AO Foundation, Arena Pharmaceuticals, ARMO Biosciences, Inc, Art Photonics GmbG Berlin, ASR Advanced Sleep Research, Astellas, AstraZeneca, BARD, Bayer Healthcare, Bayer Schering Pharma, Bayer Vital, BBraun (Sponsoring a workshop), Berlin-Brandenburger Centrum für Regenerative Therapien, Berliner Krebsgesellschaft, Biotronik, Bioven, BMBF, Boehring Ingelheimer, Boston Biomedical Inc, BRACCO Group, Brainsgate, Bristol-Myers Squibb, Cascadian Therapeutics, Inc, Celgene, CELLACT Pharma, Celldex, Therapeutics, CeloNova BioSciences, Charité Research Organisatin GmbH, Chiltern, Clovis Oncology, Inc, Covance, CUBIST, CureVac AG, Tübingen, Curis, Daiichi, DC Devices, Inc USA, Delcath Systems, Dermira Inc, Deutsche Krebshilfe, Deutsche Rheuma Liga, DFG, DSM Nutritional Products AG, Dt. Stiftung für Herzforschung, Dynavax, Eisai Ltd, European Knowledge Centre, Mosquito Way, Hatfield, Eli Lilly and Company Ltd. EORTC, Epizyme, Inc, Essex Pharma, EU Programmes, Euroscreen S.A., Fibrex Medical Inc, Focused Ultrasound Surgery Foundation, Fraunhofer Gesellschaft, Galena Biopharma, Galmed Research and Development Ltd, Ganymed, GE, Genentech Inc, GETNE (Grupo Español de Tumores Neuroendocrinos y Endocrinos), Gilead Sciences, Inc, GlaxoSmithKline, Glycotope GmbH, Berlin, Goethe Uni Frankfurt, Guerbet, Guidant Europe NV, Halozyme, Hewlett Packard GmbH, Holaira Inc, ICON (CRO), Idera Pharmaceuticals, Inc, Ignyta, Inc, Immunomedics Inc, Immunocore, Incyte, INC Research, Innate Pharma, InSightec Ltd, InspireMD, inVentiv Health Clinical UK Ltd, inVentiv Health, iOMEDICO, Ionis, Ipsen Pharma, IQVIA, ISA Therapeutics, Isis Pharmaceuticals Inc, ITM Solucin GmbH, Jansen, Kantar Health Gmbh (CRO), Kartos Therapeutics, Inc, Karyopharm Therapeutics, Inc, Kendle/MorphoSys Ag, Kite Pharma, Klifo Berlin Mitte, La Roche, Land Berlin, Lilly GmbH, Lion Biotechnology, Lombard Medical, Loxo Oncology, Inc, LSK BioPartners, USA, Lundbeck GmbH, Lux Biosciences, LYSARC, MacroGenics, MagForce, MedImmune Inc, Medpace, Medpace Germany GmbH (CRO), MedPass (CRO), Medronic, Merck, Merromack Pharmaceuticals Inc, MeVis Medical Solutions AG, Millennium Pharmaceuticals Inc, Mologen, Monika Kutzner Stiftung, MSD Sharp, NeoVacs SA, Newlink Genentics Corporation, Nexus Oncology, NIH, Novartis, Novocure, Nuvisan, Ockham Oncology, OHIRC Kanada, Orion Corporation Orion Pharma, Parexel CRO Service, Perceptive, Pfizer GmbH, Pharma Mar, Pharmaceutical Research Associates GmbH (PRA), Pharmacyclics Inc, Philipps, PIQUR Therapeutics Ltd, Pluristem, PneumRX, Inc, Portola Pharmaceuticals, PPD (CRO), PRAint, Premier-Research, Provectus Biopharmaceuticals, Inc, PSI-CRO, PulmonX International Sàrl, Quintiles GmbH, Regeneron Pharmaceuticals, Inc, Respicardia, Roche, Samsung, Sanofi, Sanofis-Aventis S.A., Schumacher GmbH (sponsoring a workshop), Seattle Genetics, Servier (CRO), SGS Life Science Services (CRO), Shore Human Genetic Therapies, Siemens, Silena Therapeutics, Spectranetics GmbH, Spectrum Pharmaceuticals, St Jude Medical, Stiftung Wolfgang Schulze, Symphogen, Taiho Oncology, Inc, Taiho Pharmaceutical Co, TauRx Therapeutics Ltd, Terumo Medical Corporation, Tesaro, TETEC AG, TEVA, Theorem, Theradex, Threshold Pharmaceuticals Inc, TNS Healthcare GmbH, Toshiba, UCB Pharma, Uni München, VDI/VDE, Vertex Pharmaceuticals Incorporated, Winicker-Norimed, Wyeth Pharma, Xcovery Holding Company, Zukunftsfond Berlin (TSB). E.D.K. is a Guerbet employee. T.P. received payments to the institution from Guerbet. In addition, T.P. receives grant support from the Berlin Institute of Health within the Clinician Scientist Programme and received research support from Siemens Healthcare and Philips Healthcare (no personal payments). Outside of the current work, T.P. is involved in clinical trials with AGO, Aprea AB, Astellas Pharma Global Inc, AstraZeneca, Celgene, Genmab A/S, Incyte Coporation, Lion Biotechnologies, Inc, Millennium Pharmaceuticals, Inc, Morphotec Inc, MSD, Tesaro Inc, and Roche (no personal payments). Correspondence to: Tobias Penzkofer, MD, Department of Diagnostic and Interventional Radiology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: tobias.penzkofer@charite.de. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Deep-Learning Generated Synthetic Double Inversion Recovery Images Improve Multiple Sclerosis Lesion Detection Objectives The aim of the study was to implement a deep-learning tool to produce synthetic double inversion recovery (synthDIR) images and compare their diagnostic performance to conventional sequences in patients with multiple sclerosis (MS). Materials and Methods For this retrospective analysis, 100 MS patients (65 female, 37 [22–68] years) were randomly selected from a prospective observational cohort between 2014 and 2016. In a subset of 50 patients, an artificial neural network (DiamondGAN) was trained to generate a synthetic DIR (synthDIR) from standard acquisitions (T1, T2, and fluid-attenuated inversion recovery [FLAIR]). With the resulting network, synthDIR was generated for the remaining 50 subjects. These images as well as conventionally acquired DIR (trueDIR) and FLAIR images were assessed for MS lesions by 2 independent readers, blinded to the source of the DIR image. Lesion counts in the different modalities were compared using a Wilcoxon signed-rank test, and interrater analysis was performed. Contrast-to-noise ratios were compared for objective image quality. Results Utilization of synthDIR allowed to detect significantly more lesions compared with the use of FLAIR images (31.4 ± 20.7 vs 22.8 ± 12.7, P < 0.001). This improvement was mainly attributable to an improved depiction of juxtacortical lesions (12.3 ± 10.8 vs 7.2 ± 5.6, P < 0.001). Interrater reliability was excellent in FLAIR 0.92 (95% confidence interval [CI], 0.85–0.95), synthDIR 0.93 (95% CI, 0.87–0.96), and trueDIR 0.95 (95% CI, 0.85–0.98). Contrast-to-noise ratio in synthDIR exceeded that of FLAIR (22.0 ± 6.4 vs 16.7 ± 3.6, P = 0.009); no significant difference was seen in comparison to trueDIR (22.0 ± 6.4 vs 22.4 ± 7.9, P = 0.87). Conclusions Computationally generated DIR images improve lesion depiction compared with the use of standard modalities. This method demonstrates how artificial intelligence can help improving imaging in specific pathologies. Received for publication September 16, 2019; and accepted for publication, after revision, October 29, 2019. Conflicts of interest and sources of funding: none declared. T.F. and H.L. share first authorship. Correspondence to: Tom Finck, MD, Department of Diagnostic and Interventional Neuroradiology, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675 Munich, Germany. E-mail: tom.finck@tum.de. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.