Gd2O3-mesoporous silica/gold nanoshells: A potential dual T1/T2 contrast agent for MRI-guided localized near-IR photothermal therapy.

A promising clinical trial utilizing gold-silica core-shell nanostructures coated with polyethylene glycol (PEG) has been reported for near-infrared (NIR) photothermal therapy (PTT) of prostate cancer. The next critical step for PTT is the visualization of therapeutically relevant nanoshell (NS) concentrations at the tumor site. Here we report the synthesis of PEGylated Gd2O3-mesoporous silica/gold core/shell NSs (Gd2O3-MS NSs) with NIR photothermal properties that also supply sufficient MRI contrast to be visualized at therapeutic doses (≥108 NSs per milliliter). The nanoparticles have r1 relaxivities more than three times larger than those of conventional T1 contrast agents, requiring less concentration of Gd3+ to observe an equivalent signal enhancement in T1-weighted MR images. Furthermore, Gd2O3-MS NS nanoparticles have r2 relaxivities comparable to those of existing T2 contrast agents, observed in agarose phantoms. This highly unusual combination of simultaneous T1 and T2 contrast allows for MRI enhancement through different approaches. As a rudimentary example, we demonstrate T1/T2 ratio MR images with sixfold contrast signal enhancement relative to its T1 MRI and induced temperature increases of 20 to 55 °C under clinical illumination conditions. These nanoparticles facilitate MRI-guided PTT while providing real-time temperature feedback through thermal MRI mapping.

Ultrathin Gd-Oxide Nanosheet as Ultrasensitive Companion Diagnostic Tool for MR Imaging and Therapy of Submillimeter Microhepatocellular Carcinoma.

Early stage hepatocellular carcinoma (HCC) presents a formidable challenge in clinical settings due to its asymptomatic progression and the limitations of current imaging techniques in detecting micro-HCC lesions. Addressing this critical issue, we introduce a novel ultrathin gadolinium-oxide (Gd-oxide) nanosheet-based platform with heightened sensitivity for high-field MRI and as a therapeutic agent for HCC. Synthesized via a digestive ripening process, these Gd-oxide nanosheets exhibit an exceptional acid-responsive profile. The integration of the ultrathin Gd-oxide with an acid-responsive polymer creates an ultrasensitive high-field MRI probe, enabling the visualization of submillimeter-sized tumors with superior sensitivity. Our research underscores the ultrasensitive probe's efficacy in the treatment of orthotopic HCC. Notably, the ultrasensitive probe functions dually as a companion diagnostic tool, facilitating simultaneous imaging and therapy with real-time treatment monitoring capabilities. In conclusion, this study showcases an innovative companion diagnostic tool that holds promise for the early detection and effective treatment of micro-HCC.

Biocompatibility and potential anticancer activity of gadolinium oxide (Gd2O3) nanoparticles against nasal squamous cell carcinoma.

Chemotherapy as a cornerstone of cancer treatment is slowly being edged aside owing to its severe side effects and systemic toxicity. In this case, nanomedicine has emerged as an effective tool to address these drawbacks. Herein, a biocompatible carrier based on bovine serum albumin (BSA) coated gadolinium oxide nanoparticles (Gd2O3@BSA) was fabricated for curcumin (CUR) delivery and its physicochemical features along with its potential anticancer activity against nasal squamous cell carcinoma were also investigated. It was found that the fabricated Gd2O3@BSA containing CUR (Gd2O3@BSA-CUR) had spherical morphology with hydrodynamic size of nearly 26 nm, zeta-potential of -36 mV and high drug (CUR) loading capacity. Drug release profile disclosed that the release of CUR from the prepared Gd2O3@BSA-CUR nanoparticles occurred in a sustained- and pH-dependent manner. Also, in vitro cytotoxicity analysis revealed that the fabricated Gd2O3@BSA nanoparticles possessed excellent biosafety toward HFF2 normal cells, while Gd2O3@BSA-CUR appeared to display the greatest anticancer potential against RPMI 2650 and CNE-1 cancer cell lines. The results also show that the Gd2O3@BSA nanoparticles were compatible with the blood cells with minor hemolytic effect (< 3%). The manufactured NPs were found to be completely safe for biological applications in an in vivo subacute toxicity study. Taken together, these finding substantiate the potential anticancer activity of Gd2O3@BSA-CUR nanoparticles against nasal squamous cell carcinoma, but the results obtained demand further studies to assess their full potential.

Differences in hypersensitivity reactions and gadolinium deposition disease/symptoms associated with gadolinium exposure to gadolinium-based contrast agents: new insights based on global databases VigiBase, FAERS, and IQVIA-MIDAS.

BACKGROUND: Hypersensitivity reactions (HSRs) can occur unexpectedly and be life-threatening when gadolinium-based contrast agents (GBCAs) are used. Gadolinium deposition disease (GDD) and symptoms associated with gadolinium exposure (SAGE) have been controversial for a long time. However, similar studies are currently incomplete or outdated. Therefore, comparing the safety of different GBCAs in terms of HSRs and GDD/SAGE using the latest post-marketing safety data should yield further insights into safely using GBCAs. METHODS: The safety differences between all GBCAs to GDD and the spectrum of GBCA-related HSRs were all compared and analyzed by using the World Health Organization database VigiBase and the FDA Adverse Event Reporting System (FAERS) database in this study. A further analysis of SAGE was also conducted using FAERS data. The lower limit of the reporting odds ratio (ROR) 95% confidence interval was used for signal detection. Moreover, the frequency of HSRs was calculated by dividing the number of reports in VigiBase by the total sales volume (measured in millions) from 2008 to 2022 in the IQVIA Multinational Integrated Data Analysis System. All adverse events were standardized using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 26.0. RESULTS: This study shows that all GBCAs have the potential to induce HSRs, with nonionic linear GBCAs exhibiting a comparatively lower signal. According to standardized MedDRA query stratification analysis, gadobutrol had a greater ROR025 for angioedema. The ROR025 of gadobenate dimeglumine and gadoteridol is larger for anaphylactic/anaphylactoid shock conditions. Regarding severe cutaneous adverse reactions, only gadoversetamide and gadodiamide showed signals in FAERS and VigiBase. There were also differences in the frequency of HSRs between regions. Regarding GDD, gadoterate meglumine, and gadoteridol had a lower ROR025. An analysis of the 29 preferred terms linked to SAGE indicated that special consideration should be given to the risk of skin induration associated with gadoversetamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadodiamide, and gadoteridol. Additionally, gadodiamide and gadoteridol pose a greater risk of skin tightness compared to other GBCAs. CONCLUSIONS: The risk differences among GBCAs using data from several sources were compared in this study. However, as a hypothesis-generating method, a clear causal relationship would require further research and validation.

Promoting Electromagnetic Wave Absorption Performance by Integrating MoS2@Gd2O3/MXene Multiple Hetero-Interfaces in Wood-Derived Carbon Aerogels.

Multi-component composite materials with a magnetic-dielectric synergistic effect exhibit satisfactory electromagnetic wave absorption performance. However, the effective construction of the structure for these multi-component materials to fully exploit the advantages of each component remains a challenge. Inspired by natural biomass, this study utilizes wood as the raw material and successfully prepares high-performance MoS2@Gd2O3/Mxene loaded porous carbon aerogel (MGMCA) composite material through a one-pot hydrothermal method and carbonization treatment process. With a delicate structural design, the MGMCA is endowed with abundant heterogeneous interface structures, favorable impedance matching characteristics, and a magnetic-dielectric synergistic system, thus demonstrating multiple electromagnetic wave loss mechanisms. Benefiting from these advantages, the obtained MGMCA exhibits outstanding electromagnetic wave absorption performance, with a minimum reflection loss of -57.5 dB at an ultra-thin thickness of only 1.9 mm. This research proposes a reliable strategy for the design of multi-component composite materials, providing valuable insight for the design of biomass-based materials as electromagnetic wave absorbers.

Kilogram-Scale Synthesis of Extremely Small Gadolinium Oxide Nanoparticles as a T1-Weighted Contrast Agent for Magnetic Resonance Imaging.

Magnetic resonance imaging contrast agents are frequently used in clinics to enhance the contrast between diseased and normal tissues. The previously reported poly(acrylic acid) stabilized exceedingly small gadolinium oxide nanoparticles (ES-GdON-PAA) overcame the problems of commercial Gd chelates, but limitations still exist, i.e., high r2/r1 ratio, long blood circulation half-life, and no data for large scale synthesis and formulation optimization. In this study, polymaleic acid (PMA) is found to be an ideal stabilizer to synthesize ES-GdONs. Compared with ES-GdON-PAA, the PMA-stabilized ES-GdON (ES-GdON-PMA) has a lower r2/r1 ratio (2.05, 7.0 T) and a lower blood circulation half-life (37.51 min). The optimized ES-GdON-PMA-9 has an exceedingly small particle size (2.1 nm), excellent water dispersibility, and stability. A facile, efficient, and environmental friendly synthetic method is developed for large-scale synthesis of the ES-GdONs-PMA. The weight of the optimized freeze-dried ES-GdON-PMA-26 synthesized in a 20 L of reactor reaches the kilogram level. The formulation optimization is also finished, and the concentrated ES-GdON-PMA-26 formulation (CGd = 100 mm) after high-pressure steam sterilization possesses eligible physicochemical properties (i.e., pH value, osmolality, viscosity, and density) for investigational new drug application.

Distinguishing metabolic signals of liver tumors from surrounding liver cells using hyperpolarized 13 C MRI and gadoxetate.

PURPOSE: To use the hepatocyte-specific gadolinium-based contrast agent gadoxetate combined with hyperpolarized (HP) [1-13 C]pyruvate MRI to selectively suppress metabolic signals from normal hepatocytes while preserving the signals arising from tumors. METHODS: Simulations were performed to determine the expected changes in HP 13 C MR signal in liver and tumor under the influence of gadoxetate. CC531 colon cancer cells were implanted into the livers of five Wag/Rij rats. Liver and tumor metabolism were imaged at 3 T using HP [1-13 C] pyruvate chemical shift imaging before and 15 min after injection of gadoxetate. Area under the curve for pyruvate and lactate were measured from voxels containing at least 75% of normal-appearing liver or tumor. RESULTS: Numerical simulations predicted a 36% decrease in lactate-to-pyruvate (L/P) ratio in liver and 16% decrease in tumor. In vivo, baseline L/P ratio was 0.44 ± 0.25 in tumors versus 0.21 ± 0.08 in liver (p = 0.09). Following administration of gadoxetate, mean L/P ratio decreased by an average of 0.11 ± 0.06 (p < 0.01) in normal-appearing liver. In tumors, mean L/P ratio post-gadoxetate did not show a statistically significant change from baseline. Compared to baseline levels, the relative decrease in L/P ratio was significantly greater in liver than in tumors (-0.52 ± 0.16 vs. -0.19 ± 0.25, p < 0.05). CONCLUSIONS: The intracellular hepatobiliary contrast agent showed a greater effect suppressing HP 13 C MRI metabolic signals (through T1 shortening) in normal-appearing liver when compared to tumors. The combined use of HP MRI with selective gadolinium contrast agents may allow more selective imaging in HP 13 C MRI.

Gadolinium retention effect on macrophages - a potential cause of MRI contrast agent Dotarem toxicity.

Gadolinium is a component of the MRI contrast agent Dotarem. Although Dotarem is the least toxic among MRI contrasts used, gadolinium present in Dotarem accumulates for many years in various organs and tissues exerting toxic effects. We showed previously that gadolinium remains in macrophages for at least 7 days after exposure to Dotarem. However, very little is known about the effect of gadolinium retention on the immune cells such as macrophages. We studied the effect of 1-day and 7-day retention of gadolinium on various functions and molecular pathways of macrophages. Gadolinium retention for 7 days decreased macrophage adhesion and motility and dysregulated the expression of adhesion and fibrotic pathway-related proteins such as Notch1 and its ligand Jagged1, adhesion/migration-related proteins PAK1 and Shp1, immune response-related transcription factors Smad3 and TCF19, and chemokines CXCL10 and CXCL13, and dysregulated the mRNA expression of fibrosis-related genes involved in extracellular matrix (ECM) synthesis, such as Col6a1, Fibronectin, MMP9, and MMP12. It also completely (below a level of detection) shut down the transcription of anti-inflammatory M2 macrophage polarization marker the Arg-1. Such changes, if they occur in MRI patients, can be potentially detrimental to the patient's immune system and immune response-related processes.

Arrhythmic risk profile in mitral valve prolapse: A systematic review and metanalysis of 1715 patients.

INTRODUCTION: Mitral valve prolapse (MVP) is a common clinical condition in the general population. A subgroup of patients with MVP may experience ventricular arrhythmias and sudden cardiac death ("arrhythmic mitral valve prolapse" [AMVP]) but how to stratify arrhythmic risk is still unclear. Our meta-analysis aims to identify predictive factors for arrhythmic risk in patients with MVP. METHODS: We systematically searched Medline, Cochrane, Journals@Ovid, Scopus electronic databases for studies published up to December 28, 2022 and comparing AMVP and nonarrhythmic mitral valve prolapse (NAMVP) for what concerns history, electrocardiographic, echocardiographic and cardiac magnetic resonance features. The effect size was estimated using a random-effect model as odds ratio (OR) and mean difference (MD). RESULTS: A total of 10 studies enrolling 1715 patients were included. Late gadolinium enhancement (LGE) (OR: 16.67; p = .005), T-wave inversion (TWI) (OR: 2.63; p < .0001), bileaflet MVP (OR: 1.92; p < .0001) and mitral anulus disjunction (MAD) (OR: 2.60; p < .0001) were more represented among patients with AMVP than in NAMVP. Patients with AMVP were shown to have longer anterior mitral leaflet (AML) (MD: 2.63 mm; p < .0001), posterior mitral leaflet (MD: 2.96 mm; p < .0001), thicker AML (MD: 0.49 mm; p < .0001), longer MAD length (MD: 1.24 mm; p < .0001) and higher amount of LGE (MD: 1.41%; p < .0001) than NAMVP. AMVP showed increased mechanical dispersion (MD: 8.04 ms; 95% confidence interval: 5.13-10.96; p < .0001) compared with NAMVP. CONCLUSIONS: Our meta-analysis proved that LGE, TWI, bileaflet MVP, and MAD are predictive factors for arrhythmic risk in MVP patients.

Diabetes mellitus is associated to high-risk late gadolinium enhancement and worse outcomes in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Diabetes mellitus (DM) is associated with a worse prognosis in patients with heart failure. Our aim was to analyze the clinical and imaging features of patients with DM and their association with outcomes in comparison to nondiabetic patients in a cohort of patients with nonischemic dilated cardiomyopathy (DCM). METHODS: This is a prospective cohort study of patients with DCM evaluated in a tertiary care center from 2018 to 2021. Transthoracic echocardiography and cardiac magnetic resonance findings were assessed. A high-risk late gadolinium enhancement (LGE) pattern was defined as epicardial, transmural, or septal plus free-wall. The primary outcome was a composite of heart failure hospitalizations and all-cause mortality. Multivariable analyses were performed to evaluate the impact of DM on outcomes. RESULTS: We studied 192 patients, of which 51 (26.6%) had DM. The median left ventricular ejection fraction was 30%, and 106 (55.2%) had LGE. No significant differences were found in systolic function parameters between patients with and without DM. E/e values were higher (15 vs. 11.9, p = 0.025), and both LGE (68.6% vs. 50.4%; p = 0.025) and a high-risk LGE pattern (31.4% vs. 18.5%; p = 0.047) were more frequently found in patients with DM. The primary outcome occurred more frequently in diabetic patients (41.2% vs. 23.6%, p = 0.017). DM was an independent predictor of outcomes (OR 2.01; p = 0.049) and of LGE presence (OR 2.15; p = 0.048) in the multivariable analysis. Patients with both DM and LGE had the highest risk of events (HR 3.1; p = 0.003). CONCLUSION: DM is related to a higher presence of LGE in DCM patients and is an independent predictor of outcomes. Patients with DM and LGE had a threefold risk of events. A multimodality imaging approach allows better risk stratification of these patients and may influence therapeutic options.

Contrast-free dynamic susceptibility contrast using sinusoidal and bolus oxygenation challenges.

Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO2. High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.

Evaluation of gadolinium deposition in cortical bone using three-dimensional ultrashort echo time quantitative susceptibility mapping: A preliminary study.

The aim of the current study was to investigate the feasibility of three-dimensional ultrashort echo time quantitative susceptibility mapping (3D UTE-QSM) for the assessment of gadolinium (Gd) deposition in cortical bone. To this end, 40 tibial bovine cortical bone specimens were divided into five groups then soaked in phosphate-buffered saline (PBS) solutions with five different Gd concentrations of 0, 0.4, 0.8, 1.2, and 1.6 mmol/L for 48 h. Additionally, eight rabbits were randomly allocated into three groups, consisting of a normal-dose macrocyclic gadolinium-based contrast agent (GBCA) group (n = 3), a high-dose macrocyclic GBCA group (n = 3), and a control group (n = 2). All bovine and rabbit tibial bone samples underwent magnetic resonance imaging (MRI) on a 3-T clinical MR system. A 3D UTE-Cones sequence was utilized to acquire images with five different echo times (i.e., 0.032, 0.2, 0.4, 0.8, and 1.2 ms). The UTE images were subsequently processed with the morphology-enabled dipole inversion algorithm to yield a susceptibility map. The average susceptibility was calculated in three regions of interest in the middle of each specimen, and the Pearson's correlation between the estimated susceptibility and Gd concentration was calculated. The bone samples soaked in PBS with higher Gd concentrations exhibited elevated susceptibility values. A mean susceptibility value of -2.47 ± 0.23 ppm was observed for bovine bone soaked in regular PBS, while the mean QSM value increased to -1.75 ± 0.24 ppm for bone soaked in PBS with the highest Gd concentration of 1.6 mmol/L. A strong positive correlation was observed between Gd concentrations and QSM values. The mean susceptibility values of rabbit tibial specimens in the control group, normal-dose GBCA group, and high-dose GBCA group were -4.11 ± 1.52, -3.85 ± 1.33, and -3.39 ± 1.35 ppm, respectively. In conclusion, a significant linear correlation between Gd in cortical bone and QSM values was observed. The preliminary results suggest that 3D UTE-QSM may provide sensitive noninvasive assessment of Gd deposition in cortical bone.

Synthetic multi-contrast late gadolinium enhancement imaging using post-contrast magnetic resonance fingerprinting.

Late gadolinium enhancement (LGE) MRI is the non-invasive reference standard for identifying myocardial scar and fibrosis but has limitations, including difficulty delineating subendocardial scar and operator dependence on image quality. The purpose of this work is to assess the feasibility of generating multi-contrast synthetic LGE images from post-contrast T1 and T2 maps acquired using magnetic resonance fingerprinting (MRF). Fifteen consecutive patients with a history of prior ischemic cardiomyopathy (12 men; mean age 63  ±  13 years) were prospectively scanned at 1.5 T between Oct 2020 and May 2021 using conventional LGE and MRF after injection of gadolinium contrast. Three classes of synthetic LGE images were derived from MRF post-contrast T1 and T2 maps: bright-blood phase-sensitive inversion recovery (PSIR), black- and gray-blood T2 -prepared PSIR (T2 -PSIR), and a novel "tissue-optimized" image to enhance differentiation among scar, viable myocardium, and blood. Image quality was assessed on a 1-5 Likert scale by two cardiologists, and contrast was quantified as the mean absolute difference (MAD) in pixel intensities between two tissues, with different methods compared using Kruskal-Wallis with Bonferroni post hoc tests. Per-patient and per-segment scar detection rates were evaluated using conventional LGE images as reference. Image quality scores were highest for synthetic PSIR (4.0) and reference images (3.8), followed by synthetic tissue-optimized (3.3), gray-blood T2 -PSIR (3.0), and black-blood T2 -PSIR (2.6). Among synthetic images, PSIR yielded the highest myocardium/scar contrast (MAD = 0.42) but the lowest blood/scar contrast (MAD = 0.05), and vice versa for T2 -PSIR, while tissue-optimized images achieved a balance among all tissues (myocardium/scar MAD = 0.16, blood/scar MAD = 0.26, myocardium/blood MAD = 0.10). Based on reference mid-ventricular LGE scans, 13/15 patients had myocardial scar. The per-patient sensitivity/accuracy for synthetic images were the following: PSIR, 85/87%; black-blood T2 -PSIR, 62/53%; gray-blood T2 -PSIR, 100/93%; tissue optimized, 100/93%. Synthetic multi-contrast LGE images can be generated from post-contrast MRF data without additional scan time, with initial feasibility shown in ischemic cardiomyopathy patients.

Incorporation of view sharing and KWIC filtering into GRASP-Pro improves spatial resolution of single-shot, multi-TI, late gadolinium enhancement MRI.

While single-shot late gadolinium enhancement (LGE) is useful for imaging patients with arrhythmia and/or dyspnea, it produces low spatial resolution. One approach to improve spatial resolution is to accelerate data acquisition using compressed sensing (CS). Our previous work described a single-shot, multi-inversion time (TI) LGE pulse sequence using radial k-space sampling and CS, but over-regularization resulted in significant image blurring that muted the benefits of data acceleration. The purpose of the present study was to improve the spatial resolution of the single-shot, multi-TI LGE pulse sequence by incorporating view sharing (VS) and k-space weighted contrast (KWIC) filtering into a GRASP-Pro reconstruction. In 24 patients (mean age = 61 ± 16 years; 9/15 females/males), we compared the performance of our improved multi-TI LGE and standard multi-TI LGE, where clinical standard LGE was used as a reference. Two clinical raters independently graded multi-TI images and clinical LGE images visually on a five-point Likert scale (1, nondiagnostic; 3, clinically acceptable; 5, best) for three categories: the conspicuity of myocardium or scar, artifact, and noise. The summed visual score (SVS) was defined as the sum of the three scores. Myocardial scar volume was quantified using the full-width at half-maximum method. The SVS was not significantly different between clinical breath-holding LGE (median 13.5, IQR 1.3) and multi-TI LGE (median 12.5, IQR 1.6) (P = 0.068). The myocardial scar volumes measured from clinical standard LGE and multi-TI LGE were strongly correlated (coefficient of determination, R2 = 0.99) and in good agreement (mean difference = 0.11%, lower limit of the agreement = -2.13%, upper limit of the agreement = 2.34%). The inter-rater agreement in myocardial scar volume quantification was strong (intraclass correlation coefficient = 0.79). The incorporation of VS and KWIC into GRASP-Pro improved spatial resolution. Our improved 25-fold accelerated, single-shot LGE sequence produces clinically acceptable image quality, multi-TI reconstruction, and accurate myocardial scar volume quantification.

Superior Tumor Cell Uptake by Mono- and Tri-nuclear Rhodamine-Gadolinium(III) Agents.

The synthesis and characterization of a novel trinuclear rhodamine-Gd(III) complex, along with two analogous mononuclear rhodamine-Gd(III) complexes, are reported. All complexes displayed good selectivity in a human glioma cell line (T98G) when compared to a glial cell line (SVG p12), with low cytotoxicities. Superior tumor cell uptake for these Gd(III) complexes was observed at lower incubation concentrations compared to previously-reported delocalized lipophilic cations such as a rhodamine-lanthanoid (III) probe and Gd(III)-arylphosphonium complexes, with ca. 150% and 250% increases in Gd uptake, respectively.

[Gd(HB-DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP-DO3A)] (Prohance®).

[Gd(HP-DO3A)] (gadoteridol) as an active compound of ProHance® is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long-term retention of gadolinium-based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP-DO3A)]. It was deemed of interest to assess how minor structural/electronic changes associated to the ligand structure may affect basic properties of the metal complex with several [Gd(HP-DO3A)] analogues synthesized and characterized in the last years. We recently reported that the closest homolog of [Gd(HP-DO3A)], i. e.: [Gd(HB-DO3A)], in which a (±)-2-hydroxy-1-propyl pendant arm is replaced by a (±)-2-hydroxy-1-butyl moiety, showed a significantly different retention behaviour in the model interaction with collagen, despite the apparently very minor structural difference. In this paper we report a comprehensive study of the structural, thermodynamic, kinetic and relaxation properties of [Gd(HB-DO3A)], compared to the parent [Gd(HP-DO3A)] and to other closely related macrocyclic GBCAs to assess whether very minor structural changes can modulate the physico-chemical properties of Gd3+ complexes.

Enabling AI-Generated Content for Gadolinium-Free Contrast-Enhanced Breast Magnetic Resonance Imaging.

BACKGROUND: There is increasing interest in utilizing AI-generated content for gadolinium-free contrast-enhanced breast MRI. PURPOSE: To develop a generative model for gadolinium-free contrast-enhanced breast MRI and evaluate the diagnostic utility of the generated scans. STUDY TYPE: Retrospective. POPULATION: Two hundred seventy-six women with 304 breast MRI examinations (49 ± 13 years, 243/61 for training/testing). FIELD STRENGTH/SEQUENCE: ZOOMit diffusion-weighted imaging (DWI), T1-weighted volumetric interpolated breath-hold examination (T1W VIBE), and axial T2 3D SPACE at 3.0 T. ASSESSMENT: A generative model was developed to generate contrast-enhanced scans using precontrast T1W VIBE and DWI images. The generated and real images were quantitatively compared using the structural similarity index (SSIM), mean absolute error (MAE), and Dice similarity coefficient. Three radiologists with 8, 5, and 5 years of experience independently rated the image quality and lesion visibility on AI-generated and real images within various subgroups using a five-point scale. Four breast radiologists, with 8, 8, 5, and 5 years of experience, independently and blindly interpreted four reading protocols: unenhanced MRI protocol alone and combined with AI-generated scans, abbreviated MRI protocol, and full-MRI protocol. STATISTICAL ANALYSIS: Results were assessed using t-tests and McNemar tests. Using pathology diagnosis as reference standard, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each reading protocol. A P value <0.05 was considered significant. RESULTS: In the test set, the generated images showed similarity to the real images (SSIM: 0.935 ± 0.047 [SD], MAE: 0.015 ± 0.012 [SD], and Dice coefficient: 0.726 ± 0.177 [SD]). No significant difference in lesion visibility was observed between real and AI-generated scans of the mass, non-mass, and benign lesion subgroups. Adding AI-generated scans to the unenhanced MRI protocol slightly improved breast cancer detection (sensitivity: 92.86% vs. 85.71%, NPV: 76.92% vs. 70.00%); achieved non-inferior diagnostic utility compared to the AB-MRI protocol and full-protocol (sensitivity: 92.86%, 95.24%; NPV: 75.00%, 81.82%). DATA CONCLUSION: AI-generated gadolinium-free contrast-enhanced breast MRI has potential to improve the sensitivity of unenhanced MRI in detecting breast cancer. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Gadolinium Contrast Agent Deposition in Children.

Over the past few years, a large number of studies have evidenced increased signal intensity in the deep brain nuclei on unenhanced T1-MRI images achieved by the application of gadolinium-based contrast agents (GBCAs). The deposition of gadolinium in the brain, bone, and other tissues following administration of GBCAs has also been confirmed in histological studies in rodents and in necropsy studies in adults and children. Given the distinct physiological characteristics of children, this review focuses on examining the current research on gadolinium deposition in children, particularly studies utilizing novel methods and technologies. Furthermore, the article compares safety research findings of linear GBCAs and macrocyclic GBCAs in children, with the aim of offering clinicians practical guidance based on the most recent research outcomes. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

Gadolinium Retention and Nephrotoxicity in a Mouse Model of Acute Ischemic Stroke: Linear Versus Macrocyclic Agents.

BACKGROUND: Gadolinium (Gd)-based contrast agents (GBCAs) have been widely used for acute ischemic stroke (AIS) patients. GBCAs or AIS alone may cause the adverse effects on kidney tissue, respectively. However, whether GBCAs and AIS would generate a synergistic negative effect remains undefined. PURPOSE: To evaluate synergistic negative effects of AIS and GBCAs on renal tissues in a mouse model of AIS, and to compare the differences of these negative effects between linear and macrocyclic GBCAs. STUDY TYPE: Animal study. ANIMAL MODEL: Seventy-two healthy mice underwent transient middle cerebral artery occlusion (tMCAO) and sham operation to establish AIS and sham model (N = 36/model). 5.0 mmol/kg GBCAs (gadopentetate or gadobutrol) or 250 µL saline were performed at 4.5 hours and 1 day after model establishing (N = 12/group). ASSESSMENT: Inductively coupled plasma mass spectrometry (ICP-MS) was performed to detect Gd concentrations. Serum biochemical analyzer was performed to measure the serum creatinine (Scr), uric acid (UA), and blood urea nitrogen (BUN). Pathological staining was performed to observe tubular injury, cell apoptosis, mesangial hyperplasia, and interstitial fibrosis. STATISTICAL TESTS: Two-way analysis of variances with post hoc Sidak's tests and independent-samples t-tests were performed. A P-value <0.05 was considered statistically significant. RESULTS: AIS groups showed higher Gd concentration than sham group on day 1 p.i. regardless of gadopentetate or gadobutrol used. Increased total Gd concentration was also found in AIS + gadopentetate group compared with the sham group on day 28 p.i. Significantly higher rates for renal dysfunction, higher tubular injury scores, and higher numbers of apoptotic cells on days 1 or 28 p.i. were found for AIS mice injected with GBCA. AIS + gadopentetate group displayed more severe renal damage than the AIS + gadobutrol group. DATA CONCLUSION: AIS and GBCAs may cause increased total Gd accumulation and nephrotoxicity in a mouse, especially linear GBCAs were used. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4.

MRI Gadolinium-Based Contrast Media: Meeting Radiological, Clinical, and Environmental Needs.

Gadolinium-based contrast agents (GBCAs) are routinely used in magnetic resonance imaging (MRI). They are essential for choosing the most appropriate medical or surgical strategy for patients with serious pathologies, particularly in oncologic, inflammatory, and cardiovascular diseases. However, GBCAs have been associated with an increased risk of nephrogenic systemic fibrosis in patients with renal failure, as well as the possibility of deposition in the brain, bones, and other organs, even in patients with normal renal function. Research is underway to reduce the quantity of gadolinium injected, without compromising image quality and diagnosis. The next generation of GBCAs will enable a reduction in the gadolinium dose administered. Gadopiclenol is the first of this new generation of GBCAs, with high relaxivity, thus having the potential to reduce the gadolinium dose while maintaining good in vivo stability due to its macrocyclic structure. High-stability and high-relaxivity GBCAs will be one of the solutions for reducing the dose of gadolinium to be administered in clinical practice, while the development of new technologies, including optimization of MRI acquisitions, new contrast mechanisms, and artificial intelligence may help reduce the need for GBCAs. Future solutions may involve a combination of next-generation GBCAs and image-processing techniques to optimize diagnosis and treatment planning while minimizing exposure to gadolinium. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.