Gadolinium Retention as a Safety Signal: Experience of a Manufacturer Objectives The purpose of this manuscript is to review the successive regulatory actions and decisions following the initial publication by Kanda and colleagues in 2014 regarding gadolinium retention in the human brain after multiple gadolinium-based contrast agents (GBCAs) administrations. Materials and Methods Starting from 2014, the actions and decisions made by all regulatory authorities were collected and summarized region by region. Volumes of GBCA sales in 2018 per region and main countries are also presented as an indicator of patients’ exposure to those products. Results All regulatory authorities agreed on the absence of evidence of any harmful effect of gadolinium retention in humans. However, based on the same amount of preclinical and clinical evidence available in adults and children, regulatory authorities used different approaches resulting in different actions and decisions regarding the labeling and market authorizations of GBCAs, as well as the specific actions requested to the manufacturers. Conclusions The manufacturers of GBCAs had to face different situations according to the countries, due to the different positions and expectations from regulatory agencies. They have adapted their responses to the different positions of the regulatory agencies and conducted specific preclinical and clinical investigations to provide the expected evidence. It is also their responsibility to continuously monitor the benefit-risk balance of the products and to propose risk minimization measures to the regulatory agencies. Received for publication June 18, 2019; and accepted for publication, after revision, July 8, 2019. Conflicts of interest and source of funding: E. Lancelot and P. Desché are employees of Guerbet. Correspondence to: Eric Lancelot, PharmD, PhD, Guerbet, BP57400, 95943 Roissy CDG Cedex, France. E-mail: eric.lancelot@guerbet.com. 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. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Using a Dual-Input Convolutional Neural Network for Automated Detection of Pediatric Supracondylar Fracture on Conventional Radiography Objectives This study aimed to develop a dual-input convolutional neural network (CNN)–based deep-learning algorithm that utilizes both anteroposterior (AP) and lateral elbow radiographs for the automated detection of pediatric supracondylar fracture in conventional radiography, and assess its feasibility and diagnostic performance. Materials and Methods To develop the deep-learning model, 1266 pairs of AP and lateral elbow radiographs examined between January 2013 and December 2017 at a single institution were split into a training set (1012 pairs, 79.9%) and a validation set (254 pairs, 20.1%). We performed external tests using 2 types of distinct datasets: one temporally and the other geographically separated from the model development. We used 258 pairs of radiographs examined in 2018 at the same institution as a temporal test set and 95 examined between January 2016 and December 2018 at another hospital as a geographic test set. Images underwent preprocessing, including cropping and histogram equalization, and were input into a dual-input neural network constructed by merging 2 ResNet models. An observer study was performed by radiologists on the geographic test set. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the model and human readers were calculated and compared. Results Our trained model showed an AUC of 0.976 in the validation set, 0.985 in the temporal test set, and 0.992 in the geographic test set. In AUC comparison, the model showed comparable results to the human readers in the geographic test set; the AUCs of human readers were in the range of 0.977 to 0.997 (P's > 0.05). The model had a sensitivity of 93.9%, a specificity of 92.2%, a PPV of 80.5%, and an NPV of 97.8% in the temporal test set, and a sensitivity of 100%, a specificity of 86.1%, a PPV of 69.7%, and an NPV of 100% in the geographic test set. Compared with the developed deep-learning model, all 3 human readers showed a significant difference (P's < 0.05) using the McNemar test, with lower specificity and PPV in the model. On the other hand, there was no significant difference (P's > 0.05) in sensitivity and NPV between all 3 human readers and the proposed model. Conclusions The proposed dual-input deep-learning model that interprets both AP and lateral elbow radiographs provided an accurate diagnosis of pediatric supracondylar fracture comparable to radiologists. Received for publication June 17, 2019; and accepted for publication, after revision, July 26, 2019. Conflicts of interest and sources of funding: none declared. This retrospective study was approved by the institutional review board, which waived the need for patient informed consent. Correspondence to: Yeon Jin Cho, MD, Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. E-mail: blue1010c@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Medication-Related Osteonecrosis of the Jaw—Comparison of Bone Imaging Using Ultrashort Echo-Time Magnetic Resonance Imaging and Cone-Beam Computed Tomography Objective The aim of this study was to compare bone imaging between ultrashort echo-time (UTE) magnetic resonance (MR) imaging and cone-beam computed tomography (CBCT) as the reference standard in patients with medication-related osteonecrosis of the jaw (MRONJ). Materials and Methods A 1-year retrospective, blinded, and randomized qualitative analysis of UTE MR images and CBCT from 19 patients with clinically diagnosed MRONJ was performed by 2 independent radiologists. Medication-related osteonecrosis of the jaw imaging hallmarks such as osteolysis, periosteal thickening, and medullary osteosclerosis were rated visually (0 and 1 to 3 for normal and mild to severe changes) for defined anatomic regions of the jaw. In addition, segmentation of these regions was performed on coregistered MR/CBCT images for the following quantitative comparison of signal intensity (SI) on MR and gray values (GVs) on CBCT images. Interreader/modality agreement (Cohen kappa), standard testing for significant differences of (non)parametric values, and Pearson correlation of signal intensity/GV were used for statistical analysis. Results The anterior corpus of the mandible was most often affected by MRONJ (P < 0.001). Overall, interreader agreement of qualitative MRONJ hallmark scores was almost perfect (κ = 0.81) and without significant differences between modalities (κ = 0.81 vs 0.82, CBCT vs MR, respectively). Intermodality agreement for qualitative gradings was substantial for both readers (κ = 0.77 and 0.70). Signal intensity/GV in MRONJ-affected areas differed significantly from healthy bone (P < 0.001) as well as correlation significantly between modalities (r = −0.77; P < 0.001). Conclusions Qualitative assessment of MRONJ with radiation-free UTE MR imaging is comparable to reference standard CBCT. Quantitative measurements of both modalities significantly distinguish diseased from normal bone with strong correlations among the quantitative values in both modalities. Received for publication June 14, 2019; and accepted for publication, after revision, August 9, 2019. 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: Florian A. Huber, MD, Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: florian.huber@usz.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cloverleaf Sign in Pelvic Magnetic Resonance Imaging for Deep Infiltrating Endometriosis: Association With Longer Operation Times, Greater Blood Loss, and Higher Rates of Bowel Resection Objectives The aim of this study was to evaluate the significance of a new imaging sign, the “cloverleaf sign,” in diagnosing deep infiltrating endometriosis (DIE) with magnetic resonance imaging (MRI) in concordance to intraoperative findings. Materials and Methods This retrospective study included 103 patients operated during the January 2016 to June 2018 period with preoperative 1.5 T and 3 T MRI, with or without vaginal and rectal gel filling. Magnetic resonance imaging scans were read blinded to intraoperative findings by a specialized gynecologic radiologist and a junior radiologist, and then compared with intraoperative findings by looking at the operation report, postoperative diagnosis, and intraoperative images and videos by an experienced gynecologist surgeon specialized in endometriosis surgery. All endometriosis lesions were confirmed by pathology. The “cloverleaf sign” was defined as a cloverleaf-like figure in imaging morphology; the “leaves” formed by at least 3 different organs come together in the center of the figure formed by constrictive adhesions including T2-weighted (T2W) hypointense DIE. Operation times, intraoperative blood loss, and the frequency of DIE and bowel resections were analyzed in cloverleaf and noncloverleaf groups. The 2-sample Wilcoxon rank-sum (Mann-Whitney U) test and multivariate analysis of variance were used to calculate the significance of an overall impact of cloverleaf sign on operation time, blood loss, and the amount of the bowel resection rate. P < 0.05 was considered statistically significant. Results The prevalence of DIE in the study population was 79.6%. A total of 11.5% of the patients had no endometriosis, 32.6% had rASRM I and II, and 55.9% had rASRM III and IV. Forty-six patients (45%) had received rectal and vaginal gel opacification before scanning, 57 (55%) did not. A cloverleaf sign on MRI was detected in 34 patients (15 in gel filling and 19 in nonfilling group). The interreader agreement was almost perfect 0.91 (κ). The median operation time in the cloverleaf group was 248 minutes (interquartile range [IQR], 165–330) compared with 145 minutes in the noncloverleaf group (IQR, 90–210), that is, significantly higher (P < 0.001). Intraoperative blood loss was also significantly higher in the conglomerate group (125 vs 50 mL; IQR, 100–300 vs 50–100; P < 0.001). Of the bowel resections in our study population, 41% (14/34) were performed on patients with a cloverleaf sign in the MRI, compared with 13% (9/69) in patients without the cloverleaf sign. Conclusions The “cloverleaf” MRI sign was associated with significantly longer operation time, increased intraoperative blood loss, and higher rates of bowel resection in DIE patients. Received for publication May 2, 2019; and accepted for publication, after revision, July 14, 2019. The Ethics Committee of Bern approved this study (BASEC No. KEK BE 2017-00952). Conflicts of interest and sources of funding: none declared. Correspondence to: Kirsi Härmä, MD, Department of Diagnostic, Interventional, and Pediatric Radiology, University Hospital of Bern, Inselspital, University of Bern, Bern, Switzerland, Freiburgstrasse 10, 3010 Bern-CH, Switzerland. E-mail: kirsihannele.haermae@insel.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Dedicated Spiral Breast Computed Tomography With a Single Photon-Counting Detector: Initial Results of the First 300 Women Objectives The aim of this study was to describe our initial clinical experiences using a dedicated spiral breast computed tomography (B-CT) with a single photon-counting detector. Materials and Methods This retrospective study was approved by the institutional review board. Examinations of 300 consecutive women undergoing B-CT were evaluated on reason of assignment for B-CT instead of mammography, detection rate of breast cancer, and quality criteria of data acquisition. Further evaluated performance indicators were the number of additional ultrasounds examinations due to unclear findings or dense breast tissue and reliability of the technical data acquisition. Results Five hundred ninety-one B-CT acquisitions in 300 women were performed. The main reason for preference of B-CT over mammography was the lack of breast compression (254 of 300, 84.7%), which was desired due to personal reasons or mastodynia, whereas 10 patients (0.3%) had implants hampering mammography. One hundred two possible lesions were detected in B-CT including 4 cases of breast cancer (1.3% of all patients). Additional ultrasound was performed in 226 patients (102 due to detected lesions and 124 due to dense breast tissue). Three malignant lesions were only detected in an additional ultrasound (1% of all patients). As a quality criterion, the pectoralis muscle was included in 341 of 591 examinations, but complete assessment of breast tissue was only possible in 149, respectively 140 examinations. No movement artifacts were noted. In 99% of all women, the examination could be realized. Conclusions The dedicated B-CT provides high-quality images. It can be used as alternative particularly in those patients not otherwise willing to perform mammography because of the breast compression. Received for publication April 30, 2019; and accepted for publication, after revision, July 14, 2019. Nicole Berger and Magda Marcon contributed equally and share the first co-author position. This work was supported by a “Filling the Gap” grant to N.Berger and a “PromedicaStiftung” grant to M. Marcon. The funding sources were not involved in the study design, collection, analysis and interpretation of data, manuscript writing, or in the decision to submit the manuscript for publication. Conflicts of interest and sources of funding: none declared. Correspondence to: Nicole Berger, MD, Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: nicole.berger@usz.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Recent and Upcoming Technological Developments in Computed Tomography: High Speed, Low Dose, Deep Learning, Multienergy The advent of computed tomography (CT) has revolutionized radiology, and this revolution is still going on. Starting as a pure head scanner, modern CT systems are now able to perform whole-body examinations within a couple of seconds in isotropic resolution, single-rotation whole-organ perfusion, and temporal resolution to fulfill the needs of cardiac CT. Because of the increasing number of CT examinations in all age groups and overall medical-driven radiation exposure, dose reduction remains a hot topic. Although fast gantry rotation, broad detector arrays, and different dual-energy solutions were main topics in the past years, new techniques such as photon counting detectors, powerful x-ray tubes for low-kV scanning, automated image preprocessing, and machine learning algorithms have moved into focus today. The aim of this article is to give an overview of the technical specifications of up-to-date available CT systems and recent hardware and software innovations for CT systems in the near future. Received for publication April 15, 2019; and accepted for publication, after revision, June 25, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Michael M. Lell, MD, Department of Radiology and Nuclear Medicine, Klinikum Nürnberg, Paracelsus Medical University, Prof.-Ernst-Nathan-Straße 1, 90419 Nuernberg, Germany. E-mail: michael.lell@klinikum-nuernberg.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Risk of Hypersensitivity Reactions to Iopromide After Intra-Arterial Versus Intravenous Administration: A Nested Case-Control Analysis of 133,331 Patients Objective The aim of this study was to compare the risk of hypersensitivity reactions to iopromide after intra-arterial (IA) administration and intravenous (IV) administration. Materials and Methods Four observational studies were pooled. Almost half of the study population (48.1%) was from Europe, and one quarter each from China (27.6%) and other Asia countries (24.1%). All patients received iopromide either intra-arterially or intravenously for angiographic procedures (mostly cardio-angiography) or contrast-enhanced computed tomography. A nested case-control analysis, including a multivariable logistic regression model, was performed. Cases were defined by patients with a typical and unequivocal hypersensitivity (assumed non–IgE-mediated) reaction; controls were patients without any recorded reaction. The primary target variable is the odds ratio of having a hypersensitivity reaction after IA versus IV administration. Results A total of 133,331 patients met the inclusion criteria, 105,460 and 27,871 patients received iopromide IV or IA, respectively. Hypersensitivity reactions were recorded for 822 patients, and 132,509 patients served as controls. Major risk factors for hypersensitivity reactions were method of injection (IV vs IA), age (18 to <50 years vs ≥65 years), history of allergy or previous contrast media reaction (all P < 0.001), and asthma (P = 0.005). A total of 766 patients (0.7%) and 56 patients (0.2%) were recorded with hypersensitivity reactions after IV or IA administration, respectively (P < 0.0001). Adjusted odds ratio (IA vs IV) was 0.23 (95% confidence interval, 0.16–0.32) for all countries together: for China only, 0.22 (0.11–0.44); for all countries without China, 0.36 (0.25–0.53). Most frequent reactions were erythema/urticaria/rash, pruritus, and cough/sneezing. Conclusions Hypersensitivity reactions to iopromide were significantly less frequently recorded after IA administrations. This could be related to the delayed and diluted arrival of iopromide to the lungs. Received for publication May 28, 2019; and accepted for publication, after revision, July 14, 2019. Conflicts of interest and sources of funding: J.E., A.M., P.L., and K.V. are employees of Bayer; R.K. is a statistician for PAREXEL and paid for his service. Correspondence to: Jan Endrikat, MD, PhD, Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. E-mail: jan.endrikat@bayer.com. 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. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Spectral Photon-Counting Computed Tomography for Coronary Stent Imaging: Evaluation of the Potential Clinical Impact for the Delineation of In-Stent Restenosis Objectives In-stent restenosis (ISR) is one of the main long-term complications after coronary stent placement, and the ability to evaluate ISR noninvasively using coronary computed tomography (CT) angiography remains challenging. For this application, spectral photon-counting CT (SPCCT) has the potential to increase image quality and reduce artifacts due to its advanced detector technology. Our study aimed to verify the technical and clinical potential of a novel SPCCT prototype using an ISR phantom setup. Materials and Methods Soft plaque-like restenosis (45 HU; approximately 50% of the stent lumen) were inserted into 10 different coronary stents (3 mm diameter), which were placed in a vessel phantom and filled with a contrast agent (400 HU). A research prototype SPCCT and a clinical dual-layer CT (DLCT; IQon; Philips) with comparable acquisition and reconstruction parameters were used to scan the phantoms. Conventional polyenergetic (PolyE) and monoenergetic (MonoE) images with 4 different energy levels (40, 60, 90, 120 keV) were reconstructed. Qualitative (delineation of the stenosis and adjacent residual lumen using a 5-point Likert scale) and quantitative (image noise, visible lumen diameter, lumen diameter adjacent to the stenosis, contrast-to-noise ratio of the restenosis) parameters were evaluated for both systems. Results The qualitative results averaged over all reconstructions were significantly superior for SPCCT compared with DLCT (eg, subjective rating of the best reconstruction of each scanner: DLCT PolyE: 2.80 ± 0.42 vs SPCCT MonoE 40 keV: 4.25 ± 1.03). Stenosis could be clearly detected in 9 and suspected in 10 of the 10 stents with both SPCCT and DLCT. The residual lumen next to the stenosis was clearly delineable in 7 of 10 stents (0.64 ± 0.11 mm or 34.97% of the measured stent lumen) with SPCCT, while it was not possible to delineate the residual lumen for all stents using DLCT. The measured diameter of the lumen within the stent was significantly higher for SPCCT compared with DLCT in all reconstructions with the best results for the MonoE 40 keV images (SPCCT: 1.80 ± 0.17 mm; DLCT: 1.50 ± 0.31 mm). The image noise and the contrast-to-noise ratio were better for DLCT than for SPCCT (contrast-to-noise ratio: DLCT MonoE 40: 31.58 ± 12.54; SPCCT MonoE 40: 4.64 ± 1.30). Conclusions Spectral photon-counting CT allowed for the noninvasive evaluation of ISR with reliable results regarding the residual lumen for most tested stents and the clear identification or suspicion of stenosis for all stents. In contrast, the residual lumen could not be detected for a single stent using DLCT. Received for publication April 30, 2019; and accepted for publication, after revision, July 14, 2019. Grischa Bratke and Tilman Hickethier contributed equally to this work. Conflicts of interest and sources of funding: G. Pahn, P. Coulon, and Y. Yagil are currently working for Philips. For the remaining authors, none were 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: Grischa Bratke, MD, Department of Radiology, University of Cologne, Kerpenerstr. 62, 50937 Cologne, Germany. E-mail: grischa.bratke@uk-koeln.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Dual-Energy Low-keV or Single-Energy Low-kV CT for Endoleak Detection?: A 6-Reader Study in an Aortic Aneurysm Phantom Objectives The aim of this study was to compare image quality, conspicuity, and endoleak detection between single-energy low-kV images (SEIs) and dual-energy low-keV virtual monoenergetic images (VMIs+) in computed tomography angiography of the aorta after endovascular repair. Materials and Methods An abdominal aortic aneurysm phantom simulating 36 endoleaks (2 densities; diameters: 2, 4, and 6 mm) in a medium- and large-sized patient was used. Each size was scanned using single-energy at 80 kVp (A) and 100 kVp (B), and dual-energy at 80/Sn150kVp for the medium (C) and 90/Sn150kVp for the large size (D). VMIs+ at 40 keV and 50 keV were reconstructed from protocols C and D. Radiation dose was 3 mGy for the medium and 6 mGy for the large size. Objective image quality and normalized noise power spectrum were determined. Subjective image quality, conspicuity, and sensitivity for endoleaks were independently assessed by 6 radiologists. Sensitivity was compared using Marascuilo procedure and Fisher exact test. Conspicuities were compared using Wilcoxon-matched pairs test, analysis of variance, and Tukey test. Results The contrast-to-noise-ratio of the aorta was significantly higher for VMI+ compared with SEI (P < 0.001). Noise power spectrum showed a higher noise magnitude and coarser texture in VMI+. Subjective image quality and overall conspicuity was lower for VMI+ compared with SEI (P < 0.05). Sensitivity for endoleaks was overall higher in the medium phantom for SEI (60.9% for A, 62.2% for B) compared with VMI+ (54.2% for C, 49.3% for D) with significant differences between protocols B and D (P < 0.05). In the large phantom, there was no significant difference in sensitivity among protocols (P = 0.79), with highest rates for protocols B (31.4%) and C (31.7%). Conclusions Our study indicates that low-keV VMI+ results in improved contrast-to-noise-ratio of the aorta, whereas noise properties, subjective image quality, conspicuity, and sensitivity for endoleaks were overall superior for SEI. Received for publication May 29, 2019; and accepted for publication, after revision, July 6, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Hatem Alkadhi, MD, MPH, EBCR, FESER, Institute for Diagnostic and Interventional Radiology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. E-mail: hatem.alkadhi@usz.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Gadolinium Retention in Erythrocytes and Leukocytes From Human and Murine Blood Upon Treatment With Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging Objectives Being administered intravenously, the tissue that gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging mostly encounter is blood. Herein, it has been investigated how much Gd is internalized by cellular blood components upon the in vitro incubation of GBCAs in human blood or upon intravenous administration of GBCAs to healthy mice. We report results that show how the superb sensitivity of inductively coupled plasma–mass spectrometry (ICP-MS) allows the detection of very tiny amounts of GBCAs entering red blood cells (RBCs) and white blood cells (WBCs). This finding may introduce new insights in the complex matter relative to excretion and retention pathway of administered GBCAs. Materials and Methods The study was tackled by 2 independent approaches. First, human blood was incubated in vitro with 5 mM of GBCAs (gadoteridol, gadobenate dimeglumine, gadodiamide, and gadopentetate dimeglumine) for variable times (30 minutes, 1 hour, 2 hours, and 3 hours) at 37°C. Then, blood cell components were isolated by using the Ficoll Histopaque method, washed 3 times, mineralized, and analyzed by ICP-MS for total Gd quantification. Furthermore, blood components derived from human blood incubated with gadodiamide or gadoteridol underwent UPLC-MS (ultra performance liquid chromatography–mass spectrometry) analysis for determination of the amount of intact Gd-DTPA-BMA and Gd-HPDO3A. Second, the distribution of Gd in the blood components of healthy CD-1 mice was administered intravenously with a single dose (1.2 mmol/kg) of gadodiamide or gadoteridol. Blood samples were separated and processed at different time points (24 hours, 48 hours, 96 hours, and 10 days after GBCA administration). As for human blood, ICP-MS quantification of total Gd and UPLC-MS determination of the amount of intact GBCAs were carried out. Results The amount of Gd taken up by RBCs and WBCs was well detectable by ICP-MS. The GBCAs seem to be able to cross the membrane by diffusion (RBCs) or, possibly, by macropinocytosis (WBCs). Ex vivo studies allowed it to be established that the structure of the different GBCAs were not relevant to determine the amount of Gd internalized in the cells. Although the amount of Gd steadily decreases over time in gadoteridol-labeled cells, in the case of gadodiamide, the amount of Gd in the cells does not decrease (even 10 days after the administration of the GBCA). Moreover, while gadoteridol maintains its structural integrity upon cellular uptake, in the case of gadodiamide, the amount of intact complex markedly decreases over time. Conclusions The detection of significant amounts of Gd in RBCs and WBCs indicates that GBCAs can cross blood cell membranes. This finding may play a role in our understanding of the processes that are at the basis of Gd retention in the tissues of patients who have received the administration of GBCAs. Received for publication June 4, 2019; and accepted for publication, after revision, July 9, 2019. Silvio Aime is the senior author of this study. Conflicts of interest and sources of funding: The study was supported by the “Progetto di Ateneo Compagnia di San Paolo” (CSTO160182), EuroBioimaging Italy CNR, and “Regional project Gadoplus (IR2) Industrializzazione dei Risultati della Ricerca (F.E.S.R. 2014/2020).” E.D.G. was supported by FIRC-AIRC (Fondazione Italiana per la Ricerca sul Cancro AIRC) fellowship. The other authors declare no conflict 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: Eliana Gianolio, PhD, Department of Molecular Biotechnologies and Health Sciences, University of Turin, Via Nizza 52, Turin, Italy. E-mail: eliana.gianolio@unito.it. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.