Smart forecasting of artifacts in contrast-enhanced breast MRI before contrast agent administration.

OBJECTIVES: To evaluate whether artifacts on contrast-enhanced (CE) breast MRI maximum intensity projections (MIPs) might already be forecast before gadolinium-based contrast agent (GBCA) administration during an ongoing examination by analyzing the unenhanced T1-weighted images acquired before the GBCA injection. MATERIALS AND METHODS: This IRB-approved retrospective analysis consisted of n = 2884 breast CE MRI examinations after intravenous administration of GBCA, acquired with n = 4 different MRI devices at different field strengths (1.5 T/3 T) during clinical routine. CE-derived subtraction MIPs were used to conduct a multi-class multi-reader evaluation of the presence and severity of artifacts with three independent readers. An ensemble classifier (EC) of five DenseNet models was used to predict artifacts for the post-contrast subtraction MIPs, giving as the input source only the pre-contrast T1-weighted sequence. Thus, the acquisition directly preceded the GBCA injection. The area under ROC (AuROC) and diagnostics accuracy scores were used to assess the performance of the neural network in an independent holdout test set (n = 285). RESULTS: After majority voting, potentially significant artifacts were detected in 53.6% (n = 1521) of all breast MRI examinations (age 49.6 ± 12.6 years). In the holdout test set (mean age 49.7 ± 11.8 years), at a specificity level of 89%, the EC could forecast around one-third of artifacts (sensitivity 31%) before GBCA administration, with an AuROC = 0.66. CONCLUSION: This study demonstrates the capability of a neural network to forecast the occurrence of artifacts on CE subtraction data before the GBCA administration. If confirmed in larger studies, this might enable a workflow-blended approach to prevent breast MRI artifacts by implementing in-scan personalized predictive algorithms. CLINICAL RELEVANCE STATEMENT: Some artifacts in contrast-enhanced breast MRI maximum intensity projections might be predictable before gadolinium-based contrast agent injection using a neural network. KEY POINTS: • Potentially significant artifacts can be observed in a relevant proportion of breast MRI subtraction sequences after gadolinium-based contrast agent administration (GBCA). • Forecasting the occurrence of such artifacts in subtraction maximum intensity projections before GBCA administration for individual patients was feasible at 89% specificity, which allowed correctly predicting one in three future artifacts. • Further research is necessary to investigate the clinical value of such smart personalized imaging approaches.

Neurologic Effects of Gadolinium Retention in the Brain after Gadolinium-based Contrast Agent Administration.

Background Concerns over the neurotoxic potential of retained gadolinium in brain tissues after intravenous gadolinium-based contrast agent (GBCA) administration have led to pronounced worldwide use changes, yet the clinical sequelae of gadolinium retention remain undefined. Purpose To assess clinical and neurologic effects and potential neurotoxicity of gadolinium retention in rats after administration of various GBCAs. Materials and Methods From March 2017 through July 2018, 183 male Wistar rats received 20 intravenous injections of 2.5 mmol per kilogram of body weight (80 human equivalent doses) of various GBCAs (gadodiamide, gadobenate, gadopentetate, gadoxetate, gadobutrol, gadoterate, and gadoteridol) or saline over 4 weeks. Rats were evaluated 6 and 34 weeks after injection with five behavioral tests, and inductively coupled plasma mass spectrometry, transmission electron microscopy, and histopathology were performed on urine, serum, cerebrospinal fluid (CSF), basal ganglia, dentate nucleus, and kidney samples. Dunnett post hoc test and Wilcoxon rank sum test were used to compare differences between treatment groups. Results No evidence of differences in any behavioral test was observed between GBCA-exposed rats and control animals at either 6 or 34 weeks (P = .08 to P = .99). Gadolinium concentrations in both neuroanatomic locations were higher in linear GBCA-exposed rats than macrocyclic GBCA-exposed rats at 6 and 34 weeks (P < .001). Gadolinium clearance over time varied among GBCAs, with gadobutrol having the largest clearance (median: 62% for basal ganglia, 70% for dentate) and gadodiamide having no substantial clearance. At 34 weeks, gadolinium was largely cleared from the CSF and serum of gadodiamide-, gadobenate-, gadoterate-, and gadobutrol-exposed rats, especially for the macrocyclic agents (range: 70%-98% removal for CSF, 34%-94% removal for serum), and was nearly completely removed from urine (range: 96%-99% removal). Transmission electron microscopy was used to detect gadolinium foci in linear GBCA-exposed brain tissue, but no histopathologic differences were observed for any GBCA. Conclusion In this rat model, no clinical evidence of neurotoxicity was observed after exposure to linear and macrocyclic gadolinium-based contrast agents at supradiagnostic doses. © RSNA, 2022 Online supplemental material is available for this article.

Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration.

Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.

Diagnostic Yield of Electroanatomic Voltage Mapping in Guiding Endomyocardial Biopsies.

BACKGROUND: Electroanatomic voltage mapping (EVM) is a promising modality for guiding endomyocardial biopsies (EMBs). However, few data support its feasibility and safety. We now report the largest cohort of patients undergoing EVM-guided EMBs to show its diagnostic yield and to compare it with a cardiac magnetic resonance (CMR)-guided approach. METHODS: We included 162 consecutive patients undergoing EMB at our institution from 2010 to 2019. EMB was performed in pathological areas identified at EVM and CMR. CMR and EVM sensitivity and specificity regarding the identification of pathological substrates of myocardium were evaluated according to EMB results. RESULTS: Preoperative CMR showed late gadolinium enhancement in 70% of the patients, whereas EVM identified areas of low voltage in 61%. Right (73%), left (19%), or both ventricles (8%) underwent sampling. EVM proved to have sensitivity similar to CMR (74% versus 77%), with specificity being 70% and 47%, respectively. In 12 patients with EMB-proven cardiomyopathy, EVM identified pathological areas that had been undetected at CMR evaluation. Sensitivity of pooled EVM and CMR was as high as 95%. EMB analysis allowed us to reach a new diagnosis, different from the suspected clinical diagnosis, in 39% of patients. The complications rate was low, mostly related to vascular access, with no patients requiring urgent management. CONCLUSIONS: EVM proved to be a promising tool for targeted EMB because of its sensitivity and specificity for identification of myocardial pathological substrates. EVM was demonstrated to have accuracy similar to CMR. EVM and CMR together conferred a positive predictive value of 89% on EMB.

In vivo evaluation of PEGylated-liposome encapsulating gadolinium complexes for gadolinium neutron capture therapy.

Gadolinium neutron capture therapy (GdNCT) is a form of binary radiotherapy. It utilizes nuclear reactions that occur when gadolinium-157 is irradiated with thermal neutrons, producing high-energy γ-rays and Auger electrons. Herein, we evaluate the potential of GdNCT for cancer treatment using PEGylated liposome incorporated with an FDA-approved MRI contrast agent. The clinical gadolinium complex (Gadovist®) was successfully encapsulated inside the aqueous core of PEGylated liposomes by repeated freeze and thaw cycling. At a concentration of 152 µM Gd, the Gd-liposome showed high cytotoxicity upon thermal-neutron irradiation. In animal experiments, when a CT26 tumor model was administered with Gd-liposomes (19 mg 157Gd per kg) followed by 20-min irradiation of thermal neutron at a flux of 1.94 × 104 cm-2 s-1, tumor growth was suppressed by 43%, compared to that in the control group, on the 23rd day of post-irradiation. After two-cycle GdNCT treatment at a 10-day interval, tumor growth was more efficiently retarded. On the 31st day after irradiation, the weight of the excised tumor in the GdNCT group (38 mg 157Gd per kg per injection) was only 30% of that of the control group. These results demonstrate the potential of GdNCT using PEGylated liposomes containing MRI contrast agents in cancer treatment.

Use of Intravenous Gadolinium-based Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation.

Inaugural consensus statements were developed and endorsed by the American College of Radiology (ACR) and the National Kidney Foundation to improve and standardize the care of patients with kidney disease who have indication(s) to receive ACR-designated group II or group III intravenous gadolinium-based contrast media (GBCM). The risk of nephrogenic systemic fibrosis (NSF) from group II GBCM in patients with advanced kidney disease is thought to be very low (zero events following 4931 administrations to patients with estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2; upper bounds of the 95% confidence intervals: 0.07% overall, 0.2% for stage 5D chronic kidney disease [CKD], 0.5% for stage 5 CKD and no dialysis). No unconfounded cases of NSF have been reported for the only available group III GBCM (gadoxetate disodium). Depending on the clinical indication, the potential harms of delaying or withholding group II or group III GBCM for an MRI in a patient with acute kidney injury or eGFR less than 30 mL/min per 1.73 m2 should be balanced against and may outweigh the risk of NSF. Dialysis initiation or alteration is likely unnecessary based on group II or group III GBCM administration. This article is a simultaneous joint publication in Radiology and Kidney Medicine. The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article.

Clinical Efficacy of Reduced-Dose Gadobutrol Versus Standard-Dose Gadoterate for Contrast-Enhanced MRI of the CNS: An International Multicenter Prospective Crossover Trial (LEADER-75).

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.

Late gadolinium enhancement is a risk factor for major adverse cardiac events in unrecognised myocardial infarction without apparent symptoms: a meta-analysis.

AIM: To assess the prognostic role of unrecognised myocardial infarction (UMI) detected at late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRII). MATERIALS AND METHODS: Electronic databases including PubMed, EMBASE, Medline, and Cochrane were searched systematically for studies exploring the predictive value of UMI detected by LGE-CMRI for major adverse cardiac events (MACEs) and all-cause mortality in patients without apparent symptoms. Pooled hazard ratios (HRs) along with their 95% confidence intervals (CIs) were obtained from a random-effects model. Subgroup analyses were performed according to the different participants and outcomes. RESULTS: Eight studies (2,009 participants) were identified comprising 442 patients with UMI detected at LGE-CMRI and 1,567 without UMI. The presence of UMI on LGE was associated with a significantly increased risk for MACEs (HRs: 3.44, 95% CI: 2.06 to 5.75; p<0.001) and all-cause mortality (HRs: 2.43, 95% CI: 1.00 to 5.87; p=0.05). In the subgroup analysis, the presence of UMI on LGE remained significantly associated with the risk of MACEs in patients with suspected coronary artery disease (HRs: 3.82, 95% CI: 2.49 to 5.85; p<0.01) and diabetes mellitus (HRs: 4.97, 95% CI: 3.02 to 8.18; p<0.01). CONCLUSION: The presence of UMI detected by LGE-CMRI is associated with an increased risk of MACEs and all-cause mortality in patients without symptoms. LGE-CMRI could provide important prognostic information and guide risk stratification in patients with UMI.

Prognostic value of late gadolinium enhancement in arrhythmogenic right ventricular cardiomyopathy: a meta-analysis.

AIM: To assess systematically the prognostic value of cardiac magnetic resonance imaging (CMRI) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). MATERIALS AND METHODS: The full text of studies of the clinical efficacy of late gadolinium enhancement (LGE) in ARVC was retrieved in multiple databases. Stata 14 was adopted for meta-analysis and bias analysis. Heterogeneity was assessed with the I2 statistic. RESULTS: After exclusions, 561 patients were included in five studies, and the eligibility criteria were met. The meta-analysis suggested that there was a significant difference between LGE positive and negative patients with ARVC in all-cause mortality (relative risk [RR] = 4.78, 95% confidence interval [CI] = 1.41, 16.23, p=0.012; p for heterogeneity = 0.692, I2 = 0%); major adverse cardiovascular events (MACE) (RR=2.48, 95% CI = 1.24, 4.96, p=0.010; p for heterogeneity = 0.596, I2 = 0%); ventricular tachycardia (RR=3.13, 95% CI = 1.69, 5.78, p<0.001; p for heterogeneity = 0.825, I2 = 0%); implanted cardiac defibrillators (RR=3.15, 95% CI = 1.69, 5.87], p<0.001; p for heterogeneity = 0.353, I2 = 9.4%). CONCLUSION: LGE in ARVC patients is a predictor of all-cause mortality and MACE.

QRS-T angle in patients with Hypertrophic Cardiomyopathy - A comparison with Cardiac Magnetic Resonance Imaging.

Objective: We sought to investigate the possible association of a wide QRS-T angle on the surface EKG and myocardial fibrosis on contrast-enhanced cardiovascular magnetic (CMR) imaging in patients with hypertrophic cardiomyopathy (HCM). Background: Risk stratification in HCM patients is challenging. Late gadolinium enhancement (LGE) visualizes myocardial fibrosis with unique spatial resolution and is a strong and independent prognosticator in these patients. The QRS-T angle from the surface EKG is a promising prognostic marker in various cardiac pathologies. Methods: 70 patients with HCM obtained a standardized digital 12-lead EKG for the calculation of the QRS-T angle and underwent comprehensive CMR imaging for visualization of fibrosis by LGE. Patients were divided into groups according to the absence or presence of fibrosis on CMR. Results: 43 of 70 patients with HCM showed LGE on CMR following contrast administration. HCM patients with LGE (fibrosis) had wider QRS-T angles as compared to the patient group without LGE (100±54 vs. 46±31; <0.001). A QRS-T angle of 90 degrees or more was a strong predictor (OR 32.84, CI 4.08-264.47; p <0.001) of HCM with LGE. Conclusion: There is a strong association of a wide QRS-T angle and myocardial fibrosis in patients with HCM.

Association of QRS-T angle and Late Gadolinium Enhancement in patients with a Clinical Suspicion of Myocarditis.

Objective: To investigate the association of a wide QRS-T angle on the surface ECG and late gadolinium enhancement on contrast-enhanced cardiovascular magnetic (CMR) imaging in patients with clinically suspected myocarditis. Background: Diagnosis and risk stratification in patients with suspected myocarditis is particularly challenging due to a great spectrum of clinical presentations. Late gadolinium enhancement (LGE) visualizes myocardial necrosis and fibrosis in patients with biopsy-proven myocarditis. The presence or absence of late gadolinium enhancements in these patients is prognostically meaningful. The QRS-T angle from the surface ECG, on the other hand, may serve as a simple and easily available risk marker in suspected myocarditis. Methods: We enrolled 97 consecutive patients that were referred to CMR imaging for a clinical suspicion of myocarditis. All patients obtained a standardized digital 12-lead ECG for the calculation of the QRS-T angle and underwent contrast-enhanced CMR imaging. Patients were divided into two groups according to the absence or presence of LGE on CMR. Results: 78 of 97 patients with suspected myocarditis had LGE on CMR. Patients with LGE had wider QRS-T angles as compared to the patient group without LGE (53.95-47.5 vs. 26.2-21.2; p<0.001). The sensivity, specificity, negative predictive value and positive predictive value for a QRS-T angle above 90 degrees for LGE positive myocarditis were 16.5%, 100%, 24.7%, and 100%, respectively. Conclusion: A wide QRS-T angle of 90 degrees or more is linked to myocardial fibrosis or necrosis (late gadolinium enhancement) in patients with suspected myocarditis.

Patterns of use, effectiveness and safety of gadolinium contrast agents: a European prospective cross-sectional multicentre observational study.

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.

Acute Sixth Nerve Palsy and Retinal Hemorrhages as the Presenting Features of Acute Lymphoblastic Leukemia.

ABSTRACT: A 36-year-old apparently healthy man presented with acute onset of diplopia. Examination demonstrated left sixth nerve palsy with 3 retinal hemorrhages noted in one eye. Gadolinium-enhanced high-resolution skull base MRI revealed left sixth nerve enhancement involving the cisternal segment. Complete blood count, cerebrospinal fluid analysis, bone marrow biopsy, and flow cytometry confirmed acute T-cell lymphoblastic leukemia with central nervous system involvement. This case demonstrates the value of high-resolution MRI in the evaluation of cranial nerve palsy in young adults and also emphasizes the importance of systemic work up in these cases, particularly when retinal findings are present.

Substantially thinner internal granular layer and reduced molecular layer surface in the cerebellar cortex of the Tc1 mouse model of down syndrome - a comprehensive morphometric analysis with active staining contrast-enhanced MRI.

Down Syndrome is a chromosomal disorder that affects the development of cerebellar cortical lobules. Impaired neurogenesis in the cerebellum varies among different types of neuronal cells and neuronal layers. In this study, we developed an imaging analysis framework that utilizes gadolinium-enhanced ex vivo mouse brain MRI. We extracted the middle Purkinje layer of the mouse cerebellar cortex, enabling the estimation of the volume, thickness, and surface area of the entire cerebellar cortex, the internal granular layer, and the molecular layer in the Tc1 mouse model of Down Syndrome. The morphometric analysis of our method revealed that a larger proportion of the cerebellar thinning in this model of Down Syndrome resided in the inner granule cell layer, while a larger proportion of the surface area shrinkage was in the molecular layer.

Safety of Intrathecal Administration of Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis.

Background The use of MR cisternography with intrathecal administration of gadolinium-based contrast agents (GBCAs) is limited by a lack of understanding of the relationship between intrathecal GBCA exposure and dose-related adverse events. Purpose To perform a systematic review to establish an understanding of the dose-response relationship of intrathecal GBCAs and to characterize related adverse events, particularly at higher doses. Materials and Methods Medline, Embase, CINAHL, and Central databases were searched for studies reporting intrathecal GBCA use. Data extraction included studies focused on rates and types of adverse events after intrathecal GBCA exposure. A two-tailed independent sample t test statistic was used to evaluate the relationship between GBCA dose and the presence of serious versus nonserious adverse events. Meta-analysis was used to determine the overall incidence of adverse events. Study quality and publication bias were assessed using the modified Newcastle-Ottawa scale and a funnel plot (effect size measured using Hedges' g followed by the Egger test), respectively. Results Fifty-three studies with a total of 1036 patients were included for analysis. The overall rate of adverse events after intrathecal administration of GBCA was 13% (95% confidence interval [CI]: 9.3%, 18%). Meta-analysis revealed moderate heterogeneity (I2 = 62%). Serious adverse event rates could not be determined with meta-analysis. They were reported in 10 studies and were primarily neurologic in nature, with two cases of coma-one resulting in death. Serious adverse events were associated with significantly higher GBCA doses when compared with nonserious adverse events (mean difference, 4.5 mmol; 95% CI: 2.3 mmol, 6.6 mmol; P = .008). For serious adverse events, there was no clear dose-dependent increase in severity above 2.0 mmol. Conclusion Overall, intrathecal administration of GBCAs at doses greater than 1.0 mmol are associated with serious neurotoxic complications with relative clinical safety at lower doses. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kanal in this issue.

Breakthrough Hypersensitivity Reactions to Gadolinium-based Contrast Agents and Strategies to Decrease Subsequent Reaction Rates: A Systematic Review and Meta-Analysis.

Background Hypersensitivity reactions to gadolinium-based contrast agents (GBCAs) that occur despite corticosteroid premedication (breakthrough reactions) are not well understood. Purpose To determine the GBCA breakthrough reaction rate overall and according to GBCA class and to determine the effect of using an alternative GBCA or allergy skin testing on the risk of a breakthrough reaction. Materials and Methods In this systematic review and meta-analysis, MEDLINE (from 1946 to 2019), Embase (from 1947 to 2019), and the Cochrane Central Register of Controlled Trials (2019 only) were searched for patients with a breakthrough reaction to a GBCA who were undergoing repeat GBCA administration. Breakthrough reaction rates were determined with random-effects modeling and meta-regression. Secondary analyses of GBCA class, switching to an alternative GBCA, and allergy skin testing were assessed. Quality Assessment of Diagnostic Accuracy Studies 2 was used to determine risk of bias and applicability. Percentages are meta-regression results and do not directly reflect raw data. Results Of the 148 identified studies, 23 were included, encompassing 120 patients and 130 GBCA administrations. The overall breakthrough reaction rate was 39% (95% confidence interval [CI]: 30%, 49%; 37 of 103 administrations). Breakthrough reaction rates for macrocyclic (36%; 95% CI: 25%, 48%; 23 of 64 administrations) and protein-binding linear (31%; 95% CI: 1%, 94%; [one of seven administrations) GBCAs did not differ (P = .90). There were insufficient analyzable data for gadodiamide, gadoversetamide, and gadopentetate. Hypersensitivity reaction rate after switching GBCAs was 50% (95% CI: 21%, 79%; three of nine administrations) with and 71% (95% CI: 21%, 95%; four of five administrations) without corticosteroid premedication, which did not differ (P = .82 and P = .17, respectively) from the observed rate when using corticosteroid premedication and the same GBCA (36%; 95% CI: 26%, 48%; 37 of 84 administrations). Hypersensitivity reaction rate after allergy skin testing (17%; 95% CI: 7%, 29%; zero of 21 studies) did not differ when compared with use of the same agent with corticosteroid premedication (P = .10). Meta-analysis limitations were the small number of patients and the high risk of bias. Conclusion Patients with a prior hypersensitivity reaction to a gadolinium-based contrast agent (GBCA) often had breakthrough reactions. The effect of switching to an alternative GBCA or using allergy skin testing to decrease reaction risk lacked enough available data for meaningful comparisons. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Prince in this issue.

Contrast-to-Dose Relationship of Gadopiclenol, an MRI Macrocyclic Gadolinium-based Contrast Agent, Compared with Gadoterate, Gadobenate, and Gadobutrol in a Rat Brain Tumor Model.

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.

Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?

Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.

DSP p.(Thr2104Glnfs*12) variant presents variably with early onset severe arrhythmias and left ventricular cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. METHODS: We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. RESULTS: We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. CONCLUSIONS: The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.

Assessment of gadolinium deposition in the brain tissue of pediatric and adult congenital heart disease patients after contrast enhanced cardiovascular magnetic resonance.

BACKGROUND: Contrast enhanced magnetic resonance imaging (MRI) is an important tool for the assessment of extracardiac vasculature and myocardial viability. Gadolinium (Gd) brain deposition after contrast enhanced MRI has recently been described and resulted in a warning issued by the United States Food and Drug Administration. However, the prevalence of brain deposition in children and adults with congenital heart disease (CHD) undergoing cardiovascular magnetic resonance (CMR) is unclear. We hypothesized that Gd exposure as part of one or more CMRs would lead to a low rate of brain deposition in pediatric and adult CHD patients. METHODS: We queried our institutional electronic health record for all pediatric and adult CHD patients who underwent contrast enhanced CMR from 2005 to 2018 and had a subsequent brain MRI. Cases were age- and gender-matched to controls who were never exposed to Gd and underwent brain MRIs. The total number of contrast enhanced MRIs, type of Gd, and total Gd dose were determined. Brain MRIs were reviewed by a neuroradiologist for evidence of Gd deposition using qualitative and quantitative assessment. Quantitative assessment was performed using the dentate nucleus to pons signal intensity ratio (dp-SIR) on T1 weighted imaging. Continuous variables were analyzed using Mann-Whitney U and Spearman rank correlation tests. Normal SIR was defined as the 95% CI of the control population dp-SIR. RESULTS: Sixty-two cases and 62 controls were identified. The most contrast enhanced MRIs in a single patient was five and the largest lifetime dose of Gd that any patient received was 0.75 mmol/kg. There was no significant difference in the mean dp-SIR of cases and controls (p = 0.11). The dp-SIR was not correlated with either the lifetime dose of Gd (rs = 0.21, p = 0.11) or the lifetime number of contrast enhanced studies (rs = 0.21, p = 0.11). Two cases and 2 controls had dp-SIRs above the upper bound of the 95% confidence interval for the control group. One case had qualitative imaging-based evidence of Gd deposition in the brain but had a dp-SIR within the normal range. CONCLUSION: In our cohort of pediatric and adult CHD patients undergoing contrast enhanced CMR, there was a low incidence of qualitative and no significant quantitative imaging-based evidence of Gd brain deposition.