An NMR relaxometry approach for quantitative investigation of the transchelation of gadolinium ions from GBCAs to a competing macromolecular chelator.

Gadolinium-based contrast agents (GBCAs) have been used in clinical Magnetic Resonance Imaging (MRI) for more than 30 years. However, there is increasing evidence that their dissociation in vivo leads to long-term depositions of gadolinium ions in the human body. In vitro experiments provide critical insights into kinetics and thermodynamic equilibria of underlying processes, which give hints towards the in vivo situation. We developed a time-resolved MRI relaxometry-based approach that exploits distinct relaxivities of Gd3+ in different molecular environments. Its applicability to quantify the transmetallation of GBCAs, the binding of Gd3+ to competing chelators, and the combined transchelation process is demonstrated. Exemplarily, the approach is applied to investigate two representative GBCAs in the presence of Zn2+ and heparin, which is used as a model for a macromolecular and physiologically occurring chelator. Opposing indirect impacts of heparin on increasing the kinetic stability but reducing the thermodynamic stability of GBCAs are observed. The relaxivity of resulting Gd-heparin complexes is shown to be essentially increased compared to that of the parent GBCAs so that they might be one explanation for observed long-term MRI signal enhancement in vivo. In forthcoming studies, the presented method could help to identify the most potent Gd-complexing macromolecular species.

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats.

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug-drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro-in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis-Menten constant (Km,u) of gadoxetate was 106 µM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK-IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE-MRI profiles and elimination from the liver. Therefore, in vivo rat DCE-MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE-MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.

HBP-enhancing hepatocellular adenomas and how to discriminate them from FNH in Gd-EOB MRI.

BACKGROUND: Recent studies provide evidence that hepatocellular  adenomas  (HCAs) frequently take up gadoxetic acid (Gd-EOB) during the hepatobiliary phase (HBP). The purpose of our study was to investigate how to differentiate between Gd-EOB-enhancing HCAs and focal nodular hyperplasias (FNHs). We therefore retrospectively included 40 HCAs classified as HBP Gd-EOB-enhancing lesions from a sample of 100 histopathologically proven HCAs in 65 patients. These enhancing HCAs were matched retrospectively with 28 FNH lesions (standard of reference: surgical resection). Two readers (experienced abdominal radiologists blinded to clinical data) reviewed the images evaluating morphologic features and subjectively scoring Gd-EOB uptake (25-50%, 50-75% and 75-100%) for each lesion. Quantitative lesion-to-liver enhancement was measured in arterial, portal venous (PV), transitional and HBP. Additionally, multivariate regression analyses were performed. RESULTS: Subjective scoring of intralesional Gd-EOB uptake showed the highest discriminatory accuracies (AUC: 0.848 (R#1); 0.920 (R#2)-p < 0.001) with significantly higher uptake scores assigned to FNHs (Cut-off: 75%-100%). Typical lobulation and presence of a central scar in FNH achieved an accuracy of 0.750 or higher in at least one reader (lobulation-AUC: 0.809 (R#1); 0.736 (R#2); central scar-AUC: 0.595 (R#1); 0.784 (R#2)). The multivariate regression emphasized the discriminatory power of the Gd-EOB scoring (p = 0.001/OR:22.15 (R#1) and p < 0.001/OR:99.12 (R#2). The lesion-to-liver ratio differed significantly between FNH and HCA in the PV phase and HBP (PV: 132.9 (FNH) and 110.2 (HCA), p = 0.048 and HBP: 110.3 (FNH) and 39.2 (HCA), p < 0.001)), while the difference was not significant in arterial and transitional contrast phases (p > 0.05). CONCLUSION: Even in HBP-enhancing HCA, characterization of Gd-EOB uptake was found to provide the strongest discriminatory power in differentiating HCA from FNH. Furthermore, a lobulated appearance and a central scar are more frequently seen in FNH than in HCA.

Combining 18F-FDG PET and Gd-EOB-DTPA-enhanced MRI for staging liver fibrosis.

AIM: To evaluate the diagnostic performance of combining 18F-2-fluoro-2-D-deoxyglucose-positron emission tomography (18F-FDG PET) and gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for liver fibrosis staging. MATERIALS AND METHODS: Male New Zealand white rabbits (n = 48) were treated with carbon tetrachloride (CCl4) to induce liver fibrosis, while control group rabbits (n = 8) received normal saline. The liver tissues of rabbits were histopathologically examined (classified according to the METAVIR classification system) for liver fibrosis staging and real-time polymerase chain reaction (RT-PCR) was used to ensure diagnostic accuracy. Integrated PET/MRI was performed. The mean standardised uptake value (SUVmean) and relative enhancement (RE) were evaluated for different liver fibrosis stages using a Mann-Whitney U test. The performance of PET/MRI was evaluated by using the receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC). KEY FINDINGS: In total, 10, 16, and 8 rabbits classified into no fibrosis (F0), mild fibrosis (F1-2), and severe fibrosis (F3-4) categories, respectively. There were significant differences in SUVmean and RE between F0 and F3-4 and between F1-2 and F3-4 (p < 0.01), but no significance between F0 and F1-2 (p > 0.5). Combined SUVmean and RE performed well in staging liver fibrosis, with AUC of 0.8 for F0 or greater, 0.744 for F0 or F1-2, 0.945 for F1-2 or F3-4, and 0.962 for F3-4. SIGNIFICANCE: Combining SUVmean and RE provides high accuracy for grading liver fibrosis, especially in the differentiation between F1-2 and F3-4. 18F-FDG and Gd-EOB-DTPA-enhanced PET/MRI could be a non-invasive diagnostic method to guide the selection of clinical treatment options.

Unusual Distribution Kinetics of Gadoxetate in Healthy Human Subjects Genotyped for OATP1B1: Application of Population Analysis and a Minimal Physiological-Based Pharmacokinetic Model.

Gadoxetate (Gd-EOB-DTPA) is a hepatobiliary-specific contrast agent for magnetic resonance imaging. Using a minimal physiological-based pharmacokinetic (PBPK) model, it has been shown for the first time, that the rapid initial decline of plasma concentration after intravenous injection is the result of an uptake into hepatocytes rather than of a distribution into the extravascular extracellular space. About 50% of the steady-state distribution volume is related to hepatic uptake. The hepatic extraction ratio and hepatic clearance estimated based on the liver model as a part of the PBPK model were in accordance with literature data. The same holds for the predicted time course of the amount of gadoxetate in liver parenchyma. In elucidating the impact of OATP1B1 genotype (*1a/*1a and *15/*15) on the pharmacokinetics of gadoxetate, we found that tissue uptake and back-transfer rates were significantly reduced, whereas the hepatic sinusoidal efflux rate was significantly increased in carriers of the *15/*15 haplotype compared with those of the *1a/*1a (wild type). The model is potentially useful for determining hepatic kinetic parameters and distribution properties of drugs.

Albumin-based nanoparticles as contrast medium for MRI: vascular imaging, tissue and cell interactions, and pharmacokinetics of second-generation nanoparticles.

This multidisciplinary study examined the pharmacokinetics of nanoparticles based on albumin-DTPA-gadolinium chelates, testing the hypothesis that these nanoparticles create a stronger vessel signal than conventional gadolinium-based contrast agents and exploring if they are safe for clinical use. Nanoparticles based on human serum albumin, bearing gadolinium and designed for use in magnetic resonance imaging, were used to generate magnet resonance images (MRI) of the vascular system in rats ("blood pool imaging"). At the low nanoparticle doses used for radionuclide imaging, nanoparticle-associated metals were cleared from the blood into the liver during the first 4 h after nanoparticle application. At the higher doses required for MRI, the liver became saturated and kidney and spleen acted as additional sinks for the metals, and accounted for most processing of the nanoparticles. The multiple components of the nanoparticles were cleared independently of one another. Albumin was detected in liver, spleen, and kidneys for up to 2 days after intravenous injection. Gadolinium was retained in the liver, kidneys, and spleen in significant concentrations for much longer. Gadolinium was present as significant fractions of initial dose for longer than 2 weeks after application, and gadolinium clearance was only complete after 6 weeks. Our analysis could not account quantitatively for the full dose of gadolinium that was applied, but numerous organs were found to contain gadolinium in the collagen of their connective tissues. Multiple lines of evidence indicated intracellular processing opening the DTPA chelates and leading to gadolinium long-term storage, in particular inside lysosomes. Turnover of the stored gadolinium was found to occur in soluble form in the kidneys, the liver, and the colon for up to 3 weeks after application. Gadolinium overload poses a significant hazard due to the high toxicity of free gadolinium ions. We discuss the relevance of our findings to gadolinium-deposition diseases.

Anterior pituitary gland T1 signal intensity is influenced by time delay after injection of gadodiamide.

To test the hypothesis of washout from the anterior pituitary (AP) gland after serial injections of gadodiamide. We included 59 patients with history of at least 5 injections of gadodiamide. Values of mean signal intensity of the AP and of the central pons were measured on unenhanced sagittal T1-weighted images. AP-to-pons signal intensity ratios were calculated dividing the values of the AP by those of the pons. The measurements were performed using MR images acquired at four different time points including baseline (prior to any gadodiamide injection), minimum post-injection time delay, maximum post-injection time delay, and last available MR scans. Normalized ratios (i.e. ratios divided total volume of injected gadodiamide) were also calculated. To assess the difference between ratios, non-parametric Wilcoxon signed-rank test was applied. The correlations were tested with non-parametric Spearman correlation coefficient. A p-value < 0.05 was considered as statistically significant. A statistically significant increase of AP signal intensity was found by comparing the baseline scans with both the minimum time delay (p = 0.003) and maximum time delay scans (p = 0.005). We found significant higher normalized ratios for minimum post-injection time delay with respect to maximum post-injection time delay (p < 0.001). The normalized ratios demonstrated a statistically significant negative correlation with the post-injection time delay (r = - 0.31; p = 0.006). The findings of this study suggest that washout phenomena of retained/deposited gadolinium from the AP are influenced by the total injected volume and post-injection time delay.

N-acetylcysteine-PLGA nano-conjugate: effects on cellular toxicity and uptake of gadopentate dimeglumine.

Gadolinium as a contrast agent in MRI technique combined with DTPA causes contrast induced nephropathy (CIN) and nephrogenic systemic fibrosis (NSF) which can reduce by usage of antioxidants such as N-acetyl cysteine by increasing the membrane's permeability leads to lower cytotoxicity. In this study, N-acetyl cysteine-PLGA Nano-conjugate was synthesized according to stoichiometric rules of molar ratios andafter assessment by FTIR, NMR spectroscopy and Atomic Force Microscopy (AFM) imaging was combined with Magnevist® (gadopentetate dimeglumine) and its effects on the renal cells were evaluated. MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] and cellular uptake assays have indicated relatively significant toxicity of magnevist (P < 0.05) on three cell lines including HEK293, MCF7 and L929 compared to other synthesized ligands that shown no toxicity. Moreover, systemic evaluation has shown no notable changes of blood urea nitrogen (BUN) and creatinine in kidney of mice. In consequence, antioxidant effect was increased as well as the renal toxicity of the contrast agent reduced at the cell level. As a result, PLGA-NAC nano-conjugate can be a promising choice for decreasing the magnevist toxicity for treatment and prevention of CIN and will be able to open a new horizon to research on reduction of toxicity of contrast agents by using nanoparticles.

Gadolinium Retention in the Central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis.

Background Despite the wide use of gadolinium-based contrast agents (GBCAs) for enhanced MRI, their neurochemical and behavioral consequences, if any, remain poorly understood. Purpose To investigate the effect of repeated exposure to a linear or macrocyclic GBCA on gadolinium retention in the central and peripheral nervous system of rats and to assess the functional implications of such retention on hippocampal neurogenesis and sensory and cognitive processing. Materials and Methods Seventy male Sprague-Dawley rats (4 weeks old) received intraperitoneal injections of gadoterate meglumine (0.6 or 2.5 mmol per kilogram of body weight), gadodiamide (0.6 or 2.5 mmol/kg), or saline daily for 20 days (February 2018-March 2019). The 5-bromo-2'-deoxyuridine injections were administered every 3 days to determine the number of proliferating cells and the number of newly maturing neurons in the hippocampus. Sensory and cognitive behavioral tests were performed to assess the effect of GBCAs on pain sensitivity and spatial working memory function, respectively. Finally, inductively coupled plasma mass spectrometry analysis was used to quantify gadolinium retention in the brain, spinal cord, and peripheral nerves 24 hours after the last GBCA administration. One-way and mixed-design analyses of variance were used for statistical analysis. Results All GBCAs resulted in significant gadolinium retention in central and peripheral nervous tissues (1.8-333.2 nmol Gd/g tissue). Pain hypersensitivity to thermal and mechanical stimuli (P < .001) was observed after gadodiamide exposure in rats but not after gadoterate meglumine exposure. Rats injected with both GBCAs showed no changes in spatial working memory or in hippocampal cell proliferation and maturation. Conclusion Gadolinium was retained in the spinal cord and peripheral nerves in rats exposed to multiple administrations of linear and macrocyclic contrast agents. Gadodiamide (linear contrast agent) but not gadoterate meglumine (macrocyclic contrast agent) led to pain hypersensitivity, but neither affected spatial working memory performance, hippocampal cellular proliferation, or hippocampal neurogenesis. © RSNA, 2020 See also the editorial by Radbruch in this issue.

Hepatic uptake index in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced magnetic resonance imaging estimates functional liver reserve and predicts post-hepatectomy liver failure.

BACKGROUND: Recent evidence suggests that gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced (Gd-EOB-DTPA) magnetic resonance imaging may be used to evaluate liver function. The aim of this study was to assess whether the signal intensity of Gd-EOB-DTPA magnetic resonance imaging may be used to predict functional liver reserve and posthepatectomy liver failure in patients undergoing hepatectomy for liver tumors. METHODS: This is an observational retrospective study on 137 preoperative Gd-EOB-DTPA magnetic resonance imaging of patients undergoing hepatectomy between 2015 and 2018. Mean signal intensity of liver (L20) and spleen (S20) were measured on T1-weighted single-breath-hold 3-dimensional fat-saturated gradient echo sequences acquired 20 minutes after Gd-EOB-DTPA administration. The hepatocellular uptake index of liver volume (VL) was calculated with the formula VL([L20/S20] - 1) and was tested with several score systems for liver diseases and to the occurrence of post-hepatectomy liver failure. RESULTS: Patients with diseased liver had significantly lower values of hepatic uptake index in comparison with those with normal function. This was found for a Model for End-Stage Liver Disease score ≤9 versus >9 (P = .04), combination of bilirubin and cholinesterases levels score ≤2 versus >2 (P = .02), albumin to bilirubin grades (P = .03), and Humanitas score ≤6 versus >6 (P = .03). Twenty-two patients (16%) developed posthepatectomy liver failure, and 2 (1.4%) died within 90 days. The hepatocellular uptake index was significantly lower in those patients with posthepatectomy liver failure (P < .01). Receiver operating characteristics curve analysis revealed valuable hepatocellular uptake index ability in predicting post-hepatectomy liver failure (area under the curve = 0.84; 95% confidence interval, 0.71-0.92; P < .01), with a cutoff value of 574.33 (98% sensitivity; 83% specificity). CONCLUSION: The hepatocellular uptake index hepatocellular uptake index measured on preoperative Gd-EOB-DTPA magnetic resonance imaging identifies patients with diseased liver and predicts posthepatectomy liver failure. This index could be used to discern those patients at higher risk of complications after hepatectomy.

Hepatocyte-specific contrast-enhanced MRI findings of focal nodular hyperplasia-like nodules in the liver following chemotherapy in pediatric cancer patients.

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.

Assessment of tumor treatment response using active contrast encoding (ACE)-MRI: Comparison with conventional DCE-MRI.

PURPOSE: To investigate the validity of contrast kinetic parameter estimates from Active Contrast Encoding (ACE)-MRI against those from conventional Dynamic Contrast-Enhanced (DCE)-MRI for evaluation of tumor treatment response in mouse tumor models. METHODS: The ACE-MRI method that incorporates measurement of T1 and B1 into the enhancement curve washout region, was implemented on a 7T MRI scanner to measure tracer kinetic model parameters of 4T1 and GL261 tumors with treatment using bevacizumab and 5FU. A portion of the same ACE-MRI data was used for conventional DCE-MRI data analysis with a separately measured pre-contrast T1 map. Tracer kinetic model parameters, such as Ktrans (permeability area surface product) and ve (extracellular space volume fraction), estimated from ACE-MRI were compared with those from DCE-MRI, in terms of correlation and Bland-Altman analyses. RESULTS: A three-fold increase of the median Ktrans by treatment was observed in the flank 4T1 tumors by both ACE-MRI and DCE-MRI. In contrast, the brain tumors did not show a significant change by the treatment in either ACE-MRI or DCE-MRI. Ktrans and ve values of the tumors from ACE-MRI were strongly correlated with those from DCE-MRI methods with correlation coefficients of 0.92 and 0.78, respectively, for the median values of 17 tumors. The Bland-Altman plot analysis showed a mean difference of -0.01 min-1 for Ktrans with the 95% limits of agreement of -0.12 min-1 to 0.09 min-1, and -0.05 with -0.37 to 0.26 for ve. CONCLUSION: The tracer kinetic model parameters estimated from ACE-MRI and their changes by treatment closely matched those of DCE-MRI, which suggests that ACE-MRI can be used in place of conventional DCE-MRI for tumor progression monitoring and treatment response evaluation with a reduced scan time.

[In vivo dynamic changes of inner ear guinea pigs with 9.4 T esla MRI].

Objective: To observe the imaging characteristics of guinea pig cochlear structure using 9.4 Tesla magnetic resonance imaging system at different time intervals of contrast agent distribution in the inner ear. Methods: Form May 2015 to October 2015, five albino guinea pigs were injected with Gd-DTPA via the right internal jugular vein (3 ml/kg). Inner ears were scanned with 9.4T MRI. At the 10 th, 30 th, 60 th, 90 th and 120 th minutes post-Gd-DTPA, we took inner ear images to detect changes of endolymph and perilymph. Using Image J software, we acquired MRI gray value through the first, second, third and apical turn of cochlear at different time points. Analysis by one-way ANOVA was taken to analyze the resultsusing GraphPad Prism 5 software. Results: Only outlines of the cochlea and vestibule were visible before Gd-DTPA injection and there was no clear distinction between endolymph and perilymph. Cochlea vestibule on T1 weighted images was enhanced at the 10 th (the first turn of cochlear 8 203±819) after injection, and then imaging of each part of cochlea, including cochlea, vestibule, semicircular canal and even endolymph and perilymph, can be distinguished clearly, because they enhanced gradually at the 30 th(10 489±819), 60 th(13 965±591), and at 90 th(18 050±1 250) after injection. While at the 120 th(18 952±1 185) minute, imaging was not significantly enhanced than at the 90 th minute. The speed and volume of contrast agent spreaded into the various parts of the inner ear were different, and changes with distribution of contrast agent in each part of the inner ear showed a rising process in a certain period of time. The distribution of contrast agent in the inner ear had concentration gradient via basal turn higher and apical turn lower. Conclusions: Endolymph of inner ear can be distinguished from the perilymph using a 9.4T MRI system with Gd-DTPA, and the best observation timer was 90 minutes after intravenous injection of contrast agent. In summary, our study provides the clearly visualized imaging evidence of the changes of the lymphatic fluid, which may be useful for diagnosis of inner ear diseases such as Meniere's Disease.

DCE-MRI of locally-advanced carcinoma of the uterine cervix: Tofts analysis versus non-model-based analyses.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide biomarkers of the outcome of locally-advanced cervical carcinoma (LACC). There is, however, no agreement on how DCE-MR recordings should be analyzed. Previously, we have analyzed DCE-MRI data of LACC using non-model-based strategies. In the current study, we analyzed DCE-MRI data of LACC using the Tofts pharmacokinetic model, and the biomarkers derived from this analysis were compared with those derived from the non-model-based analyses. METHODS: Eighty LACC patients given cisplatin-based chemoradiotherapy with curative intent were included in the study. Treatment outcome was recorded as disease-free survival (DFS) and overall survival (OS). DCE-MRI series were analyzed voxelwise to produce Ktrans and ve frequency distributions, and ROC analysis was used to identify the parameters of the frequency distributions having the greatest potential as biomarkers. The prognostic power of these parameters was compared with that of the non-model-based parameters LETV (low-enhancing tumor volume) and TVIS (tumor volume with increasing signal). RESULTS: Poor DFS and OS were associated with low values of Ktrans, whereas there was no association between treatment outcome and ve. The Ktrans parameters having the greatest prognostic value were p35-Ktrans (the Ktrans value at the 35 percentile of a frequency distribution) and RV-Ktrans (the tumor subvolume with Ktrans values below 0.13 min- 1). Multivariate analysis including clinical parameters and p35-Ktrans or RV-Ktrans revealed that RV-Ktrans was the only independent prognostic factor of DFS and OS. There were significant correlations between RV-Ktrans and LETV and between RV-Ktrans and TVIS, and the prognostic power of RV-Ktrans was similar to that of LETV and TVIS. CONCLUSIONS: Biomarkers of the outcome of LACC can be provided by analyzing DCE-MRI series using the Tofts pharmacokinetic model. However, these biomarkers do not appear to have greater prognostic value than biomarkers determined by non-model-based analyses.

Within-network brain connectivity in Crohn's disease patients with gadolinium deposition in the cerebellum.

PURPOSE: Patients with Crohn's disease (CD) undergo multiple gadolinium-based contrast agent injections across their lifespan to enhance signal intensity of the intestinal wall and differentiate active from quiescent inflammatory disease. Thus, CD patients are prone to gadolinium accumulation in the brain and represent a non-neurological population to explore gadolinium-related brain toxicity. Possible effects are expected to be greater on the cerebellar network due to the high propensity of the dentate nucleus to accumulate gadolinium. Herein, we provide a whole-brain network analysis of resting-state fMRI dynamics in long-term quiescent CD patients with normal renal function and MRI evidence of gadolinium deposition in the brain. METHODS: Fifteen patients with CD and 16 healthy age- and gender-matched controls were enrolled in this study. Relevant resting-state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data. An unpaired two-sample t test (with age and sex as nuisance variables) was used to investigate between different RSNs. Clusters were determined by using threshold-free cluster enhancement and a family-wise error corrected cluster significance threshold of p < 0.05. RESULTS: Patients showed significantly decreased resting-state functional connectivity (p < 0.05, FWE corrected) of several regions of the right frontoparietal (FPR) and the dorsal attention (DAN) RSNs. No differences between the two groups were found in the functional connectivity maps of all the other RSNs, including the cerebellar network. CONCLUSION: Our findings suggest a non-significant impact of gadolinium deposition on within-network cerebellar functional connectivity of long-term quiescent CD patients.

The anterior eye chamber: entry of the natural excretion pathway of gadolinium contrast agents?

OBJECTIVE: Previous studies provided evidence that gadolinium can be found in the aqueous chamber (AC) of the eye several hours post injection (p.i.) of gadolinium-based contrast agents (GBCAs). This study aimed to investigate whether gadolinium can be detected promptly after injection of a macrocyclic GBCA on contrast-enhanced T1-weighted MRI in the AC of children. METHODS: This retrospective study encompassed MRI of 200 healthy eyes of children suffering from retinoblastoma of the contralateral eye. MRI was performed with an orbital coil with the children in a state of general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between pre and post contrast-enhanced T1-weighted images (Dotarem®, Guerbet, 0.1 ml/kg body weight, mean (standard deviation) p.i. time = 12:24 (± 2:31) min). RESULTS: A highly significant signal intensity increase was found in the AC of healthy eyes 12 min after GBCA injection (median ∆SIR (interquartile range) = + 0.08 (0.05-0.12), p < 0.0001). In addition, gadolinium enhancement showed a strong negative correlation with children's age in multivariate analysis with adjustment for p.i. time (p < 0.0001). CONCLUSIONS: GBCA leakage into the AC of healthy infantile eyes was found promptly after injection. The negative correlation between patient age and GBCA enhancement might be explained by a maturation process of the blood-aqueous barrier or Schlemm's canal. Future studies should assess the duration and potential diagnostic applications as well as possible safety concerns of gadolinium presence in the AC. KEY POINTS: • Leakage of gadolinium-based contrast agent into the aqueous chamber of infantile eyes was found promptly after intravenous injection (p < 0.0001). • Gadolinium enhancement of the anterior eye chamber was negatively correlated with the children's age (p < 0.0001).

Longitudinal Monitoring of Gd-DTPA Following Convection Enhanced Delivery in the Brainstem.

BACKGROUND: Convection-enhanced delivery (CED) has been introduced into contemporary therapeutic strategies for incurable brain neoplasms as diffuse intrinsic pontine glioma. Therapeutic benefit in part is predictably dependent on drug distribution within tumors. However, therapeutics can rarely be detected through conventional imaging techniques. Coinfusion of the tracer gadolinium-diethylenetriaminepentacetate (Gd-DTPA) has been advocated to monitor drug distributive features including volume, tumor coverage, and efflux during and after administration. The kinetics of Gd-DTPA are unclear as longitudinal magnetic resonance imaging is rarely performed. Understanding these changes would have important implications related to the timing of diagnostic imaging and reliance on tracers as surrogates of pharmacokinetic drug monitoring. CASE DESCRIPTION: The behavior of Gd-DTPA as a surrogate is presented in a time-dependent fashion as measured by repeated magnetic resonance imaging based on the case of a child with recurrent diffuse intrinsic pontine glioma treated with an oncolytic virus (ICOVIR-5) delivered by CED with coinfused Gd-DTPA (1 mM, for a volume of 2000 µL). Initial Vd/Vi was 1.46. Gd-DTPA was observed up to 18 hours post CED but not thereafter. CONCLUSIONS: This longitudinal imaging assessment provides a rare opportunity to better characterize the kinetics of surrogate tracers delivered by CED to the brainstem, highlighting the importance of immediate and longitudinal monitoring.

Increased and More Heterogeneous Gadoxetic Acid Uptake of the Liver Parenchyma after Hepatitis C Virus Eradication by Direct Antiviral Agent.

We evaluated the changes of gadoxetic acid uptake of the liver parenchyma after hepatitis C virus (HCV) eradication by direct-antiviral agent (DAA) therapy. The increase rate of the liver-to-muscle signal intensity ratio, the skewness and the kurtosis were calculated in the hepatobiliary phase. After sustained virological response, gadoxetic acid uptake of the liver parenchyma increased, but became heterogeneous. Our study proved that HCV eradication by DAA therapy could significantly affect gadoxetic acid uptake.

Convolutional neural network-automated hepatobiliary phase adequacy evaluation may optimize examination time.

PURPOSE: To develop and evaluate the performance of a fully-automated convolutional neural network (CNN)-based algorithm to evaluate hepatobiliary phase (HBP) adequacy of gadoxetate disodium (EOB)-enhanced MRI. Secondarily, we explored the potential of the proposed CNN algorithm to reduce examination length by applying it to EOB-MRI examinations. METHODS: We retrospectively identified EOB-enhanced MRI-HBP series from examinations performed 2011-2018 (internal and external datasets). Our algorithm, comprising a liver segmentation and classification CNN, produces an adequacy score. Two abdominal radiologists independently classified series as adequate or suboptimal. The consensus determination of HBP adequacy was used as ground truth for CNN model training and validation. Reader agreement was evaluated with Cohen's kappa. Performance of the algorithm was assessed by receiver operating characteristics (ROC) analysis and computation of the area under the ROC curve (AUC). Potential examination duration reduction was evaluated descriptively. RESULTS: 1408 HBP series from 484 patients were included. Reader kappa agreement was 0.67 (internal dataset) and 0.80 (external dataset). AUCs were 0.97 (0.96-0.99) for internal and 0.95 (0.92-96) for external and were not significantly different from each other (p = 0.24). 48 % (50/105) examinations could have been shorter by applying the algorithm. CONCLUSION: A proposed CNN-based algorithm achieves higher than 95 % AUC for classifying HBP images as adequate versus suboptimal. The application of this algorithm could potentially shorten examination time and aid radiologists in recognizing technically suboptimal images, avoiding diagnostic pitfalls.

Dual Plasma Sampling Method to Determine the Hepatic and Renal Clearance of the 2 Diastereoisomers of Gd-EOB-DTPA.

OBJECTIVES: The aim of this study was to develop a method to determine hepatic and renal clearance of the 2 diastereoisomers (Gd-A, Gd-B) of Gd-EOB-DTPA separately. MATERIALS AND METHODS: Between July 2017 and February 2018, 41 patients with hepatic disease were prospectively included. For each patient, 1 mL of iopromide (to determine glomerular filtration rate [GFR]) was coadministered with Gd-EOB-DTPA (Gd-A and Gd-B; 65:35 wt/wt). The plasma clearances of Gd-A (PCL-GdA) and Gd-B (PCL-GdB) as well as the iopromide (GFR) were generated by using dual plasma sampling method. Meanwhile, the patient's urine was collected for measurement of renal clearance of Gd-A (RCL-GdA) and Gd-B (RCL-GdB) to confirm its agreement with GFR. Hepatic clearances of Gd-A (HCL-GdA) and Gd-B (HCL-GdB) were calculated by subtracting the GFR from PCL-GdA and PCL-GdB, respectively, and were correlated with indocyanine green (ICG) 15 minutes retention rate (ICG R15). Pharmacokinetic parameters were compared between the two isomers and between Child-Pugh classifications using student's t test. RESULTS: Within the group of 41 patients evaluated, both RCL-GdA and RCL-GdB demonstrated a good correlation and agreement to GFR (statistics shown in the main body). HCL-GdA demonstrated a strong negative correlation (r = -0.86, P < 0.001) with ICG R15 and was much higher than HCL-GdB (116.18 ± 75.48 vs 19.74 ± 14.24 mL/min, P < 0.001). HCL-GdB demonstrated a weak correlation (r = -0.26, P = 0.102) with ICG R15. HCL-GdA of noncirrhosis and Child-Pugh class A (151.74 ± 68.28 mL/min, n = 26) was higher than that of Child-Pugh class B (54.54 ± 39.13 mL/min, n = 15; P = 0.001). CONCLUSIONS: A practical method was established for the determination of hepatic and renal clearance of the 2 isomers of Gd-EOB-DTPA. The 2 isomers have equal renal clearance and different hepatic clearance. The HCL-GdA may serve as a novel marker to reflect liver function reserve.