Diagnostic algorithm for subcentimeter hepatocellular carcinoma using alpha-fetoprotein and imaging features on gadoxetic acid-enhanced MRI.

OBJECTIVE: To investigate the role of serum alpha-fetoprotein (AFP) in diagnosing subcentimeter hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI (EOB-MRI). METHODS: This study retrospectively enrolled treatment-naïve patients with chronic hepatitis B who had a solitary subcentimeter observation on EOB-MRI from January 2017 to March 2023. Final diagnosis was confirmed by pathology for HCC and pathology or follow-up for benign controls. The AFP cutoff value for HCC was determined using Youden's index. Diagnostic criteria were developed according to significant findings in logistic regression analyses based on AFP and imaging features. The diagnostic performance of possible criteria was compared to the diagnostic hallmarks of HCC (arterial-phase hyperintensity and portal-phase hypointensity). RESULTS: A total of 305 patients (mean age, 51.5 ± 10.7 years; 153 men) were divided into derivation and temporal validation cohorts. Four findings, namely AFP >13.7 ng/mL, arterial-phase hyperintensity, portal-phase hypointensity, and transitional-phase hypointensity, were predictors of HCC. A new criterion (at least three of the four findings) showed higher sensitivity than the diagnostic hallmarks (derivation cohort, 71.6% vs. 52.3%, p < 0.001; validation cohort, 75.0% vs. 47.5%, p = 0.003) without decreasing specificity (derivation cohort, 92.5% vs. 92.5%, p > 0.999; validation cohort, 92.0% vs. 92.0%, p > 0.999). Another criterion (all four findings) achieved a slightly higher specificity than the diagnostic hallmark (derivation cohort, 99.1% vs. 92.5%, p = 0.023; validation cohort, 100.0% vs. 92.0%, p = 0.134). Subgroup analysis for hepatobiliary hypointense observations yielded similar results. CONCLUSION: Including AFP in the diagnostic algorithm may improve the diagnostic performance for subcentimeter HCC. CLINICAL RELEVANCE STATEMENT: Combining imaging features on gadoxetic acid-enhanced MRI with alpha-fetoprotein may enhance the diagnostic performance for subcentimeter HCC in treatment-naïve patients with chronic hepatitis B. KEY POINTS: • The traditional diagnostic hallmark of HCC (arterial-phase hyperintensity and portal-phase hypointensity) shows modest diagnostic performance for subcentimeter HCC on EOB-MRI. • Serum alpha-fetoprotein > 13.7 ng/mL, arterial-phase hyperintensity, portal-phase hypointensity, and transitional-phase hypointensity were independent predictors for subcentimeter HCC. • A criterion of at least three of the four above findings achieved a higher sensitivity without decreasing specificity.

Suboptimal performance of LI-RADS v2018 on gadoxetic acid-enhanced MRI for detecting hepatocellular carcinoma in liver transplant candidates.

OBJECTIVES: To evaluate the diagnostic performance for hepatocellular carcinoma (HCC) detection of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 on gadoxetic acid-enhanced MRI, comparing liver transplant candidates (LT group) with patients who underwent surgical resection (SR group), and to determine significant clinical factors for diagnostic performance of LI-RADS v2018. METHODS: Patients who underwent gadoxetic acid-enhanced MRI and subsequent SR or LT for HCC were retrospectively included between January 2019 and December 2020. The sensitivity and specificity of LI-RADS LR-5 for HCC were compared between the two groups using generalized estimating equations. The accuracy of patient allocation according to the Milan criteria was calculated for the LT group. Univariable and multivariable logistic regression analyses were performed to determine significant clinical factors associated with the sensitivity of LI-RADS. RESULTS: Of the 281 patients, 237 were assigned to the SR group, and 44 were assigned to the LT group. The LT group showed significantly lower per-patient (48.5% vs. 79.6%, p < .001) and per-lesion sensitivity (31.0% vs. 75.9%, p < .001) than the SR group, whereas no significant difference in both per-patient (100.0% vs. 91.7%, p > .99) and per-lesion specificities (100.0% vs. 94.1%, p > .99). The accuracy of patient allocation was 50.0%. Sensitivity was significantly lower in patients with a smaller lesion size (p < .001), a larger lesion number (p = .002), and a higher Child-Pugh score (p = .009). CONCLUSION: LI-RADS v2018 on gadoxetic acid-enhanced MRI might be insufficient in liver transplant candidates and other diagnostic imaging tests should be considered in patients with these significant clinical factors. CLINICAL RELEVANCE STATEMENT: In liver transplant candidates with a smaller lesion size, a larger lesion number, and a higher Child-Pugh score, imaging tests other than gadoxetic acid-enhanced MRI may be clinically useful to determine the transplant eligibility. KEY POINTS: • The sensitivity of the Liver Imaging Reporting and Data System (LI-RADS) was lower in liver transplant candidates than in those who underwent surgical resection. • With the use of gadoxetic acid-enhanced MRI, the accuracy of patient allocation for liver transplantation on the basis of the Milan criteria was suboptimal. • The sensitivity of LI-RADS v2018 was significantly associated with lesion size, lesion number, and Child-Pugh classification.

The Breakdown of Blood-Labyrinth Barrier Makes it Easier for Drugs to Enter the Inner Ear.

PURPOSE: This study aimed to investigate dynamic change of permeability of blood-labyrinth barrier (BLB) after noise exposure and its effect on the drug delivery efficiency of systemic administration. METHODS: Gadopentetate dimeglumine (Gd-DTPA) and dexamethasone (DEX) were used as tracers, and magnetic resonance imaging (MRI) and immunofluorescence were used to observe the change of the BLB after strong noise exposure in guinea pigs. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to observe the effect of the breakdown of BLB after noise exposure on the drug delivery efficiency of intravenous DEX. The guinea pigs were divided into 6 groups: normal group (N), 1, 3, 5, 8, and 12 days after noise exposure groups (P1, P3, P5, P8, P12), with 5 animals in each group. RESULTS: The BLB changes dynamically after noise exposure. Increased permeability of the blood-endolymph barrier, the endolymph-perilymph barrier, and the blood-nerve barrier was observed at days 1-3, 1-5, and 1-8, respectively, after noise exposure in guinea pigs. Higher drug concentration in the cochlear tissue was obtained by intravenous administration of DEX in guinea pigs during the time window of increased permeability of the BLB. CONCLUSION: After noise exposure, the increased BLB permeability makes it easier for drugs to enter the inner ear from blood. In guinea pigs, 1-8 days after strong noise exposure, the drug delivery efficiency of systemic administration increased. After 8 days, the efficiency gradually returned to normal level. 1-8 days after noise exposure may be the best intervention time for systemic administration. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2377-2386, 2024.

Comparison of non-radiomics imaging features and radiomics models based on contrast-enhanced ultrasound and Gd-EOB-DTPA-enhanced MRI for predicting microvascular invasion in hepatocellular carcinoma within 5 cm.

OBJECTIVES: The purpose of this study is to establish microvascular invasion (MVI) prediction models based on preoperative contrast-enhanced ultrasound (CEUS) and ethoxybenzyl-enhanced magnetic resonance imaging (EOB-MRI) in patients with a single hepatocellular carcinoma (HCC) ≤ 5 cm. METHODS: Patients with a single HCC ≤ 5 cm and accepting CEUS and EOB-MRI before surgery were enrolled in this study. Totally, 85 patients were randomly divided into the training and validation cohorts in a ratio of 7:3. Non-radiomics imaging features, the CEUS and EOB-MRI radiomics scores were extracted from the arterial phase, portal phase and delayed phase images of CEUS and the hepatobiliary phase images of EOB-MRI. Different MVI predicting models based on CEUS and EOB-MRI were constructed and their predictive values were evaluated. RESULTS: Since univariate analysis revealed that arterial peritumoral enhancement on the CEUS image, CEUS radiomics score, and EOB-MRI radiomics score were significantly associated with MVI, three prediction models, namely the CEUS model, the EOB-MRI model, and the CEUS-EOB model, were developed. In the validation cohort, the areas under the receiver operating characteristic curve of the CEUS model, the EOB-MRI model, and the CEUS-EOB model were 0.73, 0.79, and 0.86, respectively. CONCLUSIONS: Radiomics scores based on CEUS and EOB-MRI, combined with arterial peritumoral enhancement on CEUS, show a satisfying performance of MVI predicting. There was no significant difference in the efficacy of MVI risk evaluation between radiomics models based on CEUS and EOB-MRI in patients with a single HCC ≤ 5 cm. CLINICAL RELEVANCE STATEMENT: Radiomics models based on CEUS and EOB-MRI are effective for MVI predicting and conducive to pretreatment decision-making in patients with a single HCC within 5 cm. KEY POINTS: • Radiomics scores based on CEUS and EOB-MRI, combined with arterial peritumoral enhancement on CEUS, show a satisfying performance of MVI predicting. • There was no significant difference in the efficacy of MVI risk evaluation between radiomics models based on CEUS and EOB-MRI in patients with a single HCC ≤ 5 cm.

Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells.

Gadopentetic acid and gadodiamide are paramagnetic gadolinium-based contrast agents (GBCAs) that are routinely used for dynamic contrast-enhanced magnetic resonance imaging (MRI) to monitor disease progression in cancer patients. However, growing evidence indicates that repeated administration of GBCAs may lead to gadolinium (III) cation accumulation in the cortical bone tissue, skin, basal ganglia, and cerebellum, potentially leading to a subsequent slow long-term discharge of Gd3+. Gd3+ is a known activator of the TRPC5 channel that is implicated in breast cancer's resistance to chemotherapy. Herein, we found that gadopentetic acid (Gd-DTPA, 1 mM) potentiated the inward and outward currents through TRPC5 channels, which were exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd3+-sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-Gq/11-PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd3+ insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7 and SK-BR-3) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect the IC50 values of ADM. However, treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 and SK-BR-3 cells, promoting the survival of these two breast cancer cells in the presence of ADM. The antagonist of TRPC5, AC1903 (1 µM), increased ADM nuclear accumulation induced by Gd-DTPA-treatment. These data indicate that prolonged GBCA treatment may lead to increased breast cancer cell survival owing to the upregulation of TRPC5 expression and the increased ADM resistance. We propose that while focusing on providing medical care of the best personalized quality in the clinic, excessive administration of GBCAs should be avoided in patients with metastatic breast cancer to reduce the risk of promoting breast cancer cell drug resistance.

Contrast-Enhanced Cardiac Magnetic Resonance Imaging With a Manganese-Based Alternative to Gadolinium for Tissue Characterization of Acute Myocardial Infarction.

Background Late gadolinium enhancement cardiac magnetic resonance imaging is an effective and reproducible method for characterizing myocardial infarction. However, gadolinium-based contrast agents are contraindicated in patients with acute and chronic renal insufficiency. In addition, several recent studies have noted tissue deposition of free gadolinium in patients who have undergone serial contrast-enhanced magnetic resonance imaging. There is a clinical need for alternative forms of magnetic resonance imaging contrast agents that are acceptable in the setting of renal insufficiency. Methods and Results Three days after 80 minutes of ischemia/reperfusion of the left anterior descending coronary artery, cardiac magnetic resonance imaging was performed to assess myocardial lesion burden using both contrast agents. Late gadolinium enhancement cardiac magnetic resonance imaging was examined 10 and 15 minutes after contrast injection. Contrast agents were administered in alternating manner with a 2- to 3-hour washout period between contrast agent injections. Lesion evaluation and image processing were performed using Segment Medviso software. Mean infarct size and transmurality, measured using RVP-001, were not different compared with those measured using late gadolinium enhancement images. Bland-Altman analysis demonstrated a nominal bias of 0.13 mL (<1% of average total lesion volume) for RVP-001 in terms of gross infarct size measurement. Conclusions The experimental manganese-based contrast agent RVP-001 appears to be an effective agent for assessment of myocardial infarction location, size, and transmurality, and it may be useful as an alternative to gadolinium-based agents.

An improved diagnostic algorithm for subcentimeter hepatocellular carcinoma on gadoxetic acid-enhanced MRI.

OBJECTIVES: Accurate diagnosis of subcentimeter hepatocellular carcinoma (HCC) is a challenge also with gadoxetic acid-enhanced MRI (EOB-MRI). This study aimed to assess the diagnostic accuracy of the Liver Imaging Reporting and Data System (LI-RADS) for subcentimeter HCC and to determine whether new diagnostic criteria (washout either on portal venous phase (PVP) or transitional phase (TP)) would improve the diagnostic performance. METHODS: We evaluated 240 subcentimeter observations in 225 consecutive treatment-naïve patients at risk of HCC. Final diagnoses were 132 HCCs (all by pathology) and 108 non-HCC (41 by pathology and 67 by follow-up). Two radiologists assessed MR imaging features and assigned LI-RADS categories. A variety of diagnostic criteria were developed by combining significant MRI features based on washout on PVP or TP. Diagnostic performance was compared. RESULTS: Non-rim arterial phase hyperenhancement (non-rim APHE), washout on PVP or TP, and hepatobiliary-phase hypointensity were significant predictors for subcentimeter HCC diagnosis according to multivariable analysis. One criterion (non-rim APHE and washout on PVP or TP) yielded higher sensitivity (68.2% vs. 56.8%, p = 0.011) with comparable specificity (91.7% vs. 92.6%, p > 0.999) compared to the LR-4 category. This criterion had improved sensitivity (68.2% vs. 49.2%, p < 0.001) and slightly decreased specificity (91.7% vs. 94.4%, p = 0.250) compared to non-rim APHE with washout on PVP. CONCLUSIONS: LI-RADS exhibits modest diagnostic performance for subcentimeter HCC. Our new criterion (non-rim APHE and non-peripheral washout on PVP or TP) may increase the diagnostic sensitivity without compromised specificity compared to the LR-4 category. KEY POINTS: • The LR-4 category shows modest diagnostic performance for the diagnosis of subcentimeter HCC on EOB-MRI with a sensitivity and specificity of 56.8% and 92.6%, respectively. • Non-rim APHE, non-peripheral washout on PVP or TP, and HBP hypointensity were independent predictors for the diagnosis of subcentimeter HCC. • The combination of non-rim APHE and non-peripheral washout on PVP or TP improves the sensitivity from 56.8 to 68.2% (p = 0.011) with comparable specificity (91.7 vs. 92.6%, p > 0.999).

Influence of dilution on arterial-phase artifacts and signal intensity on gadoxetic acid-enhanced liver MRI.

OBJECTIVES: To investigate the effect of saline-diluted gadoxetic acid, done for arterial-phase (AP) artifact reduction, on signal intensity (SI), and hence focal lesion conspicuity on MR imaging. METHODS: We retrospectively examined 112 patients who each had at least two serial gadoxetic acid-enhanced liver MRIs performed at 1 ml/s, first with non-diluted (ND), then with 1:1 saline-diluted (D) contrast. Two blinded readers independently analyzed the artifacts and graded dynamic images using a 5-point scale. The absolute SI of liver parenchyma, focal liver lesions (if present), aorta, and portal vein at the level of the celiac trunk and the SI of the paraspinal muscle were measured in all phases. The signal-to-norm (SINorm) of the vascular structures, hepatic parenchyma and focal lesions, and the contrast-to-norm (CNorm) of focal liver lesions were calculated. RESULTS: AP artifacts were significantly reduced with dilution. Mean absolute contrast-enhanced liver SI was significantly higher on the D exams compared to the ND exams. Likewise, SINorm of liver parenchyma was significantly higher in all contrast-enhanced phases except transitional phase on the D exams. SINorm values in the AP for the aorta and in the PVP for portal vein were significantly higher on the diluted exams. The CNorm was not significantly different between ND and D exams for lesions in any imaging phase. The interclass correlation coefficient was excellent (0.89). CONCLUSION: Gadoxetic acid dilution injected at 1ml/s produces images with significantly fewer AP artifacts but no significant loss in SINorm or CNorm compared to standard non-diluted images. KEY POINTS: • Diluted gadoxetic acid at slow injection (1 ml/s) yielded images with higher SINorm of the liver parenchyma and preserved CNorm for focal liver lesions. • Gadoxetic acid-enhanced MRI injected at 1 ml/s is associated with arterial-phase (AP) artifacts in 31% of exams, which may degrade image quality and limits focal liver lesion detection. • Saline dilution of gadoxetic acid 1:1 combined with a slow injection rate of 1 ml/s significantly reduced AP artifacts from 31 to 9% and non-diagnostic AP artifacts from 16 to 1%.

Comparison of imaging findings of macrotrabecular-massive hepatocellular carcinoma using CT and gadoxetic acid-enhanced MRI.

OBJECTIVES: To investigate the imaging findings of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) on CT and MRI, and examine their diagnostic performance and prognostic significance. METHODS: We retrospectively enrolled 220 consecutive patients who underwent hepatic resection between June 2009 and December 2013 for single treatment-naïve HCC, who have preoperative CT and gadoxetic acid-enhanced MRI. Independent reviews of histopathology and imaging were performed by two reviewers. Previously reported imaging findings, LI-RADS category, and CT attenuation of MTM-HCC were investigated. The diagnostic performance of the MTM-HCC diagnostic criteria was compared across imaging modalities. RESULTS: MTM-HCC was associated with ≥ 50% arterial phase hypovascular component, intratumoral artery, arterial phase peritumoral enhancement, and non-smooth tumor margin on CT and MRI (p < .05). Arterial phase hypovascular components were less commonly observed on MRI subtraction images than on CT or MRI, while non-rim arterial phase hyperenhancement and LR-5 were more commonly observed on MRI subtraction images than on MRI (p < .05). MTM-HCC showed lower tumor attenuation in the CT arterial phase (p = .01). Rhee's criteria, defined as ≥ 50% hypovascular component and ≥ 2 ancillary findings (intratumoral artery, arterial phase peritumoral enhancement, and non-smooth tumor margin), showed similar diagnostic performance for MRI (sensitivity, 41%; specificity, 97%) and CT (sensitivity, 31%; specificity, 94%). Rhee's criteria on CT were independent prognostic factors for overall survival. CONCLUSION: The MRI diagnostic criteria for MTM-HCC are applicable on CT, showing similar diagnostic performance and prognostic significance. For MTM-HCC, arterial phase subtraction images can aid in the HCC diagnosis by depicting subtle arterial hypervascularity. KEY POINTS: • MTM-HCC on CT demonstrated previously described MRI findings, including arterial phase hypovascular component, intratumoral artery, arterial phase peritumoral enhancement, and necrosis. • The MRI diagnostic criteria for MTM-HCC were also applicable to CT, showing comparable diagnostic performance and prognostic significance. • On arterial phase subtraction imaging, MTM-HCC more frequently demonstrated non-rim enhancement and LR-5 and less frequently LR-M than MRI arterial phase, which may aid in the diagnosis of HCC.

Dual-modal polypeptide-containing contrast agents for magnetic resonance/fluorescence imaging.

Dual-modal magnetic resonance/fluorescent imaging (MRI/FI) attracts moreandmoreattentions in diagnosis of tumors. A corresponding dual-modal imaging agent with sufficient tumor sensitivity and specificity should be matched to improve imaging quality. Tripeptide (RGD) and pentapeptide (YIGSR) were selected as the tumor-targeting groups and attached to gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and rhodamine B (RhB), and then make two novel polypeptide-based derivatives (RGD-Gd-DTPA-RhB and YIGSR-Gd-DTPA-RhB), respectively. These derivatives were further characterized and their properties, such as cell uptake, cell cytotoxicity, MRI and FI assay, were measured. YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB had high relaxivity, good tumor-targeting property, low cell cytotoxicity and good red FI in B16F10 melanoma cells. Moreover, YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB possessed high uptake to B16F10 melanoma, and then achieve highly enhanced FI and MRI of tumors in mice for a prolonged time. Therefore, YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB can be applied as the potential agents for tumor targeted MRI/FI in vivo.

Transient severe motion artifacts on gadoxetic acid-enhanced MRI: risk factor analysis in 2230 patients.

OBJECTIVES: To determine risk factors for transient severe motion (TSM) artifact on arterial phase of gadoxetic acid-enhanced MRI using a large cohort. METHODS: A total of 2230 patients who underwent gadoxetic acid-enhanced MRI was consecutively included. Two readers evaluated respiratory motion artifact on arterial phase images using a 5-point grading scale. Clinical factors including demographic data, underlying disease, laboratory data, presence of ascites and pleural effusion, and previous experience of gadoxetic acid-enhanced MRI were investigated. Univariable and multivariable logistic regression analyses were performed to determine significant risk factors for TSM. Predictive value of TSM was calculated according to the number of significant risk factors. RESULTS: Overall incidence of TSM was 5.0% (111/2230). In the multivariable analysis, old age (≥ 65 years; odds ratio [OR] = 2.01 [95% CI, 1.31-3.07]), high body mass index (≥ 25 kg/m2; OR = 1.76 [1.18-2.63]), chronic obstructive pulmonary disease (OR = 6.11 [2.32-16.04]), and moderate to severe pleural effusion (OR = 3.55 [1.65-7.65]) were independent significant risk factors for TSM. Presence of hepatitis B (OR = 0.66 [0.43-0.99]) and previous experience of gadoxetic acid-enhanced MRI (OR = 0.52 [0.33-0.83]) were negative risk factors for TSM. When at least one of the significant factors was present, the predictive risk was 5.7% (109/1916), whereas it was 16.3% (17/104) when at least four factors were present. CONCLUSION: Knowing risk factors for transient severe motion artifact on gadoxetic acid-enhanced MRI can be clinically useful for providing diagnostic strategies more tailored to individual patients. KEY POINTS: • Old age, high body mass index, chronic obstructive pulmonary disease, and moderate to severe pleural effusion were independent risk factors for transient severe motion artifact on gadoxetic acid-enhanced MRI. • Patients with hepatitis B or previous experience of gadoxetic acid-enhanced MRI were less likely to show transient severe motion artifact. • As the number of risk factors for transient severe motion artifact increased, the predicted risk for it also showed a tendency to increase.

Performance of adding hepatobiliary phase image in magnetic resonance imaging for detection of hepatocellular carcinoma: a meta-analysis.

OBJECTIVES: To determine the performance of diagnostic algorithm of adding hepatobiliary phase (HBP) images in Gd-EOB-DTPA-enhanced MRI for the detection of hepatocellular carcinoma (HCC) measuring up to 3 cm in patients with chronic liver disease. METHODS: We searched multiple databases from inception to April 10, 2020, to identify studies on using Gd-EOB-DTPA-enhanced MRI for the diagnostic accuracy of HCC (≤ 3 cm) in patients with chronic liver disease. The diagnostic algorithm of Gd-EOB-DTPA-enhanced MRI with HBP for HCC was defined as a nodule showing hyperintensity during arterial phase and hypointensity during the portal venous, delayed, or hepatobiliary phases. For gadoxetic acid-enhanced MRI without HBP, the diagnostic criteria were a nodule showing arterial enhancement and hypointensity on the portal venous or delayed phases. The data were extracted to calculate summary estimates of sensitivity, specificity, diagnostic odds ratio, likelihood ratio, and summary receiver operating characteristic (sROC) by using a bivariate random-effects model. RESULTS: Twenty-nine studies with 2696 HCC lesions were included. Overall Gd-EOB-DTPA-enhanced MRI with HBP had a sensitivity of 87%, specificity of 92%, and the area under the sROC curve of 95%. The summary sensitivity of Gd-EOB-DTPA-enhanced MRI with HBP was significantly higher than that without HBP (84% vs 68%, p = 0.01). CONCLUSION: Gd-EOB-DTPA-enhanced MRI with HBP showed higher sensitivity than that without HBP and had comparable specificity for diagnosis of HCC in patients with chronic liver disease. KEY POINTS: • Hypointensity on HBP is a major feature for diagnosis of HCC. • Extending washout appearance to the transitional or hepatobiliary phase on Gd-EOB-DTPA provides favorable sensitivity and comparable specificity for diagnosis HCC. • The summary sensitivity of gadoxetic acid-enhanced MRI with HBP was significantly higher than that without HBP (84% vs 68%, p = 0.01) for diagnosis of HCC in patients with chronic liver disease.

Gadodiamide Induced Autophagy and Apoptosis in Human Keratinocytes.

BACKGROUND/AIM: Gadolinium has been reported to cause liver lobular necrosis and nephrogenic systemic fibrosis. However, its toxicity to the skin remains unknown. This study aimed to investigate the effect of a high dose of gadolinium-based contrast agent gadodiamide on the human keratinocyte HaCaT cell line. MATERIALS AND METHODS: Cell viability was assessed using MTT assay, and autophagy was assessed using acridine orange and LysoTracker Red staining. Western blotting was performed to verify the changes in Bcl2 and Bax levels. RESULTS: The viability of HaCaT cells was significantly suppressed after gadodiamide treatment. Interestingly, gadodiamide caused autophagic vacuoles, whereas the autophagy inhibitors 3-methyladenine and chloroquine significantly alleviated autophagic cell death. Simultaneously, gadodiamide induced apoptosis, which was reduced by caspase inhibitors. Gadodiamide also inhibited Bcl-2 expression and promoted Bax expression. CONCLUSION: Gadodiamide induced both autophagy and apoptosis in HaCaT cells. Physicians should carefully assess the gadodiamide dosage used clinically.

Clinical usefulness of multiple arterial-phase images in gadoxetate disodium-enhanced magnetic resonance imaging: a systematic review and meta-analysis.

OBJECTIVES: The multiple arterial-phase (AP) technique was introduced for liver MRI, but it is not really known if multiple AP MRI (MA-MRI) improves image quality and lesion detection rate on gadoxetate disodium-enhanced MRI in comparison with single AP MRI (SA-MRI). We aimed to determine the clinical usefulness of MA-MRI in comparison with SA-MRI. METHODS: Original articles reporting the percentage of adequate AP imaging and the lesion detection rate on gadoxetate disodium-enhanced MA-MRI were identified in PubMed, EMBASE, and Cochrane Library databases. The pooled percentage of adequate AP imaging and lesion detection rate were calculated using random-effects meta-analysis of single proportions. Subgroup analysis was performed to explain causes of study heterogeneity, and publication bias was evaluated using Egger's test. RESULTS: Of 772 articles screened, 22 studies in 12 articles were included: 18 studies (ten MA-MRI and eight SA-MRI) suitably defined the percentage of adequate AP imaging and four (three MA-MRI and one SA-MRI) defined the lesion detection rate. MA-MRI had 16.1% higher pooled percentage of adequate AP imaging than SA-MRI (94.8% vs. 78.7%, p < 0.01). MA-MRI additionally detected 33.2% of lesions than SA-MRI (83.2% vs. 50.0%, p = 0.06). Substantial study heterogeneity was found in MA-MRI, and the definition of adequate AP imaging, lesion characteristics, and reference standards were significant factors affecting study heterogeneity (p ≤ 0.02). Significant publication bias was found in MA-MRI (p < 0.01) but not in SA-MRI studies (p = 0.87). CONCLUSIONS: Gadoxetate disodium-enhanced MA-MRI may be more clinically useful than SA-MRI, but further study is necessary to validate this finding because of study heterogeneity and publication bias. KEY POINTS: • Multiple arterial-phase MRI (MA-MRI) had a 16.1% higher pooled percentage of adequate AP imaging than single arterial-phase MRI (SA-MRI) (94.8% vs. 78.7%, p < 0.01). • MA-MRI additionally detected an extra 33.2% of lesions compared with SA-MRI (83.2% vs. 50.0%, p = 0.06). • Substantial study heterogeneity and significant publication bias were found across MA-MRI studies.

Grafting of Gd-DTPA onto MOF-808 to enhance MRI performance for guiding photothermal therapy.

Gd(III) chelates are important T1-weighted contrast agents used in clinical magnetic resonance imaging (MRI), but their low longitudinal relaxivity (r1) results in limited imaging efficiency. In this study, we utilize a geometric confinement strategy to restrict a Gd chelate (Gd-DTPA) within the channels of a porous metal-organic framework material (MOF-808) for increasing its r1 relaxivity. Moreover, the Gd-DTPA-grafted MOF-808 nanoparticles were further surface modified with polyaniline (PANI) to construct an MRI-guided photothermal therapy platform. The resulting Gd-DTPA-MOF-808@PANI shows a high r1 relaxivity of 30.1 mM-1 s-1 (0.5 T), which is 5.4 times higher than that of the commercial contrast agent Magnevist. In vivo experiments revealed that Gd-DTPA-MOF-808@PANI has good T1-weighted contrast performance and can effectively guide photothermal ablation of tumors upon 808 nm laser irradiation. This work may shed some light on the design and preparation of high relaxation rate Gd-based contrast agents for theranostic application via utilization of versatile MOF materials.

Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure.

Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16-72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.

Gadoxetate Disodium-Enhanced Imaging of Gradenigo Syndrome in End-Stage Renal Disease.

ABSTRACT: A 65-year-old man with end-stage renal disease on peritoneal dialysis was admitted for new onset binocular double vision, failure to thrive, and debilitating right-sided headaches. Medical history was significant for tympanomastoidectomy for polymicrobial mastoiditis and treatment with IV antibiotics. MRI brain without contrast was read by radiology initially as showing expected postsurgical changes; however, given patient's history of mastoiditis infection, there was a high clinical suspicion for Gradenigo syndrome. MRI brain was repeated with gadoxetate contrast to minimize the risk of nephrogenic systemic fibrosis (NSF) in a patient with severe renal disease and this revealed an intracranial empyema involving both the trigeminal and abducens nerves confirming the diagnosis of Gradenigo syndrome. This case presented a diagnostic challenge because of suboptimal visualization on initial nonenhanced MRI. Gadoxetate was chosen because of its unique properties including high hepatobiliary excretion making it a safer form of gadolinium-based contrast agent that may not have the potential to precipitate NSF.

Targeting Nanostrategies for Imaging of Atherosclerosis.

Despite the progress in cardiovascular research, atherosclerosis still represents the main cause of death worldwide. Clinically, the diagnosis of Atherosclerotic Cardiovascular Disease (ASCVD) relies on imaging methodologies including X-ray angiography and computed tomography (CT), which however still fails in the identification of patients at high risk of plaque rupture, the main cause of severe clinical events as stroke and heart attack. Magnetic resonance imaging, which is characterized by very high spatial resolution, could provide a better characterization of atherosclerotic plaque (AP) anatomy and composition, aiding in the identification of "vulnerable" plaques. In this context, hydrogel matrices, which have been demonstrated able to boost relaxometric properties of Gd-based contrast agents (CAs) by the effect of Hydrodenticity, represent a valuable tool towards the precision imaging of ASCVD improving the performance of this class of CAs while reducing systemic toxicity. In particular, hydrogel nanoparticles encapsulating Gd-DTPA can further contribute to providing CA-specific accumulation in the AP by nanoparticle surface decoration triggering an active targeting of the AP with the overall effect of allowing an earlier and more accurate diagnosis. In this work, we tested crosslinked Hyaluronic Acid Nanoparticles (cHANPs) in the complex environment of human atherosclerotic plaque. In addition, the surface of cHANPs was decorated with the antibody anti-CD36 (Ab36-cHANPs) for the active targeting of AP-associated macrophages. Results demonstrate that the Hydrodenticity of cHANPs and Ab36-cHANPs is preserved in this complex system and, preliminarily, that interaction of these probes with the AP is present.

Gadolinium-based contrast agents: in vitro paraoxonase 1 inhibition, in silico studies.

Medications show their biological effects by interaction with enzymes, which have been known to play an essential role in the pathogenesis of many diseases. Inhibition or induction of drug metabolizing enzymes has an essential place in the drug design for many kinds of diseases including cardiovascular, neurological, metabolic, and cancer. The main goal of the current study is to contribute to this growing drug design field by observing PON1-drug interactions. In recent years, the safety of gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) has discussed. In the present study, paraoxonase 1 (PON1) enzyme was purified from human serum by simple chromatographic methods with 4095.24 EU mg-1 protein specific activity. The inhibitory activities of gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide were investigated on PON1 activity of the enzyme. IC50 values were found in the range of 51.28 ± 0.14 to 285.80 ± 0.96 mM. Ki constants were found as 67.95 ± 0.60 mM, 104.97 ± 0.96 mM, 202.33 ± 1.75 mM, and 299.43 ± 2.64 mM for gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide, respectively. While the inhibition types are determined as competitive of gadoxetate disodium and gadodiamide by the Lineweaver-Burk curves, it was noncompetitive for other compounds. In addition, the molecular docking analyses of gadoxetate disodium and gadodiamide were carried out to understand the binding interactions on the active site of the PON1 enzyme. The structure-activity relationship (SAR) of the drugs was established on the basis of different substituents and their positions in the compounds.