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Background: Cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is associated with an inflammatory response. Granzyme (GzmB) and IL-1β play a key role in the pathology. Meglumine antimoniate (MA) is the first-choice drug for the treatment of CL, but therapy failure is observed in up to 50% of the cases. The protein, rSm29 of Schistosoma mansoni, down-modulates pro-inflammatory cytokine production. We evaluate if the combination of topical rSm29 plus MA increases the cure rate of CL., Methods: In this randomized clinical trial, 91 CL patients were allocated in 3 groups. All cases received MA (20 mg/kg/weight) for 20 days. Group 1 used topical rSm29 (10 µg), group 2 a placebo topically applied, and group 3 received only MA., Results: The cure rate on day 90 was 71% in subjects treated with rSm29 plus MA, and 43% in patients who received MA plus placebo or MA alone (P < 0.05). There was a decrease in GzmB and an increase in IFN-γ (P < 0.05) in supernatants of skin biopsies of the lesions obtained on D7 of therapy (P < 0.05) in patients who received rSm29., Conclusion: rSm29 associated with MA reduces GzmB levels, is more effective than MA alone, and decreases CL healing time., Clinical Trials Registration: ClinicalTrial.gov under NCT06000514., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Unexpected accumulations of gadolinium in various organs were reported after the administration of gadolinium-based contrast agents, making desirable to reduce the dose while maintaining equivalent diagnostic performance. The aim of this study was to evaluate the contrast enhancement performance of high relaxivity gadopiclenol compared with gadoterate meglumine in abdominal contrast-enhanced magnetic resonance angiography (CE-MRA)., Materials and Methods: In a first study in healthy rabbits, axial 3D gradient echo sequences were applied at 4.7 T to study arterial enhancement as a function of gadopiclenol dose (0.025, 0.05, 0.075, and 0.1 mmol Gd/kg) or gadoterate meglumine at 0.1 mmol Gd/kg (n = 5-6/group). The increase in signal-to-noise ratio (ΔSNR) in the aorta at the first pass was measured and compared. In a second, crossover study in 6 healthy pigs, abdominal CE-MRA sequences were acquired at 3 T with gadopiclenol at 0.05 mmol Gd/kg or gadoterate meglumine at 0.1 mmol Gd/kg at a 1-week interval. Quantitatively on the maximum intensity projection (MIP) images, the mean MIP SNR within the aorta of both groups was compared. Qualitatively, a blinded comparison of the angiograms was performed by an experienced radiologist to determine the preferred contrast agent., Results: In the rabbit, ∆SNR is linearly correlated with the gadopiclenol dose ( P = 0.0010). Compared with gadoterate meglumine 0.1 mmol Gd/kg, an increase in the ∆SNR is observed after 0.05, 0.075, and 0.1 mmol Gd/kg of gadopiclenol (+63% P = 0.0731, +78% P = 0.0081, and +72% P = 0.0773, respectively), whereas at 0.025 mmol Gd/kg, ∆SNR is in the same range as with gadoterate meglumine 0.1 mmol Gd/kg (+15% P > 0.9999). In pigs, contrast enhancement after gadopiclenol at 0.05 mmol/kg is +22% superior to MIP SNR after gadoterate meglumine at 0.1 mmol Gd/kg ( P = 0.3095). Qualitatively, a preference was shown for gadopiclenol images (3/6) over the gadoterate meglumine examinations (1/6), with no preference being shown for the remainder (2/6)., Conclusions: First-pass CE-MRA is feasible with gadopiclenol at 0.05 mmol Gd/kg with at least the same arterial signal enhancement and image quality as gadoterate meglumine at 0.1 mmol Gd/kg., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

In the diagnosis of migraine, which is a neurovascular disease, gadolinium-based contrast agents (GBCAs) are used to rule out more serious conditions. On the other hand, it remains unclear as a scientific gap whether GBCAs may trigger migraine-related pain. The aim of this study was to investigate the effect of GBCAs on mechanical and thermal pain behaviour in a nitroglycerin (NTG)-induced migraine model in mice. NTG (10 mg/kg) was administered intraperitoneally to adult (6-8weeks old) BALB/c mice 2 h before behavioral tests 5 times every other day on days 1st, 3rd, 5th and 9th to induce migraine model (N = 50). As GBCAs, gadobenate dimeglumine (linear-ionic), Gadodiamide (linear-nonionic), and gadobutrol (macrocyclic-nonionic) were delivered intravenously through the tail vein of mice for 5 days on test days. Mechanical pain threshold (plantar and facial withdrawal threshold) was evaluated by plantar von Frey and periorbital von Frey tests on days 1st, 5th, and 9th, and thermal pain threshold (latency) was evaluated by hot plate and cold plate tests on days 3rd and 7th. There was a statistically significant increase in mechanical and thermal hyperalgesia in NTG administered groups compared to the control group. Gadodiamide, gadobutrol and gadobenate dimeglumine administration significantly decreased latency, paw and facial withdrawal threshold (0.18 ± 0.05, 0.17 ± 0.07, 0.16 ± 0.09; 9th day values respectively) compared to NTG group (0.27 ± 0.05). The results of this in vivo study show that GBCAs produce effects that may trigger migraine attacks in migraine. It is recommended that these effects be further investigated and supported by further clinical studies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Previous in vitro studies have described sub-linear longitudinal and heightened transverse H 2 O relaxivities of gadolinium-based contrast agents (GBCAs) in blood due to their extracellular nature. However, in vivo validation is lacking., Purpose: Validate theory describing blood behavior of R 1 and R 2 * in an animal model., Study Type: Prospective, animal., Animal Model: Seven swine (54-65 kg)., Field Strength/sequence: 1.5 T; time-resolved 3D spoiled gradient-recalled echo (SPGR) and quantitative Look-Locker and multi-echo fast field echo sequences., Assessment: Seven swine were each injected three times with 0.1 mmol/kg intravenous doses of one of three GBCAs: gadoteridol, gadobutrol, and gadobenate dimeglumine. Injections were randomized for rate (1, 2, and 3 mL/s) and order, during which time-resolved aortic 3D SPGR imaging was performed concurrently with aortic blood sampling via an indwelling catheter. Time-varying [GBCA] was measured by mass spectrometry of sampled blood. Predicted signal intensity (SI) was determined from a model incorporating sub-linear R 1 and R 2 * effects (whole-blood model) and simpler models incorporating linear R 1 , with and without R 2 * effects. Predicted SIs were compared to measured aortic SI., Statistical Tests: Linear correlation (coefficient of determination, R 2 ) and mean errors were compared across the SI prediction models., Results: There was an excellent correlation between predicted and measured SI across all injections and swine when accounting for the non-linear dependence of R 1 and high blood R 2 * (regression slopes 0.91-1.04, R 2  ≥ 0.91). Simplified models (linear R 1 with and without R 2 * effects) showed poorer correlation (slopes 0.67-0.85 and 0.54-0.64 respectively, both R 2  ≥ 0.89) and higher averaged mean absolute and mean square errors (128.4 and 177.4 vs. 42.0, respectively, and 5506 and 11,419 vs. 699, respectively)., Data Conclusion: Incorporating sub-linear R 1 and high first-pass R 2 * effects in arterial blood models allows accurate SPGR SI prediction in an in vivo animal model, and might be utilized when modeling MR blood SI., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 1., (© 2023 International Society for Magnetic Resonance in Medicine.)

Background: Despite an increased interest in visualizing the lymphatic vessels with magnetic resonance lymphangiography (MRL), little literature is available describing their appearance in nonlymphedematous individuals. To determine lymphatic abnormalities, an understanding of how healthy lymphatic vessels appear and behave needs to be established. Therefore, in this study, MRL of individuals without a history of lymphatic disease was performed., Methods: A total of 25 individuals (15 women) underwent MRL of their lower limbs using a 3.0 T Philips magnetic resonance imaging scanner (Philips Medical Systems). The first nine participants were recruited to establish the concentration of gadolinium-based contrast agent (GBCA) to administer, with the remainder imaged before and after interdigital forefoot GBCA injections at the optimized dose. Outcomes, including lymphatic vessel diameter, tortuosity, and frequency of drainage via particular drainage routes, were recorded., Results: Healthy lymphatic vessels following the anteromedial pathway were routinely observed in post-contrast T1-weighted images (average tortuosity, 1.09 ± 0.03), with an average of 2.16 ± 0.93 lymphatic vessels with a diameter of 2.47 ± 0.50 mm crossing the anterior ankle. In six limbs, vessels following the anterolateral pathways were observed. No vessels traversing the posterior of the legs were seen. In a subset of 10 vessels, the lymphatic signal, measured at the ankle, peaked 29 minutes, 50 seconds ± 9 minutes, 29 seconds after GBCA administration. No lymphatic vessels were observed in T2-weighted images., Conclusions: Contrast-enhanced MRL reliably depicts the lymphatic vessels in the legs of healthy controls. Following interdigital contrast injection, anteromedial drainage appears dominant. Quantitative measures related to lymphatic vessel size, tortuosity, and drainage rate are readily obtainable and could be beneficial for detecting even subtle lymphatic impairment., Competing Interests: Disclosures None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated., Methods: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond., Results: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%)., Limitations: Some questions were answered by a limited number of people, and their responses may not be representative., Conclusion: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections., (© 2024 British Veterinary Association.)

Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.

BACKGROUND. Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity: Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. RESULTS. The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5 ± 13.5 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings ( p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin ( p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.

Ethnopharmacological Relevance: Diterpene Ginkgolides Meglumine Injection (DGMI) is made of extracts from Ginkgo biloba L, including Ginkgolides A, B, and K and some other contents, and has been widely used as the treatment of cerebral ischemic stroke in clinic. It can be learned from the "Compendium of Materia Medica" that Ginkgo possesses the effect of "dispersing toxin". The ancient Chinese phrase "dispersing toxin" is now explained as elimination of inflammation and oxidative state in human body. And it led to the original ideas for today's anti-oxidation studies of Ginkgo in apoptosis induced by optic nerve crush injury., Aim of the Study: To investigate the underlying molecular mechanism of the DGMI in retinal ganglion cells (RGCs) apoptosis., Materials and Methods: TUNEL staining was used to observe the anti-apoptotic effects of DGMI on the adult rat optic nerve injury (ONC) model, and flow cytometry and hoechst 33,342 staining were used to observe the anti-apoptotic effects of DGMI on the oxygen glucose deprivation (OGD) induced RGC-5 cells injury model. The regulation of apoptosis and MAPKs pathways were investigated with Immunohistochemistry and Western blotting., Results: This study demonstrated that DGMI is able to decrease the conduction time of F-VEP and ameliorate histological features induced by optic nerve crush injury in rats. Immunohistochemistry and TUNEL staining results indicated that DGMI can also inhibit cell apoptosis via modulating MAPKs signaling pathways. In addition, treatment with DGMI markedly improved the morphological structures and decreased the apoptotic index in RGC-5 cells. Mechanistically, DGMI could significantly inhibit cell apoptosis by inhibiting p38, JNK and Erk1/2 activation., Conclusion: The study shows that DGMI and ginkgolides inhibit RGCs apoptosis by impeding the activation of MAPKs signaling pathways in vivo and in vitro. Therefore, the present study provided scientific evidence for the underlying mechanism of DGMI and ginkgolides on optic nerve crush injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe., Methods: Prospective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting., Results: 2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious., Conclusions: This European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

Background: Cardiovascular disease is the leading cause of death in patients with Duchenne muscular dystrophy (DMD)-a fatal X-linked genetic disorder. Late gadolinium enhancement (LGE) imaging is the current gold standard for detecting myocardial tissue remodeling, but it is often a late finding. Current research aims to investigate cardiovascular magnetic resonance (CMR) biomarkers, including native (pre-contrast) T 1 and extracellular volume (ECV) to evaluate the early on-set of microstructural remodeling and to grade disease severity. To date, native T 1 measurements in DMD have been reported predominantly at 1.5T. This study uses 3T CMR: (1) to characterize global and regional myocardial pre-contrast T 1 differences between healthy controls and LGE + and LGE- boys with DMD; and (2) to report global and regional myocardial post-contrast T 1 values and myocardial ECV estimates in boys with DMD, and (3) to identify left ventricular (LV) T 1 -mapping biomarkers capable of distinguishing between healthy controls and boys with DMD and detecting LGE status in DMD., Methods: Boys with DMD (N = 28, 13.2 ± 3.1 years) and healthy age-matched boys (N = 20, 13.4 ± 3.1 years) were prospectively enrolled and underwent a 3T CMR exam including standard functional imaging and T 1 mapping using a modified Look-Locker inversion recovery (MOLLI) sequence. Pre-contrast T 1 mapping was performed on all boys, but contrast was administered only to boys with DMD for post-contrast T 1 and ECV mapping. Global and segmental myocardial regions of interest were contoured on mid LV T 1 and ECV maps. ROI measurements were compared for pre-contrast myocardial T 1 between boys with DMD and healthy controls, and for post-contrast myocardial T 1 and ECV between LGE + and LGE- boys with DMD using a Wilcoxon rank-sum test. Results are reported as median and interquartile range (IQR). p-Values < 0.05 were considered significant. Receiver Operating Characteristic analysis was used to evaluate a binomial logistic classifier incorporating T 1 mapping and LV function parameters in the tasks of distinguishing between healthy controls and boys with DMD, and detecting LGE status in DMD. The area under the curve is reported., Results: Boys with DMD had significantly increased global native T 1 [1332 (60) ms vs. 1289 (56) ms; p = 0.004] and increased within-slice standard deviation (SD) [100 (57) ms vs. 74 (27) ms; p = 0.001] compared to healthy controls. LGE- boys with DMD also demonstrated significantly increased lateral wall native T 1 [1322 (68) ms vs. 1277 (58) ms; p = 0.001] compared to healthy controls. LGE + boys with DMD had decreased global myocardial post-contrast T 1 [565 (113) ms vs 635 (126) ms; p = 0.04] and increased global myocardial ECV [32 (8) % vs. 28 (4) %; p = 0.02] compared to LGE- boys. In all classification tasks, T 1 -mapping biomarkers outperformed a conventional biomarker, LV ejection fraction. ECV was the best performing biomarker in the task of predicting LGE status (AUC = 0.95)., Conclusions: Boys with DMD exhibit elevated native T 1 compared to healthy, sex- and age-matched controls, even in the absence of LGE. Post-contrast T 1 and ECV estimates from 3T CMR are also reported here for pediatric patients with DMD for the first time and can distinguish between LGE + from LGE- boys. In all classification tasks, T 1 -mapping biomarkers outperform a conventional biomarker, LVEF.

Background: Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) requires a hematocrit (Hct) to correct contrast volume distributions in blood. However, the timely assessment of Hct can be challenging and has limited the routine clinical application of ECV. The goal of the present study was to evaluate whether ECV measurements lead to significant error if a venous Hct was unavailable on the day of CMR., Methods: 109 patients with CMR T1 mapping and two venous Hcts (Hct 0 : a Hct from the day of CMR, and Hct 1 : a Hct from a different day) were retrospectively identified. A synthetic Hct (Hct syn ) derived from native blood T1 was also assessed. The study used two different ECV methods, (1) a conventional method in which ECV was estimated from native and postcontrast T1 maps using a region-based method, and (2) an inline method in which ECV was directly measured from inline ECV mapping. ECVs measured with Hct 0 , Hct 1 , and Hct syn were compared for each method, and the reference ECV (ECV 0 ) was defined using the Hct 0 . The error between synthetic (ECV syn ) and ECV 0 was analyzed for the two ECV methods., Results: ECV measured using Hct 1 and Hct syn were significantly correlated with ECV 0 for each method. No significant differences were observed between ECV 0 and ECV measured with Hct 1 (ECV 1 ; 28.4 ± 6.6% vs. 28.3 ± 6.1%, p = 0.789) and between ECV 0 and ECV calculated with Hct syn (ECV syn ; 28.4 ± 6.6% vs. 28.2 ± 6.2%, p = 0.45) using the conventional method. Similarly, ECV 0 was not significantly different from ECV 1 (28.5 ± 6.7% vs. 28.5 ± 6.2, p = 0.801) and ECV syn (28.5 ± 6.7% vs. 28.4 ± 6.0, p = 0.974) using inline method. ECV syn values revealed relatively large discrepancies in patients with lower Hcts compared with those with higher Hcts., Conclusions: Venous Hcts measured on a different day from that of the CMR examination can still be used to measure ECV. ECV syn can provide an alternative method to quantify ECV without needing a blood sample, but significant ECV errors occur in patients with severe anemia.

Purpose: To compare magnetic resonance imaging (MRI) findings with gadoxetic acid and gadobenate dimeglumine for the diagnosis of hepatic hemangiomas., Materials and Methods: In this retrospective study, we included 26 hemangiomas (mean size was 14 mm ± 10 mm) in 19 patients (mean age 60 ± 14 years) scanned with both gadobenate dimeglumine MRI and gadoxetic acid MRI. For each patient, we collected multiple lesion variables including location, number, size and enhancement pattern on arterial, portal venous, 3-minute and hepatobiliary phases with both gadoxetic acid and gadobenate dimeglumine. The enhancement pattern with the two contrast agents was then compared., Results: The typical enhancement pattern of hepatic hemangiomas was more common-though not statistically significant-with gadobenate dimeglumine compared to gadoxetic acid (57% [15 of 26] vs 42% [11 of 26], respectively; P = 0.4057 for both peripheral globular discontinuous enhancement in the arterial phase and centripetal fill-in in the portal venous phase). A significantly higher number of hemangiomas showed centripetal fill-in or hyperintensity in the 3-minute phase with gadobenate dimeglumine compared to gadoxetic acid (88% [23 of 26) vs 58% [15 of 26]; P = 0.0266). A pseudo washout sign in the 3-minute phase was detected in one of the 5 flash-filling hemangiomas with gadoxetic acid, but not gadobenate dimeglumine. All hemangiomas were hypointense in the hepatobiliary phase with both gadobenate dimeglumine and gadoxetic acid., Conclusions: The enhancement pattern of hepatic hemangiomas may vary depending on the hepatobiliary agent, with more frequent lack of the typical pattern with gadoxetic acid compared to gadobenate dimeglumine., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We investigated the feasibility of free-breathing modified Look-Locker inversion recovery (MOLLI) sequence for measuring hepatic T1 values in children and young adults. To investigate the accuracy and the reproducibility of the T1 maps, a phantom study was performed with 12 different gadoterate meglumine concentrations and the T1 relaxation times of phantoms measured with the MOLLI sequence were compared against those measured with three different sequences: spin-echo inversion recovery, variable flip angle (VFA), and VFA with B1 correction. To evaluate the feasibility of free-breathing MOLLI sequence, hepatic T1 relaxation times obtained by free-breathing and breath-hold technique in twenty patients were compared. The phantom study revealed the excellent accuracy and reproducibility of MOLLI. In twenty patients, the mean value of hepatic T1 values obtained by free-breathing (606.7 ± 64.5 ms) and breath-hold (609.8 ± 64.0 ms) techniques showed no significant difference (p > 0.05). The Bland-Altman plot between the free-breathing and breath-hold revealed that the mean difference of T1 values was - 3.0 ms (- 0.5%). Therefore, T1 relaxation times obtained by MOLLI were comparable to the values obtained using the standard inversion recovery method. The hepatic T1 relaxation times measured by MOLLI technique with free-breathing were comparable to those obtained with breath-hold in children and young adults.

Background: Subependymal giant cell astrocytomas (SEGAs) arise in 10-26% of tuberous sclerosis complex (TSC) patients. SEGAs cause obstructive hydrocephalus and increase morbi-mortality. It is recommended that TSC patients be followed with contrast enhanced magnetic resonance imaging (CE-MRI), but repetitive use of gadolinium-based contrast-agents (GBCAs) may cause organ deposits., Objective: To compare the diagnostic performances of non-CE- and CE-MRI to differentiate SEGAs from subependymal nodules in TSC patients during follow-up., Materials and Methods: Thirty-five TSC patients (median age: 2.4 years) were enrolled in this retrospective single-center study from September 2007 to January 2019. Inclusion criteria were a certain diagnosis of TSC and at least three follow-up brain MRIs with GBCA injection. Two consecutive MRI scans per patient were selected and anonymized. Three radiologists performed a blinded review of non-enhanced and enhanced MRI sequences during different sessions. The diagnostic performances were compared (sensitivity, specificity, positive/negative predictive values, accuracy, inter/intra-observer agreements)., Results: The accuracies for detecting SEGAs were good and similar between the non-enhanced and enhanced MRI sequences. The sensitivity and specificity of non-CE-MRI to diagnose SEGA ranged from 75% to 100% and from 94% to 100%, respectively. The differences in numbers of false-positive and false-negative patients between non-CE- and CE-MRI never exceeded one case. Nodules size >10 mm, location near the Monro foramen, hydrocephalus and modifications between two consecutive MRI scans were significantly associated with the diagnosis of SEGA for the three readers (all P-values <0.05). Inter- and intra-observer agreements were also excellent for non-enhanced and enhanced MRI sequences (kappa=0.85-1 and 0.81-0.93, respectively)., Conclusion: The performances of non-enhanced and enhanced MRI sequences are comparable for detecting SEGAs, questioning the need for systematic GBCA injections for TSC patients.

Background: Pulmonary vein isolation (PVI) is an effective treatment strategy for patients with atrial fibrillation (AF), but many experience AF recurrence and require repeat ablation procedures. The goal of this study was to develop and evaluate a methodology that combines machine learning (ML) and personalized computational modeling to predict, before PVI, which patients are most likely to experience AF recurrence after PVI., Methods: This single-center retrospective proof-of-concept study included 32 patients with documented paroxysmal AF who underwent PVI and had preprocedural late gadolinium enhanced magnetic resonance imaging. For each patient, a personalized computational model of the left atrium simulated AF induction via rapid pacing. Features were derived from pre-PVI late gadolinium enhanced magnetic resonance images and from results of simulations of AF induction. The most predictive features were used as input to a quadratic discriminant analysis ML classifier, which was trained, optimized, and evaluated with 10-fold nested cross-validation to predict the probability of AF recurrence post-PVI., Results: In our cohort, the ML classifier predicted probability of AF recurrence with an average validation sensitivity and specificity of 82% and 89%, respectively, and a validation area under the curve of 0.82. Dissecting the relative contributions of simulations of AF induction and raw images to the predictive capability of the ML classifier, we found that when only features from simulations of AF induction were used to train the ML classifier, its performance remained similar (validation area under the curve, 0.81). However, when only features extracted from raw images were used for training, the validation area under the curve significantly decreased (0.47)., Conclusions: ML and personalized computational modeling can be used together to accurately predict, using only pre-PVI late gadolinium enhanced magnetic resonance imaging scans as input, whether a patient is likely to experience AF recurrence following PVI, even when the patient cohort is small.

Background: Magnetic resonance imaging (MRI) examinations with intravenous (IV) contrast are performed worldwide in routine daily practice. In order to detect and enumerate even rare adverse events (AE) and serious adverse events (SAE), and to relate them with patients' baseline characteristics and diagnostic effectiveness, high quantity sample size is necessary., Purpose: To assess safety, diagnostic effectiveness, and baseline characteristics of patients undergoing IV gadoteric acid (Dotarem®) MRI in routine practice., Material and Methods: Data from two observational post-marketing surveillance (PMS) databases compiled by 139 and 52 German centers in 2004-2011 and 2011-2013, respectively, were pooled, yielding data on a total of 148,489 patients examined over a 10-year period. Radiologists used a standardized questionnaire to report data including patient demographics, characteristics of MR examinations, and results in terms of diagnosis and patient safety., Results: Overall, 712 AEs were reported in 467 (0.3%) patients, mainly nausea (n = 224, 0.2%), vomiting (n = 29, <0.1%), urticaria (n = 20, <0.1%), and feeling hot (n = 13, <0.1%). AEs were considered related to gadoteric acid in 362 (0.2%) patients. Higher frequencies of AEs were observed among patients with a previous reaction to a contrast agent (2.0%), liver dysfunction (0.7%), bronchial asthma (0.7%), and a history of allergies (0.6%). There were 49 SAEs in 18 (<0.1%) patients, including two children. No fatal SAE was reported. Examinations were diagnostic in 99.8% of all patients, and image quality was excellent or good in 97.7% of the patients., Conclusion: Gadoteric acid is a safe peri-examinational and effective contrast agent for MRI in routine practice.

Purpose: We aimed to assess the MRI findings and follow-up of multiple focal nodular hyperplasia (FNH)- like lesions in pediatric cancer patients diagnosed by imaging findings., Methods: We retrospectively analyzed clinical data and MRI examinations of 16 pediatric patients, who had been scanned using gadoxetate disodium (n=13) and gadobenate dimeglumine (n=3). Hepatic nodules were reviewed according to their number, size, contour, T1- and T2-weighted signal intensities, arterial, portal, delayed and hepatobiliary phase enhancement patterns. Follow-up images were evaluated for nodule size, number, and appearance., Results: All 16 patients received chemotherapy in due course. Time interval between the initial diagnosis of cancer and detection of the hepatic nodule was 2-14 years. Three patients had a single lesion, 13 patients had multiple nodules. The median size of the largest nodules was 19.5 mm (range, 8-41 mm). Among 16 patients that received hepatocyte-specific agents, FNH-like nodules appeared hyperintense in 11 and isointense in 5 on the hepatobiliary phase. During follow-up, increased number and size of the nodules were seen in 4 patients. The nodules showed growth between 6-15 mm., Conclusion: Liver MRI using hepatocyte-specific agents is a significant imaging method for the diagnosis of FNH-like lesions, which can occur in a variety of diseases. Lesions can increase in size and number in pediatric patients.

Background: Late gadolinium enhancement (LGE) is an important prognostic marker in hypertrophic cardiomyopathy and an extent >15% it is associated with high risk of sudden cardiac death. We proposed a novel method, the LGE-dispersion mapping, to assess heterogeneity of scar, and evaluated its prognostic role in patients with hypertrophic cardiomyopathy., Methods: One hundred eighty-three patients with hypertrophic cardiomyopathy and a low- or intermediate 5-year risk of sudden cardiac death underwent cardiac magnetic resonance imaging. A parametric map was generated from each LGE image. A score from 0 to 8 was assigned at every pixel of these maps, indicating the number of the surrounding pixels having different quality (nonenhancement, mild-enhancement, or hyperenhancement) from the central pixel. The Global Dispersion Score (GDS) was calculated as the average score of all the pixels of the images., Results: During a median follow-up time of 6 (25th-75th, 4-10) years, 22 patients had hard cardiac events (sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, resuscitated cardiac arrest, and sustained ventricular tachycardia). Kaplan-Meier analysis showed that patients with GDS>0.86 had worse prognosis than those with lower GDS ( P <0.0001). GDS>0.86 was the only independent predictor of cardiac events (hazard ratio, 9.9 [95% CI, 2.9-34.6], P =0.0003). When compared with LGE extent >15%, GDS improved the classification of risk in these patients (net reclassification improvement, 0.39 [95% CI, 0.11-0.72], P <0.019)., Conclusions: LGE-dispersion mapping is a marker of scar heterogeneity and provides a better risk stratification than LGE presence and its extent in patients with hypertrophic cardiomyopathy and a low-intermediate 5-year risk of sudden cardiac death.

Background: Position of gadolinium atom(s) plays a key role in contrast enhancement of gadolinium-based contrast agents. To gain a better understanding of effects of distance of gadolinium in relation to the nanoconjugate platform, we designed and synthesized single- and multi-arm ("star") gadolinium conjugates equipped with antibody and peptides for targeting. The contrast agents were studied for their tumor imaging performance in a glioma mouse model., Materials and Methods: Antibody- and peptide-targeted nano contrast agents (NCAs) were synthesized using polymalic acid platforms of different sizes. Gadolinium-DOTA and intermediates were attached as amides and targeting agents such as antibodies and peptides as thioethers. For in vivo experiments, we used human U87MG xenografts as glioma models. Magnetic resonance imaging (MRI) was performed on a Bruker BioSpec 94/20USR 9.4 T small-animal scanner. Delivery of contrast agents across the blood-brain barrier was studied by fluorescent microscopy., Results: All contrast agents accumulated into tumor and showed composition-dependent imaging performance. Peptide-targeted mini-NCAs had hydrodynamic diameters in the range 5.2-9.4 nm and antibody-targeted NCAs had diameters in the range 15.8-20.5 nm. Zeta potentials were in the range of -5.4--8.2 mV and -4.6--8.8 mV, respectively. NCAs showed superior relaxivities compared to MultiHance at 9.4 T. The signal enhancement indicated maximum accumulation in tumor 30-60 minutes after intravenous injection of the mouse tail vein. Only targeted NCAs were retained in tumor for up to 3 hours and displayed contrast enhancement., Conclusion: The novel targeted NCAs with star-PEG features displayed improved relaxivity and greater contrast compared with commercial MultiHance contrast agent. The enhancement by mini-NCAs showed clearance of tumor contrast after 3 hours providing a suitable time window for tumor diagnosis in clinics. The technology provides a great tool with the promise of differential MRI diagnosis of brain tumors., Competing Interests: KLB, JYL and EH are shareholders of Arrogene, Inc. Keith L Black reports grants from NIH, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2020 Patil et al.)

Background: Thromboembolic complications such as ischemic stroke or peripheral arterial thromboembolism are known complications in hypertrophic cardiomyopathy (HCM). We sought to assess the clinical and cardiovascular magnetic resonance (CMR) characteristics of patients with HCM suffering from thromboembolic events and analyzed the predictors of these unfavorable outcomes., Methods and results: The 115 HCM patients underwent late gadolinium enhanced (LGE) CMR and were included in the study. Follow-up was 5.6±3.6 years. The primary endpoint was the occurrence of thromboembolic events (ischemic stroke or peripheral arterial thromboembolism). It occurred in 17 (14.8%) patients (event group, EG), of whom 64.7% (11) were men. During follow-up, 10 (8.7%) patients died. Patients in the EG showed more comorbidities, such as heart failure (EG 41.2% vs. NEG (non-event group) 14.3%, P<0.01) and atrial fibrillation (AF: EG 70.6% vs. NEG 36.7%, P<0.01). Left atrial end-diastolic volume was significantly higher in the EG (EG 73±24 vs. NEG 50±33 mL/m 2 , P<0.01). Both the presence and extent of LGE were enhanced in the EG (extent% EG 23±15% vs. NEG 8±9%, P<0.0001). No patient without LGE experienced a thromboembolic event. Multivariate analysis revealed AF and LGE extent as independent predictors., Conclusions: LGE extent (>14.4%) is an independent predictor for thromboembolic complications in patients with HCM and might therefore be considered as an important risk marker. The risk for thromboembolic events is significantly elevated if accompanied by AF.

Lengthy exams and breath-holding limit the use of pediatric cardiac MRI (CMR). 3D time-resolved flow MRI (4DF) is a free-breathing, single-sequence exam that obtains magnitude (anatomic) and phase contrast (PC) data. We compare the accuracy of gadobenate dimeglumine-enhanced 4DF on a 1.5 T magnet to 2D CMR in children with repaired tetralogy of Fallot (rTOF) to measure pulmonary net flow (PNF) as a reflection of pulmonary regurgitation, forward flow (FF) and ventricular volumetry. Thirty-four consecutive cases were included. 2D PCs were obtained at the valve level. Using 4DF, we measured PNF at the valve and at the main and branch pulmonary arteries. PNF measured at the valve by 4DF demonstrated the strongest correlation (r = 0.87, p < 0.001) and lowest mean difference (3.5 ± 9.4 mL/beat) to aortic net flow (ANF). Semilunar FF and stroke volume of the respective ventricle demonstrated moderate-strong correlation by 4DF (r = 0.66-0.81, p < 0.001) and strong correlation by 2D (r = 0.81-0.84, p < 0.001) with similar correlations and mean differences between techniques (p > 0.05). Ventricular volumes correlated strongly between 2D and 4DF (r = 0.75-0.96, p < 0.001), though 4DF overestimated right ventricle volumes by 11.8-19.2 mL/beat. Inter-rater reliability was excellent for 2D and 4DF volumetry (ICC = 0.91-0.99). Ejection fraction moderately correlated (r = 0.60-0.75, p < 0.001) with better reliability by 4DF (ICC: 0.80-0.85) than 2D (ICC: 0.69-0.89). 4DF exams were shorter than 2D (9 vs. 71 min, p < 0.001). 4DF provides highly reproducible and accurate measurements of flow with slight overestimation of RV volumes compared to 2D in pediatric rTOF. 4DF offers important advantages in this population with long-term monitoring needs.

Purpose: The aim of this study was to investigate the presence and chemical forms of residual gadolinium (Gd) in rat brain after a single dose of Gd-based contrast agent., Methods: Four groups of healthy rats (2 sacrifice time-points, n = 10/group, 80 rats in total) were randomized to receive a single intravenous injection of 1 of the 3 Gd-based contrast agents (GBCAs) (gadoterate meglumine, gadobenate dimeglumine, or gadodiamide) or the same volume of 0.9% saline solution. The injected concentration was 0.6 mmol/kg, corresponding to a concentration of 0.1 mmol/kg in humans after body surface normalization between rats and humans (according to the US Food and Drug Administration recommendations). Animals were sacrificed at 2 washout times: 1 (M1) and 5 (M5) months after the injection. Total Gd concentrations were determined in cerebellum by inductively coupled plasma mass spectrometry. Gadolinium speciation was analyzed by size-exclusion chromatography coupled to inductively coupled plasma mass spectrometry after extraction from cerebellum., Results: A single injection of a clinically relevant dose of GBCA resulted in the detectable presence of Gd in the cerebellum 1 and 5 months after injection. The cerebellar total Gd concentrations after administration of the least stable GBCA (gadodiamide) were significantly higher at both time-points (M1: 0.280 ± 0.060 nmol/g; M5: 0.193 ± 0.023 nmol/g) than those observed for macrocyclic gadoterate (M1: 0.019 ± 0.004 nmol/g, M5: 0.004 ± 0.002 nmol/g; P < 0.0001). Gadolinium concentrations after injection of gadobenate were significantly lower at both time-points (M1: 0.093 ± 0.020 nmol/g; M5: 0.067 ± 0.013 nmol/g; P < 0.05) than the Gd concentration measured after injection of gadodiamide. At the 5-month time-point, the Gd concentration in the gadoterate group was also significantly lower than the Gd concentration in the gadobenate group (P < 0.05). Gadolinium speciation analysis of the water-soluble fraction showed that, after injection of the macrocyclic gadoterate, Gd was still detected only in its intact, chelated form 5 months after injection. In contrast, after a single dose of linear GBCAs (gadobenate and gadodiamide), 2 different forms were detected: intact GBCA and Gd bound to soluble macromolecules (above 80 kDa). Elimination of the intact GBCA form was also observed between the first and fifth month, whereas the amount of Gd present in the macromolecular fraction remained constant 5 months after injection., Conclusions: A single injection of a clinically relevant dose of GBCA is sufficient to investigate long-term Gd retention in the cerebellar parenchyma. Administration of linear GBCAs (gadodiamide and gadobenate) resulted in higher residual Gd concentrations than administration of the macrocyclic gadoterate. Speciation analysis of the water-soluble fraction of cerebellum confirmed washout of intact GBCA over time. The quantity of Gd bound to macromolecules, observed only with linear GBCAs, remained constant 5 months after injection and is likely to represent a permanent deposition.

Background: We investigated the utility of multiparametric magnetic resonance imaging (mpMRI) using Prostate Imaging Reporting and Data System, version 2 (PI-RADSv2), scoring in patients with prostate cancer eligible for active surveillance (AS)., Materials and Methods: The medical records of the patients who had undergone mpMRI before radical prostatectomy from 2014 to 2018 were reviewed. All the patients had met the Prostate Cancer Research International AS criteria. PI-RADSv2 scores were assigned to 12 prostate regions. Unfavorable disease was stratified using the American Joint Committee on Cancer (AJCC) prognostic scale as stage IIB (Gleason score [GS], 3+4 and pathologic stage T2) and IIC-III (GS, ≥ 4+3 or pathologic stage T3)., Results: Of 376 eligible patients, 184 (48.9%), 129 (34.3%), and 63 (16.8%) had AJCC stage I, IIB, and IIC-III disease, respectively. The patients with IIC-III disease were older and had a higher prostate-specific antigen density than those with stage I or IIB disease. PI-RADS 5 lesions were more frequent in patients with stage IIC-III than in patients with stage I or IIB disease. Multivariable analysis revealed that ≥ 2 lesions with a PI-RADS 5 score was an independent predictor for unfavorable disease (hazard ratio [HR], 3.612; P < .001 for IIB; HR, 6.562; P < .001 for IIC-III), and PI-RADS score of ≥ 4 was limited for predicting AJCC stage IIB disease (HR, 2.387; P = .01)., Conclusion: mpMRI with PI-RADSv2 showed high negative predictive value for patients with prostate cancer eligible for AS. Multiple PI-RADS 4-5 lesions were associated with unfavorable disease compared with solitary lesions. Multiple PI-RADS 5 lesions were strongly associated with GS ≥ 4+3 or pathologic T3 disease. Targeted biopsy or radical treatment should be considered for these patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Conflicting data have been reported on the association of left atrial (LA) late gadolinium enhancement (LGE) with atrial voltage in patients with atrial fibrillation. The association of LGE with electrogram fractionation and delay remains to be examined. We sought to examine the association between LA LGE on cardiac magnetic resonance and electrogram abnormalities in patients with atrial fibrillation., Methods: High-resolution LGE cardiac magnetic resonance was performed before electrogram mapping and ablation in atrial fibrillation patients. Cardiac magnetic resonance features were quantified using LA myocardial signal intensity Z score (SI-Z), a continuous normalized variable, as well as a dichotomous LGE variable based on previously validated methodology. Electrogram mapping was performed pre-ablation during sinus rhythm or LA pacing, and electrogram locations were coregistered with cardiac magnetic resonance images. Analyses were performed using multilevel patient-clustered mixed-effects regression models., Results: In the 40 patients with atrial fibrillation (age, 63.2±9.2 years; 1312.3±767.3 electrogram points per patient), lower bipolar voltage was associated with higher SI-Z in patients who had undergone previous ablation (coefficient, -0.049; P <0.001) but not in ablation-naive patients (coefficient, -0.004; P =0.7). LA electrogram activation delay was associated with SI-Z in patients with previous ablation (SI-Z: coefficient, 0.004; P <0.001 and LGE: coefficient, 0.04; P <0.001) but not in ablation-naive patients. In contrast, increased LA electrogram fractionation was associated with SI-Z (coefficient, 0.012; P =0.03) and LGE (coefficient, 0.035; P <0.001) only in ablation-naive patients., Conclusions: The association of LA LGE with voltage is modified by ablation. Importantly, in ablation-naive patients, atrial LGE is associated with electrogram fractionation even in the absence of voltage abnormalities.

Background: Myocardial recovery after primary percutaneous coronary intervention in acute myocardial infarction is variable and the extent and severity of injury are difficult to predict. We sought to investigate the role of cardiovascular magnetic resonance T1 mapping in the determination of myocardial injury very early after treatment of ST-segment elevation myocardial infarction (STEMI)., Methods: STEMI patients underwent 3 T cardiovascular magnetic resonance (CMR), within 3 h of primary percutaneous intervention (PPCI). T1 mapping determined the extent (area-at-risk as %left ventricle, AAR) and severity (average T1 values of AAR) of acute myocardial injury, and related these to late gadolinium enhancement (LGE), and microvascular obstruction (MVO). The characteristics of myocardial injury within 3 h was compared with changes at 24-h to predict final infarct size., Results: Forty patients were included in this study. Patients with average T1 values of AAR ≥1400 ms within 3 h of PPCI had larger LGE at 24-h (33% ±14 vs. 18% ±10, P = 0.003) and at 6-months (27% ±9 vs. 12% ±9; P < 0.001), higher incidence and larger extent of MVO (85% vs. 40%, P = 0.016) & [4.0 (0.5-9.5)% vs. 0 (0-3.0)%, P = 0.025]. The average T1 value was an independent predictor of acute LGE (β 0.61, 95%CI 0.13 to 1.09; P = 0.015), extent of MVO (β 0.22, 95%CI 0.03 to 0.41, P = 0.028) and final infarct size (β 0.63, 95%CI 0.21 to 1.05; P = 0.005). Receiver-operating-characteristic analysis showed that T1 value of AAR obtained within 3-h, but not at 24-h, predicted large infarct size (LGE > 9.5%) with 100% positive predictive value at the optimal cut-off of 1400 ms (area-under-the-curve, AUC 0.88, P = 0.006)., Conclusion: Hyper-acute T1 values of the AAR (within 3 h post PPCI, but not 24 h) predict a larger extent of MVO and infarct size at both 24 h and 6 months follow-up. Delayed CMR scanning for 24 h could not substitute the significant value of hyper-acute average T1 in determining infarct characteristics.

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.

Background Detection of cerebral lesions at MRI may benefit from a chemically stable and more sensitively detected gadolinium-based contrast agent (GBCA). Gadopiclenol, a macrocyclic GBCA with at least twofold higher relaxivity, is currently undergoing clinical trials in humans. Purpose To determine the relationship between MRI contrast enhancement and the injected dose of gadopiclenol in a glioma rat model compared with those of conventional GBCA at label dose. Materials and Methods Between April and July 2012, 32 rats implanted with C6 glioma received two intravenous injections at a 24-hour interval. The injections were randomly selected among five doses of gadopiclenol (0.025, 0.05, 0.075, 0.1, and 0.2 mmol/kg) and three reference GBCAs (gadoterate meglumine, gadobutrol, and gadobenate dimeglumine) at 0.1 mmol/kg. MRI tumor enhancement was assessed on T1-weighted images before and up to 30 minutes after injection. Two blinded radiologists visually and qualitatively scored contrast enhancement, border delineation, and visualization of tumor morphology. Quantitatively, variations in contrast-to-noise ratio (ΔCNR) between tumor and contralateral parenchyma were calculated at each time point and were compared for each treatment at 5 minutes by using a mixed model after normality test. Results A total of 24 rats underwent the complete protocol ( n = 5-7 per group). A linear dose-dependent ΔCNR relationship was observed between 0.025 and 0.1 mmol/kg for gadopiclenol ( R  2 = 0.99). No difference in ΔCNR was observed between the three reference GBCAs ( P ≥ .55). Gadopiclenol resulted in twofold higher ΔCNR at 0.1 mmol/kg ( P < .001 vs gadobutrol and gadoterate, P = .002 vs gadobenate) and similar ΔCNR at 0.05 mmol/kg ( P = .56, P > .99, and P = .44 compared with gadobutrol, gadobenate, and gadoterate, respectively). For both readers, 0.05 mmol/kg of gadopiclenol improved contrast enhancement, border delineation, and visualization of tumor morphology (scores > 3 compared with scores between 2 and 3 for the marketed GBCA). Conclusion Gadopiclenol at 0.05 mmol/kg yielded comparable change in contrast-to-noise ratio and morphologic characterization of brain tumors compared with gadobenate, gadoterate, or gadobutrol at 0.1 mmol/kg. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Objectives: This study aimed to assess the diagnostic use of native T1 to detect cardiac amyloidosis (CA) in a large prospective cohort of patients referred for suspected systemic amyloidosis., Background: CA is a progressive and fatal underdiagnosed cause of heart failure. Cardiovascular magnetic resonance (CMR) has emerged as an extremely useful test for the non-invasive diagnosis of CA, but administration of contrast is still required to make a diagnosis., Methods: In this study, 868 patients with suspected CA referred between 2015 and 2017 underwent CMR with late gadolinium enhancement (LGE), T1 mapping, and an array of clinical investigations., Results: The final diagnosis was cardiac light-chain (AL) amyloidosis in 222, cardiac transthyretin (ATTR) amyloidosis in 214, and no cardiac involvement in 427 cases. T1 was significantly elevated in both types of CA and this was associated with high diagnostic accuracy in the overall population (area under the curve, 0.93). A native T1 <1,036 ms was associated with 98% negative predictive value for CA whereas a native T1 >1,164 ms was associated with 98% positive predictive value for CA. We propose the use of these cut-offs to exclude or confirm CA and to restrict the administration of contrast only to patients with intermediate probability (native T1 between 1,036 and 1,164 ms), 58% of patients in this population., Conclusions: Native myocardial T1 enables diagnosis of CA to be made without need for gadolinium contrast in a large proportion of patients with suspected systemic amyloidosis. We propose a diagnostic algorithm for non-contrast CMR applicable to patients with suspected amyloidosis., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

Objective: To evaluate the effectiveness of preparing a wound for plastic closure of autoskin using a negative pressure apparatus and Reamberin., Material and Methods: . The results of preoperative preparation of 24 patients with chronic wounds of various etiologies were analyzed. Depending on the treatment regimen, the patients were divided into groups: the main one ( n =18), the patients of which were divided into subgroups: in IA ( n =9) they used NPWT therapy for 5 days, in IB ( n =9) it was combined with Reamberin infusions (1.5% intravenously at a rate of 40-60 drops/min, 500 ml, once a day for 5 days). Patients of the comparison group (II, n =6) received standard preparation. In the dynamics of therapy, a morpho-histological study of wound biopsies was carried out with the determination of the area of fibroblasts, the area of the nucleus of fibroblasts, the number of vessels and the determination of their diameter. After autodermoplasty, the survival of the skin flap was determined., Results: It was found that the combined use of NPWT therapy and Reamberin significantly increases the effectiveness of therapy: the greatest effect on fibroblastogenesis was exerted by the inclusion of NPWT therapy in the regimen - an increase of 1.5 times compared with the results of the traditional regimen. The vascularization of the wound surface (increase in the area and diameter of blood vessels) was best influenced by the combined preparation (NPWT-therapy and Reamberin) preparations - an increase of 3.4 times in comparison with the comparison group, which affected the dynamics of the survival of the skin flap: it was 1.3 times higher than in the comparison group ( p <0.01)., Conclusions: The results obtained, along with good tolerability of the drug, allows us to recommend the inclusion of Reamberin in the scheme of preoperative preparation of patients with this pathology.

Background: Gadolinium concentration variation during acquisition of contrast-enhanced MR angiography (CE-MRA) may lead to artifacts., Purpose: To compare signal intensity (SI) profiles of four different contrast agent injection strategies during CE-MRA with the goal of minimizing SI variation during acquisition., Study Type: Prospective., Subjects: Forty subjects randomized to receive one of four injection profiles of gadobenate dimeglumine (0.1 mmol/kg), either undiluted (0.5 M) or diluted to 40 ml total volume. Tested profiles: 1) nondiluted single-phase ("standard" NS; 1.6 ml/s), 2) diluted single-phase (DS; 1.6 ml/s), 3) diluted biphasic (DB; 9 ml @ 3.3 ml/s, 29 ml @ 1.4 ml/s), 4) patient-tailored protocol using linear prediction (DT)., Field Strength/sequence: Time-resolved SI measured at 3T with spoiled gradient echo sequences having analogous parameters to those of CE-MRA., Assessment: Plateau arrival time, rise time, duration, peak and tail SI, plateau quality (sum of squared residuals; SSR), average SI for each injection type derived were used., Statistical Test: Two-tailed t-test., Results: Peak SI, arrival, and rise times were not significantly different between groups, excepting peak SI DB slightly > DS (P = 0.042). Duration of NS vs. the diluted groups was significantly shorter (all P < 0.0001), and DS duration was significantly shorter than that of DT and DB (NS 11.4 ± 3.5 vs. DS 22.9 ± 4.3, DB 25.4 ± 2.3, DT 28.3 ± 4.1 sec). Quality (SSR) of the 20-second plateau was significantly better for DS, DB, DT as compared with NS (all P < 0.001)., Data Conclusion: Three different strategies to power-inject diluted gadobenate dimeglumine targeting a 20-second plateau produced SI profiles with longer duration, more consistent plateau, and no significant loss in peak SI. Such injection profiles may provide more uniform SI during CE-MRA, potentially reducing blurring artifacts., Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1808-1816., (© 2019 International Society for Magnetic Resonance in Medicine.)

Background Otherwise healthy women at high risk for breast cancer undergo annual contrast agent-enhanced breast MRI screening examinations, resulting in high cumulative doses of gadolinium-based contrast agents (GBCAs). Whereas the majority of studies showed no T1 signal ratio increase in deep brain nuclei after more than six doses of macrocyclic GBCA, this has not been explored in a healthy study population. Purpose To assess whether women who are administered large cumulative doses of macrocyclic GBCA with breast MRI at high-risk breast cancer screening exhibit T1 alterations in deep brain nuclei. Materials and Methods In this prospective study from November 2017 to March 2018, healthy women who were either exposed (because of high-risk breast cancer screening) or unexposed to only gadoterate meglumine underwent 3.0-T brain MRI with a dedicated head coil, including T1 mapping and magnetization-prepared rapid gradient-echo sequences. T1 times and T1 signal intensities were measured in the dentate nucleus (DN), globus pallidus (GP), crus anterior of capsula interna (CA), and pons. Ratios of DN to pons and GP to CA were calculated, and univariable Pearson correlation coefficients were calculated. Multivariable analysis included partial regression analysis. Results This study evaluated 25 women (mean age, 51 years ± 11 [standard deviation]) who were exposed to a mean GBCA dose of 129 mL (median 112 mL; range, 70-302 mL) and 16 women (mean age, 37 years ± 10) who were never exposed to any GBCA. Infratentorially, no correlation between cumulative GBCA dose and T1 times or signal intensity ratios was detected ( P = .66 and .55, respectively). In partial correlation analysis by considering age as a confounder, there was a moderate negative correlation between GP-to-CA ratio and GBCA dose ( r = -0.40; P = .01) but not for GP T1 times ( r = 0.19; P = .24). Conclusion After administration of relatively large cumulative doses of gadoterate dimeglumine, healthy women at high risk for breast cancer who underwent annual contrast-enhanced breast MRI screening did not exhibit T1 signal increase in deep brain nuclei at 3.0-T MRI. © RSNA, 2019.

Cardiac MR (CMR) is increasingly used to assess for cardiac involvement in patients with Duchenne muscular dystrophy (DMD). The frequent use of gadolinium based contrast agents (GBCAs) has been called into question with reports of intracranial gadolinium deposition in patients receiving multiple administrations. We adopted a conservative GBCA administration policy, limiting the frequency of GBCA exposure in patients with previously documented late gadolinium enhancement. The aim of our study was to evaluate the clinical effects of this policy change. Data were retrospectively reviewed on 405 consecutive patients with DMD who underwent CMR evaluation. Patients were grouped into conservative GBCA administration or historical control. CMR reports were evaluated and clinical reports were reviewed to determine actionable changes. Ohio Medicaid reimbursements were used to estimate costs. A total of 187 patients comprised the conservative GBCA group and 218 patients the historical cohort. The conservative GBCA group had lower contrast administration rates (84% vs. 99%, p < 0.0001), shorter scan times (35.2 vs. 39.0 min, p < 0.0001), and lower estimated medical costs ($339 vs. $351/study). There was no change regarding the initial presence of first-time late gadolinium enhancement, and no difference in actionable change. Contrast administration substantially decreased 7 months post-policy change (65%) compared to the initial 7 months (96%, p < 0.0001). In the current era with unclear concern for intracranial gadolinium deposition, thoughtful GBCA administration is warranted in patients anticipated to undergo multiple CMRs. Our updated approach has resulted in fewer patients receiving contrast, shorter scan times, and less medical costs, without appreciable changes to patient management.

Introduction: Excretion of cardiovascular magnetic resonance (CMR) extracellular gadolinium-based contrast agents (GBCA) into pleural and pericardial effusions, sometimes referred to as vicarious excretion, has been described as a rare occurrence using T1-weighted imaging. However, the T1 mapping characteristics as well as presence, magnitude and dynamics of contrast excretion into these effusions is not known., Aims: To investigate and compare the differences in T1 mapping characteristics and extracellular GBCA excretion dynamics in pleural and pericardial effusions., Methods: Clinically referred patients with a pericardial and/or pleural effusion underwent CMR T1 mapping at 1.5 T before, and at 3 (early) and at 27 (late) minutes after administration of an extracellular GBCA (0.2 mmol/kg, gadoteric acid). Analyzed effusion characteristics were native T1, ΔR1 early and late after contrast injection, and the effusion-volume-independent early-to-late contrast concentration ratio ΔR1early/ΔR1late, where ΔR1 = 1/T1post-contrast - 1/T1native., Results: Native T1 was lower in pericardial effusions (n = 69) than in pleural effusions (n = 54) (median [interquartile range], 2912 [2567-3152] vs 3148 [2692-3494] ms, p = 0.005). Pericardial and pleural effusions did not differ with regards to ΔR1early (0.05 [0.03-0.10] vs 0.07 [0.03-0.12] s - 1 , p = 0.38). Compared to pleural effusions, pericardial effusions had a higher ΔR1late (0.8 [0.6-1.2] vs 0.4 [0.2-0.6] s - 1 , p < 0.001) and ΔR1early/ΔR1late (0.19 [0.08-0.30] vs 0.12 [0.04-0.19], p < 0.001)., Conclusions: T1 mapping shows that extracellular GBCA is excreted into pericardial and pleural effusions. Consequently, the previously used term vicarious excretion is misleading. Compared to pleural effusions, pericardial effusions had both a lower native T1, consistent with lesser relative fluid content in relation to other components such as proteins, and more prominent early excretion dynamics, which could be related to inflammation. The clinical diagnostic utility of T1 mapping to determine quantitative contrast dynamics in pericardial and pleural effusions merits further investigation.

Background: Three-dimensional, black-blood, contrast-enhanced, T1-weighted magnetic resonance imaging (3D-BB-ceT1-MRI) could play a role in detection of thrombi and symptomatic intracranial atherosclerotic stenosis. We investigated the role of 3D-BB-ceT1-MRI in patients with acute ischemic stroke in the posterior circulation, and compared our findings with those from susceptibility-weighted imaging (SWI)., Materials and Methods: We retrospectively reviewed 3D-BB-ceT1-MRI for patients between January 2017 and August 2018 with acute ischemic symptoms in the posterior circulation. During this period, 199 patients with acute infarction in the posterior circulation were enrolled. Time-of-flight-magnetic resonance angiography or cerebral angiography was used as the reference standard., Results: Of these 199 patients, 47 had vessel occlusion associated with acute infarction. The sensitivity of 3D-BB-ceT1-MRI for detection of vessel occlusion was significantly higher than that of SWI (95.7% versus 53.2%, P < .001). Twenty-one lesions with strong enhancement on 3D-BB-ceT1-MRI showed a negative susceptibility vessel sign (SVS) on SWI., Conclusions: 3D-BB-ceT1-MRI showed strong enhancement (due to contrast stagnation) in the intra-arterial thrombi of patients with acute infarction in the posterior circulation. 3D-BB-ceT1-MRI had higher sensitivity than that of an SVS on SWI for detection of intra-arterial thrombi., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background Gadoxetate disodium has been associated with various respiratory irregularities at arterial imaging MRI. Purpose To measure the relationship between gadolinium-based contrast agent administration and irregularities by comparing gadoxetate disodium and gadoterate meglumine at free breathing. Materials and Methods This prospective observational cohort study (January 2015 to May 2017) included consecutive abdominal MRI performed with either gadoxetate disodium or gadoterate meglumine enhancement. Participants underwent dynamic imaging by using the golden-angle radial sparse parallel sequence at free breathing. The quantitative assessment evaluated the aortic contrast enhancement, the respiratory hepatic translation, and the k-space-derived respiratory pattern. Analyses of variance compared hemodynamic metrics, respiratory-induced hepatic motion, and respiratory parameters before and after respiratory gating. Results A total of 497 abdominal MRI examinations were included. Of these, 338 participants were administered gadoxetate disodium (mean age, 59 years ± 15; 153 women) and 159 participants were administered gadoterate meglumine (mean age, 59 years ± 17; 85 women). The arterial bolus of gadoxetate disodium arrived later than gadoterate meglumine (19.7 vs 16.3 seconds, respectively; P < .001). Evaluation of the hepatic respiratory translation showed respiratory motion occurring in 70.7% (239 of 338) of participants who underwent gadoxetate-enhanced examinations and in 28.9% (46 of 159) of participants who underwent gadoterate-enhanced examinations ( P < .001). The duration of motion irregularities was longer for gadoxetate than for gadoterate (19.2 seconds vs 17.2 seconds, respectively) and the motion irregularities were more severe ( P < .001). Both the respiratory frequency and amplitude were shorter for participants administered gadoxetate from the prebolus phase to the late arterial phase compared with gadoterate ( P < .001). Conclusion The administration of two different gadolinium-based contrast agents, gadoxetate and gadoterate, at free-breathing conditions potentially leads to respiratory irregularities with differing intensity and onset. © RSNA, 2019 Online supplemental material is available for this article.

Background: Magnetic resonance arthrography (MRA) requires intra-articular injection of gadolinium-based diluted paramagnetic contrast material. To our knowledge, gadobenate dimeglumine (Gd-BOPTA) has never been used for intra-articular applications. Our aim was to test in vitro different concentrations of Gd-BOPTA to be potentially used to perform MRA., Methods: Gd-BOPTA was diluted in saline (NaCl 0.9%) to achieve different concentrations (4 mmol/l; 2 mmol/l; 1 mmol/l; 0.67 mmol/l; 0.5 mmol/l). Six sets of five sterile pipes were prepared with 5 ml of each solution, five sets added with 0.5 ml of fresh synovial fluid. Two separate pipes were prepared with 5 ml of gadopentetate dimeglumine (Gd-DTPA) at 2 mmol/l, one pipe added with 0.5 ml of synovial fluid. Pipes were imaged using a T1-weighted sequence at 1.5 T. For each pipe, signal intensity (SI) in arbitrary units (au) was measured., Results: SI reproducibility range was 86-99%. Mean Gd-BOPTA SI in pipes containing synovial fluid increased from 1236 ± 8au (0.5 mmol/l) up to 1610 ± 44au (1 mmol/l) and down to 1405 ± 33au (4 mmol/l). Mean Gd-BOPTA SI in pipes without synovial fluid increased from 1184 ± 29au (0.5 mmol/l) up to 1530 ± 38au (1 mmol/l), and down to 1347 ± 39au (4 mmol/l). SI of pipes without synovial fluid was lower than that of pipes with synovial fluid for both Gd-BOPTA and Gd-DTPA (P ≤ 0.002). Regarding pipes with synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1246 ± 27au. Compared with Gd-BOPTA, SI was not different at 0.5 mmol/l (- 0.2%, P = 0.587) while it was higher (P < 0.001) at all other concentrations (range + 13.3%[4 mmol/l] - + 28.3%[1 mmol/l]). Regarding pipes without synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1275 ± 56au. Compared with Gd-BOPTA, SI was lower at 0.5 mmol/l (- 6.8%,P < 0.001), while it was higher (P < 0.001) at all other concentrations (range + 6.1%[4 mmol/l] - + 19.6% [1 mmol/l])., Conclusions: In vitro, Gd-BOPTA at 1 mmol/ had a + 28% SI increase in comparison to Gd-DTPA 2 mmol/l. SI similar to Gd-DTPA can be obtained using one fourth concentration of Gd-BOPTA.

Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) sequences have evolved. Free-breathing motion-corrected (MOCO) LGE has potential advantages over breath-held (bh) LGE including minimal user input for the short axis (SAX) stack without breath-holds. It has previously been shown that MOCO-LGE delivers high image quality compared to bh-LGE. We sought to conduct an independent validation study to investigate real-world performance of bh-LGE versus MOCO-LGE in a high-throughput CMR center immediately after the introduction of the MOCO-LGE sequence and with elementary staff induction in its use. Four-hundred consecutive patients, referred for CMR and graded by clinical complexity, underwent CMR on either of two scanners (1.5 T, both Siemens) in a UK tertiary cardiac center. Scar imaging was by bh-LGE or MOCO-LGE (both with phase sensitive inversion recovery). Image quality, scan time, reader confidence and report reproducibility were compared between those scanned by bh-LGE versus MOCO-LGE. Readers had > 3 years CMR experience. Categorical variables were compared by χ 2 or Fisher's exact tests and continuous variables by unpaired Student's t-test. Inter-rater agreement of LGE reports was by Cohen's kappa. Image quality (low score = better) was better for MOCO-LGE (median, interquartile range [Q1-Q3]: 0 [0-0] vs. 2 [0-3], P < 0.0001). This persisted when just clinically complex patients were assessed (0 [0-1] vs. 2 [1-4] P < 0.0001). Readers were more confident in their MOCO-LGE rulings (P < 0.001) and reports more reproducible [bh-LGE vs. MOCO-LGE: kappa 0.76, confidence interval (CI) 0.7-0.9 vs. 0.82, CI 0.7-0.9]. MOCO-LGE significantly shortened LGE acquisition times compared to bh-LGE (for left ventricle SAX stack: 03:22 ± 01:14 vs 06:09 ± 01:47 min respectively, P < 0.0001). In a busy clinical service, immediately after its introduction and with elementary staff training, MOCO-LGE is demonstrably faster to bh-LGE, providing better images that are easier to interpret, even in the sickest of patients.

Rationale and Objectives: Previous studies on possible accumulation of gadolinium-based contrast agents (GBCA) in the brain suggest that macrocyclic GBCA are less likely to accumulate than linear GBCA. However, conflicting results have been reported, especially in MS. The aim of this study is to investigate retrospectively the correlation between gadoterate-meglumine (macrocyclic GBCA) use and T1 signal intensity changes (SI) in the dentate nucleus and the GP on unenhanced T1-weighted images in a large cohort of MS patients., Materials and Methods: Unenhanced T1-weighted images of 232 MS patients who previously received multiple intravenous administrations of 0.1 mmol/kg of gadoterate-meglumine were reviewed. The change in T1 SI ratios of dentate nucleus/central pons (DN/CP) and globus pallidus/centrum semiovale (GP/CSO) was calculated between the first and last MRIs and correlated with age, number of injections, time interval between MRIs, disease duration, activity, and therapy., Results: DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p < 0.0001) between the first and last MRIs. Multivariable analyses of both ratios, controlling for age, disease duration, and time interval between MRIs, showed no significant correlation between the number of gadolinium injections and the differences in DN/CP (standardized beta = -0.018, p = 0.811) or GP/CSO SI ratios (standardized beta = -0.049, p = 0.499)., Conclusion: Repeated administration of gadoterate-meglumine in MS patients did not result in increased T1 SI in the DN or the GP. The significant decrease of GP/CSO ratio between the first and last MRIs is not due to gadolinium accumulation but rather to varying MR parameters., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background Acute allergic-like and physiologic reactions occur following administration of gadolinium-based contrast agents (GBCAs) for MRI examinations. Because these reactions are uncommon, it is challenging to compare reaction rates between GBCAs and to determine risk factors. Purpose To compare reaction rates between the four GBCAs gadodiamide, gadobutrol, gadobenate dimeglumine, and gadoterate meglumine, and to determine potential risk factors for reactions. Materials and Methods This retrospective study identified all intravenous GBCA injections for MRI examinations performed at a single institution from June 1, 2009, to May 9, 2017. Reactions were identified by reviewing records from the MRI technologist, MRI nursing staff, radiologist, emergency department, and provider. Reactions were classified as allergic-like or physiologic and as mild, moderate, or severe by using American College of Radiology criteria. GBCA reaction rates and other potential risk factors were examined by using multivariable regression models with generalized estimating equations. Results Analysis included a total of 158 100 patients (median age, 55 years [interquartile range, 40-67 years], 51% women) who received a total of 281 945 GBCA injections (140 645 gadodiamide, 94 109 gadobutrol, 39 138 gadobenate, and 8053 gadoterate). At multivariate analysis, gadobenate or gadobutrol had higher rates of allergic-like reactions compared with gadodiamide (gadobenate: odds ratio [OR], 3.9 [95% confidence interval {CI}: 3.0, 5.1]; P < .001; gadobutrol: OR, 2.3 [95% CI: 1.8, 2.9]; P < .001) or gadoterate (gadobenate: OR, 4.8 [95% CI: 1.0, 23]; P = .049; gadobutrol: OR, 2.8 [95% CI: 0.6, 14]; P = .20). Physiologic reactions were more frequently observed with gadoterate (OR, 7.7 [95% CI: 2.3, 25; P = .001), gadobenate (OR, 1.8 [95% CI: 1.3, 2.5; P < .001), and gadobutrol (OR, 1.6 [95% CI: 1.3, 2.1; P < .001) administration compared with gadodiamide. Six severe allergic-like reactions (three gadobutrol, three gadobenate) occurred requiring hospitalization. Patient age ( P values .025 to < .001), sex ( P < .001), location ( P = .006), and MRI type ( P = .003 and P = .006) were associated with acute reactions. Conclusion Gadobenate and gadobutrol are associated with higher rates of allergic-like reactions compared with gadodiamide or gadoterate, and gadoterate, gadobenate, and gadobutrol are associated with higher rates of physiologic reactions compared with gadodiamide. Patient sex, age, location, and MRI type correlate with acute reaction rates. © RSNA, 2019 Online supplemental material is available for this article.

Objectives: Current findings on gadolinium deposition in the pediatric brain due to repeated exposure to macrocyclic contrast agents are inconclusive and possibly confounded by brain maturation processes. We evaluated the longitudinal effects of repeated gadoterate meglumine exposure (Dotarem; Guerbet, Villepinte, France) on the T1- and T2-weighted signal intensity (SI) in pediatric patients, and assessed the magnitude of age-related increase in T1-weighted (and decrease in T2-weighted) SI in a control cohort without prior gadolinium exposure., Materials and Methods: In this retrospective, double-cohort study, magnetic resonance imaging (MRI) data of 24 patients (0.7-16.4 years, M = 5.74, SD = 4.15) who received at least 10 doses of exclusively gadoterate meglumine were included in the longitudinal study. The MRI data of 190 controls (age range, 1-20 years; 10 patients/bin; bin width, 1 year) without any prior gadolinium-based contrast exposure were included in the control, cross-sectional study to assess the age-dependent SI changes in the regions of interest (ROIs). We measured SI (native), T1-weighted gradient echo, and T2-weighted fast spin-echo of 12 deep brain nuclei. The ROIs were measured at each of the first 11 MRI examinations of the contrast-exposed patients and in the control subject's MRI. Regions of interest's SIs, normalized by the pons, were analyzed with mixed effects models, accounting for the potential confounding factors, such as radiotherapy and chemotherapy., Results: The number of gadoterate meglumine administrations had no effect on the SI increase in any of the ROIs (all P > 0.05), but age significantly correlated with increased SI in T1-weighted globus pallidus (GP; P < 0.01) and caudate (P < 0.05), and with decreased SI in T2-weighted GP (P < 0.001) and dentate nucleus (P < 0.005) in the contrast-exposed group. The cross-sectional analyses of the control cohort showed a significant age-dependent T1-weighted SI increase in multiple ROIs, including the GP and caudate, and decrease in the T2-weighted GP and dentate nucleus (P < 0.05)., Conclusions: Repeated exposure to gadoterate meglumine was not associated with brain hyperintensity in the pediatric patients, whereas age importantly contributed to the SI changes in several deep brain nuclei.

Objective: Recent studies reported a signal intensity increase in the deep cerebellar nuclei (DCN) on magnetic resonance images caused by gadolinium deposition after the injection of gadolinium-based contrast agents (GBCAs). There is an ongoing debate if the propensity of a GBCA to deposit gadolinium is primarily determined by its class as either linear or macrocyclic. In the current study, we aimed to compare the amount and the distribution of retained gadolinium of linear and macrocyclic GBCAs in the DCN after a single injection at a dose comparable to a human patient's in a large animal model., Materials and Methods: Eighteen sheep were randomly assigned in 6 groups of 3 animals, which received a single injection of 0.1 mmol/kg body weight of either the macrocyclic GBCAs gadobutrol, gadoteridol, or gadoterate meglumine; the linear GBCAs gadobenate dimeglumine or gadodiamide; or saline. Animals were euthanized 10 weeks after injection. Local distribution and concentration of gadolinium and colocalization to other metals (iron, zinc, copper) in the DCN was assessed by laser ablation-inductively coupled plasma-mass spectrometry., Results: Average gadolinium concentration for the macrocyclic GBCAs and the saline group was below the limit of quantification (5.7 ng/g tissue). In contrast, 14 (for gadobenate) and 27 (for gadodiamide) times more gadolinium than the limit of quantification was found for the linear GBCAs gadobenate (mean, 83 ng/g) or gadodiamide (mean, 155 ng/g brain tissue). Gadolinium distribution colocalized with other metals for linear GBCAs and a specific accumulation in the DCN was found., Discussion: The current study supports the hypothesis that the amount of gadolinium deposited in the brain is primarily determined by its class as either macrocyclic or linear. The accumulation of gadolinium in the DCN for linear GBCAs explains the hyperintensities in the DCN found in previous patient studies with linear GBCAs.

Objectives: This study sought to investigate the clinical utility and the predictive relevance of absolute rest myocardial blood flow (MBF) by cardiac magnetic resonance (CMR) in acute myocardial infarction., Background: Microvascular obstruction (MVO) remains one of the worst prognostic factors in patients with reperfused ST-segment elevation myocardial infarction (STEMI). Clinical trials have focused on cardioprotective strategies to maintain microvascular functionality, but there is a need for a noninvasive test to determine their efficacy., Methods: A total of 64 STEMI patients post-primary percutaneous coronary intervention underwent 3-T CMR scans acutely and at 6 months (6M). The protocol included cine function, T 2 -weighted edema imaging, pre-contrast T1 mapping, rest first-pass perfusion, and late gadolinium enhancement imaging. Segmental MBF, corrected for rate pressure product (MBF cor ), was quantified in remote, edematous, and infarcted myocardium., Results: Acute MBF cor was significantly reduced in infarcted myocardium compared with remote MBF (MBF infarct 0.76 ± 0.20 ml/min/g vs. MBF remote 1.02 ± 0.21 ml/min/g, p < 0.001), but it significantly increased at 6M (MBF infarct 0.76 ± 0.20 ml/min/g acute vs. 0.85 ± 0.22 ml/min/g at 6M, p < 0.001). On a segmental basis, acute MBF cor had incremental prognostic value for infarct size at 6M (odds of no LGE at 6M increased by 1.4:1 [p < 0.001] for each 0.1 ml/min/g increase of acute MBF cor ) and functional recovery (odds of wall thickening >45% at 6M increased by 1.38:1 [p < 0.001] for each 0.1 ml/min/g increase of acute MBF cor ). In subjects with coronary flow reserve >2 or index of myocardial resistance <40, acute MBF was associated with long-term functional recovery and was an independent predictor of infarct size reduction., Conclusions: Acute MBF by CMR could represent a novel quantitative imaging biomarker of microvascular reversibility, and it could be used to identify patients who may benefit from more intensive or novel therapies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The acquisition of short-axis (SA) cine magnetic resonance (MR) images after the administration of contrast agent (CA) is a common, time-saving technique, but a decreased difference in the blood-myocardium contrast on these steady-state free precession (SSFP) cine scans could change the calculated parameters when using threshold-based papillary and trabecular muscle (PTM) quantification. We studied the effect of CA on the parameters calculated from pre- and post-CA SA cine images in noncompaction cardiomyopathy (NC-CMP) and healthy (H) participants using a threshold-based module. A total of 39 individuals (20 patients and 19 healthy) were included prospectively in this study. After the pre-CA SA images were acquired, i.v. gadobutrol (GA) or gadobenate dimeglumine (GD) (GA vs. GD: NC-CMP = 12 vs. 8; C = 12 vs. 7) was administered, and SA scans were repeated after two minutes. A threshold-based PTM software was used for postprocessing. Pre-CA and post-CA SA images were analyzed, and the parameters were compared in both the NC-CMP and H groups. The left ventricular volumes were significantly larger, while the left ventricular myocardial (LVmass) and trabecular mass (LVtrab) values were significantly smaller on the post-CA scans (NC-CMP: pre-CA vs. post-CA, EDV: 74.0 ± 13.6 vs. 81.1 ± 16.3 ml/m 2 , ESV: 25.3 ± 7.3 vs. 30.1 ± 11.2 ml/m 2 , LVmass-ED: 82.5 ± 17.5 vs. 75.7 ± 15.9 g/m 2 , LVtrab-ED: 25.0 ± 6.6 vs. 18.9 ± 4.7 g/m 2 ; Healthy: preCA vs. post-CA, EDV: 69.7 ± 11.9 vs. 72.2  ±  10.7 ml/m 2 , ESV: 22.6 ± 5.7 vs. 23.9 ± 6.3 ml/m 2 , LVmass-ED: 71.3 ± 13.6 vs. 68.7 ± 13.9 g/m 2 , LVtrab-ED: 19.4 ± 2.6 vs. 16.2 ± 3.0 g/m 2 ; p < 0.05). The decreased blood-myocardium contrast difference on post-CA SSFP SA cine images leads to altered cardiac parameters when using threshold-based software for evaluation.

Objective: To evaluate the performance of major features, ancillary features, and categories of Liver Imaging Reporting and Data System (LI-RADS) version 2018 at magnetic resonance (MR) imaging in the differentiation of small hepatocellular carcinoma (HCC) from dysplastic nodules (DNs)., Patients and Methods: This retrospective study included cirrhotic patients with pathologically proven untreated HCCs and DNs (≤ 2 cm) and liver MR imaging performed with gadobenate dimeglumine contrast agent within 3 months before pathological analysis, between 2015 and 2018. 37 patients with 43 observations (17 HCCs and 26 DNs) met the inclusion criteria. Two radiologists assessed major and ancillary imaging features for each liver observation and assigned a LI-RADS v2018 category in consensus. Estimates of diagnostic performance of major features, ancillary features, and LI-RADS categories were assessed based on their sensitivity, specificity, positive (PPV), and negative predictive values (NPV)., Results: Major features (nonrim arterial phase hyperenhancement, nonperipheral "washout", and enhancing "capsule") had a sensitivity of 94.1%, 88.2%, and 41.2%, and a specificity of 57.7%, 42.3%, and 88.5% for HCC, respectively. Ancillary features (hepatobiliary phase hypointensity, mild-moderate T2 hyperintensity, restricted diffusion, and fat in the lesion more than adjacent liver) had a sensitivity of 94.1%, 64.7%, 58.8%, and 11.8%, and a specificity of 26.9%, 61.5%, 65.4%, and 76.9% for HCC, respectively. The LR-5 category (determined by using major features only vs. the combination of major and ancillary features) had a sensitivity of 88.2% at both evaluations and a specificity of 76.9% and 80.8% for HCC, respectively. The combination of LR-4, LR-5 categories (determined by using major features only vs. the combination of major and ancillary features) had a sensitivity of 94.1% at both interpretations and a specificity of 65.4% and 26.9% for HCC, respectively. The use of ancillary features modified LI-RADS category in 25.6% of observations (11/43), predominantly upgraded from LR-3 to LR4 (10/11), increasing the proportion of low-grade DNs and high-grade DNs categorized as LR-4 (from 15.4% to 61.5% and from 7.7% to 46.1%, respectively)., Conclusions: The added value of ancillary features in combination with major features is limited for the non-invasive diagnosis of small HCC; however, their use modifies the final category in a substantial proportion of observations from LR-3 to LR-4, thus allowing possible changes in the management of patients at risk for HCC.

Background: Cardiovascular magnetic resonance (CMR) angiography (CMRA) is an important non-invasive imaging tool for congenital heart disease (CHD) and aortopathy patients. The conventional 3D balanced steady-state free precession (bSSFP) sequence is often confounded by imaging artifacts. We sought to compare the respiratory navigated and electrocardiogram (ECG) gated modified Dixon (mDixon) CMRA sequence to conventional non-gated dynamic multi-phase contrast enhanced CMRA (CE-CMRA) and bSSFP across a variety of diagnoses., Methods: We included 24 patients with CHD or aortopathy with CMR performed between September 2017 to December 2017. Each patient had undergone CE-CMRA, followed by a bSSFP and mDixon angiogram. Patients with CMR-incompatible implants or contraindications to contrast were excluded. The studies were rated according to image quality at a scale from 1 (poor) to 4 (excellent) based on diagnostic adequacy, artifact burden, vascular border delineation, myocardium-blood pool contrast, and visualization of pulmonary and systemic veins and coronaries. Contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR) and quantitative vascular measurements were compared between the two gated sequences. Bland-Altman plots were generated to compare paired measures., Results: All scans were diagnostically adequate. Mean (SD) quality scores were 3.4 (0.7) for the mDixon, 3.2 (0.5) for the bSSFP and 3.4 (0.5) for the CE-CMRA. Qualitatively, the intracardiac anatomy and myocardium-blood pool definition were better in the bSSFP; however, mDixon images showed enhanced vessel wall sharpness with less blurring surrounding the anatomical borders distally. Coronary origins were identified in all cases. Pulmonary veins were visualized in 92% of mDixon sequences, 75% of bSSFP and 96% of CE-CMRA. Similarly, neck veins were identified in 92, 83 and 96% respectively. Artifacts prevented vascular measurement in 6/192 (3%) and 4/192 (2%) of total vascular measurements for the mDixon and bSSFP, respectively. However, the size of signal void and field distortion were significantly worse in the latter, particularly for flow and metal induced artifacts., Conclusion: In patients with congenital heart disease, ECG gated mDixon angiography yields high fidelity vascular images including better delineation of head and neck vasculature and pulmonary veins and fewer artifacts than the comparable bSSFP sequence. It should be considered as the preferred strategy for successful CHD imaging in patients with valve stenosis, vascular stents, or metallic implants.

Objectives: This study sought to explore the Fabry myocardium in relation to storage, age, sex, structure, function, electrocardiogram changes, blood biomarkers, and inflammation/fibrosis., Background: Fabry disease (FD) is a rare, x-linked lysosomal storage disorder. Mortality is mainly cardiovascular with men exhibiting cardiac symptoms earlier than women. By cardiovascular magnetic resonance, native T1 is low in FD because of sphingolipid accumulation., Methods: A prospective, observational study of 182 FD (167 adults, 15 children; mean age 42 ± 17 years, 37% male) who underwent cardiovascular magnetic resonance including native T1, late gadolinium enhancement (LGE), and extracellular volume fraction, 12-lead electrocardiogram, and blood biomarkers (troponin and N-terminal pro-brain natriuretic peptide)., Results: In children, T1 was never below the normal range, but was lower with age (9 ms/year, r = -0.78 children; r = -0.41 whole cohort; both p < 0.001). Over the whole cohort, the T1 reduction with age was greater and more marked in men (men: -1.9 ms/year, r = -0.51, p < 0.001; women: -1.4 ms/year, r = -0.47 women, p < 0.001). Left ventricular hypertrophy (LVH), LGE, and electrocardiogram abnormalities occur earlier in men. Once LVH occurs, T1 demonstrates major sex dimorphism: with increasing LVH in women, T1 and LVH become uncorrelated (r = -0.239, p = 0.196) but in men, the correlation reverses and T1 increases (toward normal) with LVH (r = 0.631, p < 0.001), a U-shaped relationship of T1 to indexed left ventricular mass in men., Conclusions: These data suggest that myocyte storage starts in childhood and accumulates faster in men before triggering 2 processes: a sex-independent scar/inflammation regional response (LGE) and, in men, apparent myocyte hypertrophy diluting the T1 lowering of sphingolipid., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use., Methods: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T 1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured., Results: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts., Conclusion: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models., (© 2019 International Society for Magnetic Resonance in Medicine.)

An alteration of parenchymal cerebrospinal fluid circulation (CSF) has been proposed to take part in the pathophysiology of multiple sclerosis. By using an intragate T1-weighted high-resolution MRI of the spinal cord of freely breathing mice injected with a gadolinium chelate in the cisterna magna , we show that a parenchymal CSF circulation exists in the spinal cord, in addition to that originally described in the brain. In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, we show a reduction of parenchymal CSF circulation specifically in the spinal cord but not in the brain.