Three-Dimensional Multifrequency MR Elastography for Microvascular Invasion and Prognosis Assessment in Hepatocellular Carcinoma.

BACKGROUND: Pretreatment identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is important when selecting treatment strategies. PURPOSE: To improve models for predicting MVI and recurrence-free survival (RFS) by developing nomograms containing three-dimensional (3D) MR elastography (MRE). STUDY TYPE: Prospective. POPULATION: 188 patients with HCC, divided into a training cohort (n = 150) and a validation cohort (n = 38). In the training cohort, 106/150 patients completed a 2-year follow-up. FIELD STRENGTH/SEQUENCE: 1.5T 3D multifrequency MRE with a single-shot spin-echo echo planar imaging sequence, and 3.0T multiparametric MRI (mp-MRI), consisting of diffusion-weighted echo planar imaging, T2-weighted fast spin echo, in-phase out-of-phase T1-weighted fast spoiled gradient-recalled dual-echo and dynamic contrast-enhanced gradient echo sequences. ASSESSMENT: Multivariable analysis was used to identify the independent predictors for MVI and RFS. Nomograms were constructed for visualization. Models for predicting MVI and RFS were built using mp-MRI parameters and a combination of mp-MRI and 3D MRE predictors. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, chi-squared or Fisher's exact tests, multivariable analysis, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log rank tests. P < 0.05 was considered significant. RESULTS: Tumor c and liver c were independent predictors of MVI and RFS, respectively. Adding tumor c significantly improved the diagnostic performance of mp-MRI (AUC increased from 0.70 to 0.87) for MVI detection. Of the 106 patients in the training cohort who completed the 2-year follow up, 34 experienced recurrence. RFS was shorter for patients with MVI-positive histology than MVI-negative histology (27.1 months vs. >40 months). The MVI predicted by the 3D MRE model yielded similar results (26.9 months vs. >40 months). The MVI and RFS nomograms of the histologic-MVI and model-predicted MVI-positive showed good predictive performance. DATA CONCLUSION: Biomechanical properties of 3D MRE were biomarkers for MVI and RFS. MVI and RFS nomograms were established. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Three-dimensional multifrequency magnetic resonance elastography improves preoperative assessment of proliferative hepatocellular carcinoma.

BACKGROUND: To investigate the viscoelastic signatures of proliferative hepatocellular carcinoma (HCC) using three-dimensional (3D) magnetic resonance elastography (MRE). METHODS: This prospective study included 121 patients with 124 HCCs as training cohort, and validation cohort included 33 HCCs. They all underwent preoperative conventional magnetic resonance imaging (MRI) and tomoelastography based on 3D multifrequency MRE. Viscoelastic parameters of the tumor and liver were quantified as shear wave speed (c, m/s) and loss angle (φ, rad), representing stiffness and fluidity, respectively. Five MRI features were evaluated. Multivariate logistic regression analyses were used to determine predictors of proliferative HCC to construct corresponding nomograms. RESULTS: In training cohort, model 1 (Combining cirrhosis, hepatitis virus, rim APHE, peritumoral enhancement, and tumor margin) yielded an area under the curve (AUC), sensitivity, specificity, accuracy of 0.72, 58.73%,78.69%, 67.74%, respectively. When adding MRE properties (tumor c and tumor φ), established model 2, the AUC increased to 0.81 (95% CI 0.72-0.87), with sensitivity, specificity, accuracy of 71.43%, 81.97%, 75%, respectively. The C-index of nomogram of model 2 was 0.81, showing good performance for proliferative HCC. Therefore, integrating tumor c and tumor φ can significantly improve the performance of preoperative diagnosis of proliferative HCC (AUC increased from 0.72 to 0.81, p = 0.012). The same finding was observed in the validation cohort, with AUC increasing from 0.62 to 0.77 (p = 0.021). CONCLUSIONS: Proliferative HCC exhibits low stiffness and high fluidity. Adding MRE properties (tumor c and tumor φ) can improve performance of conventional MRI for preoperative diagnosis of proliferative HCC. CRITICAL RELEVANCE STATEMENT: We investigated the viscoelastic signatures of proliferative hepatocellular carcinoma (HCC) using three-dimensional (3D) magnetic resonance elastography (MRE), and find that adding MRE properties (tumor c and tumor φ) can improve performance of conventional MRI for preoperative diagnosis of proliferative HCC.

Assessment of Albumin ECM Accumulation and Inflammation as Novel In Vivo Diagnostic Targets for Multi-Target MR Imaging.

Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-)-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE-/--group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R2 = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls' Prussian blue stain (R2 = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis.

Quantitative MRI for Assessment of Treatment Outcomes in a Rabbit VX2 Hepatic Tumor Model.

Globally, primary and secondary liver cancer is one of the most common cancer types, accounting 8.2% of deaths worldwide in 2018. One of the key strategies to improve the patient's prognosis is the early diagnosis, when liver function is still preserved. In hepatocellular carcinoma (HCC), the typical wash-in/wash-out pattern in conventional magnetic resonance imaging (MRI) reaches a sensitivity of 60% and specificity of 96-100%. However, in recent years functional MRI sequences such as hepatocellular-specific gadolinium-based dynamic-contrast enhanced MRI, diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) have been demonstrated to improve the evaluation of treatment success and thus the therapeutic decision-making and the patient's outcome. In the preclinical research setting, the VX2 liver rabbit tumor, which once originated from a virus-induced anaplastic squamous cell carcinoma, has played a longstanding role in experimental interventional oncology. Especially the high tumor vascularity allows assessing the treatment response of locoregional interventions such as radiofrequency ablation (RFA) and transcatheter arterial embolization (TACE). Functional MRI has been used to monitor the tumor growth and viability following interventional treatment. Besides promising results, a comprehensive overview of functional MRI sequences used so far in different treatment setting is lacking, thus lowering the comparability of study results. This review offers a comprehensive overview of study protocols, results, and limitations of quantitative MRI sequences applied to evaluate the treatment outcome of VX2 hepatic tumor models, thus generating a unique basis for future MRI studies and potential translation into the clinical setting. Level of Evidence: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2020;52:668-685.

Non-invasive structure-function assessment of the liver by 2D time-harmonic elastography and the dynamic Liver MAximum capacity (LiMAx) test.

BACKGROUND AND AIM: Accurate assessment of structural and functional characteristics of the liver could improve the diagnosis and the clinical management of patients with chronic liver diseases. However, the structure-function relationship in the progression of chronic liver disease remains elusive. The aim of this study is the combined measurement of liver function by the 13 C-methacetin Liver MAximum capacity (LiMAx) test and tissue-structure related stiffness by 2D time-harmonic elastography for the assessment of liver disease progression. METHODS: LiMAx test and time-harmonic elastography were applied, and the serological scores fibrosis 4 index and aspartate aminotransferase to platelet ratio index were calculated in patients with chronic liver diseases (n = 75) and healthy control subjects (n = 22). In 47 patients who underwent surgery, fibrosis was graded by histological examination of the resected liver tissue. RESULTS: LiMAx values correlated negatively with liver stiffness (r = -0.747), aminotransferase to platelet ratio index (r = -0.604), and fibrosis 4 (r = -0.573). Median (interquartile range) LiMAx values decreased with fibrosis progression from 395 µg/kg/h (371-460 µg/kg/h) in participants with no fibrosis to 173 µg/kg/h (126-309 µg/kg/h) in patients with severe fibrosis. Median liver stiffness increased progressively with the stage of fibrosis from no fibrosis (1.56 m/s [1.52-1.63 m/s]) to moderate fibrosis (1.60 m/s [1.54-1.67 m/s]) to severe fibrosis (1.85 m/s [1.76-1.92 m/s]). CONCLUSION: Our findings show that structural changes in the liver due to progressing liver diseases and reflected by increased tissue stiffness correlate with a functional decline of the organ as reflected by a decreased metabolic capacity of the liver.

MR Elastography-Based Assessment of Matrix Remodeling at Lesion Sites Associated With Clinical Severity in a Model of Multiple Sclerosis.

Magnetic resonance imaging (MRI) with gadolinium based contrast agents (GBCA) is routinely used in the clinic to visualize lesions in multiple sclerosis (MS). Although GBCA reveal endothelial permeability, they fail to expose other aspects of lesion formation such as the magnitude of inflammation or tissue changes occurring at sites of blood-brain barrier (BBB) disruption. Moreover, evidence pointing to potential side effects of GBCA has been increasing. Thus, there is an urgent need to develop GBCA-independent imaging tools to monitor pathology in MS. Using MR-elastography (MRE), we previously demonstrated in both MS and the animal model experimental autoimmune encephalomyelitis (EAE) that inflammation was associated with a reduction of brain stiffness. Now, using the relapsing-remitting EAE model, we show that the cerebellum-a region with predominant inflammation in this model-is especially prone to loss of stiffness. We also demonstrate that, contrary to GBCA-MRI, reduction of brain stiffness correlates with clinical disability and is associated with enhanced expression of the extracellular matrix protein fibronectin (FN). Further, we show that FN is largely expressed by activated astrocytes at acute lesions, and reflects the magnitude of tissue remodeling at sites of BBB breakdown. Therefore, MRE could emerge as a safe tool suitable to monitor disease activity in MS.

Comparison of non-invasive assessment of liver fibrosis in patients with alpha1-antitrypsin deficiency using magnetic resonance elastography (MRE), acoustic radiation force impulse (ARFI) Quantification, and 2D-shear wave elastography (2D-SWE).

PURPOSE: Although it has been known for decades that patients with alpha1-antitrypsin deficiency (AATD) have an increased risk of cirrhosis and hepatocellular carcinoma, limited data exist on non-invasive imaging-based methods for assessing liver fibrosis such as magnetic resonance elastography (MRE) and acoustic radiation force impulse (ARFI) quantification, and no data exist on 2D-shear wave elastography (2D-SWE). Therefore, the purpose of this study is to evaluate and compare the applicability of different elastography methods for the assessment of AATD-related liver fibrosis. METHODS: Fifteen clinically asymptomatic AATD patients (11 homozygous PiZZ, 4 heterozygous PiMZ) and 16 matched healthy volunteers were examined using MRE and ARFI quantification. Additionally, patients were examined with 2D-SWE. RESULTS: A high correlation is evident for the shear wave speed (SWS) determined with different elastography methods in AATD patients: 2D-SWE/MRE, ARFI quantification/2D-SWE, and ARFI quantification/MRE (R = 0.8587, 0.7425, and 0.6914, respectively; P≤0.0089). Four AATD patients with pathologically increased SWS were consistently identified with all three methods-MRE, ARFI quantification, and 2D-SWE. CONCLUSION: The high correlation and consistent identification of patients with pathologically increased SWS using MRE, ARFI quantification, and 2D-SWE suggest that elastography has the potential to become a suitable imaging tool for the assessment of AATD-related liver fibrosis. These promising results provide motivation for further investigation of non-invasive assessment of AATD-related liver fibrosis using elastography.

Comparison of ultrasound shear wave elastography with magnetic resonance elastography and renal microvascular flow in the assessment of chronic renal allograft dysfunction.

Background Monitoring of renal allograft function is essential for early identification of dysfunction and improvement of kidney transplant (KTX) outcome. Purpose To non-invasively assess renal stiffness in KTX recipients using ultrasound shear wave elastography (USE) in correlation with multifrequency magnetic resonance elastography (MRE), renal allograft function, and renal microvascular flow determined using a novel ultrasound microvascular imaging technique. Material and Methods This prospective study investigated 25 KTXs (functional KTX [FCT], n = 14; chronic KTX insufficiency [DYS], n = 11) in 20 KTX recipients (mean age = 43 ± 14 years). USE was performed using a high-frequency broadband linear transducer and compared with MRE. Shear wave velocity (SWV) was correlated with the estimated glomerular filtration rate (eGFR). Qualitative differences in renal microvascular flow were obtained using SMI. Results FCT had higher SWV than DYS in both cortex and pyramids (cortex, FCT: 3.75 ± 0.82 m/s vs. DYS: 2.79 ± 0.73 m/s, P = 0.0002; pyramid, FCT: 2.89 ± 0.46 m/s vs. DYS: 2.39 ± 0.34 m/s, P = 0.044). Cutoff values of 3.265 m/s for cortex, 2.535 m/s for pyramids, and 2.985 m/s for combined non-hilar parenchyma provided sensitivities of 72.7%, 77.8%, and 90.9% and specificities of 71.4%, 78.6%, and 85.7% for detecting renal allograft dysfunction with area under the receiver operating characteristic curve (AUC) values of 0.831, 0.841, 0.925 (95% confidence interval [CI] = 0.67-0.99, 0.66-1.02, 0.83-1.03). USE correlated positively with eGFR ( r = 0.741, P = 0.0004) and with MRE-derived SWV ( r = 0.562, P = 0.004). Renal microvascular flow was decreased in DYS. Conclusion USE is sensitive to renal allograft dysfunction, which is characterized by reduced SWV and renal perfusion. USE has higher image resolution than MRE, while MRE has slightly better diagnostic accuracy.

Multifrequency Magnetic Resonance Elastography for the Assessment of Renal Allograft Function.

OBJECTIVE: The aim of this study was to apply multifrequency magnetic resonance elastography (MMRE) for assessment of kidney function based on renal stiffness of allografts in transplant recipients and native kidneys in controls. METHODS: In this prospective study, MMRE was used to measure stiffness in transplant kidneys in 22 recipients (age range, 23-73 years; 7 females) and in native kidneys in 11 controls (age range, 26-55 years; 4 females) after internal review board approval. The MMRE was performed on a 1.5 T magnetic resonance imaging scanner using 4 vibration frequencies from 40 to 70 Hz. Stiffness maps were computed by multifrequency reconstruction of the magnitude shear modulus (|G*|). Clinical markers such as glomerular filtration rate (GFR) and resistive index (RI) were acquired. Differences in renal stiffness among groups were compared by Mann-Whitney U test. Correlations were tested using Pearson correlation. RESULTS: Functioning transplants had higher stiffness (|G*| = 9.00 ± 1.71 kPa) than nonfunctioning transplants (|G*| = 5.88 ± 1.71 kPa, P < 0.001) and native kidneys (|G*| = 6.63 ± 1.63 kPa, P < 0.01). A cutoff value of 7.04 kPa provided sensitivity (83.33%) and specificity (86.67%) for detecting renal allograft dysfunction with an area under the receiver operating characteristic curve value of 0.9278 (95% confidence interval, 0.83-1.00). |G*| correlated positively with GFR (r = 0.52, P = 0.015) and negatively with RI (r = -0.52, P = 0.016). CONCLUSIONS: Multifrequency magnetic resonance elastography has good diagnostic accuracy in detecting renal allograft dysfunction. Renal stiffness is significantly lower in recipients with nonfunctioning transplant kidneys and correlates with clinical markers such as GFR and RI.

In vivo abdominal magnetic resonance elastography for the assessment of portal hypertension before and after transjugular intrahepatic portosystemic shunt implantation.

OBJECTIVE: The objective of this study was to investigate the correlation between hepatic venous pressure gradient (HVPG) and in vivo viscoelasticity of the liver and spleen before and after transjugular intrahepatic portosystemic shunt (TIPS) implantation. MATERIALS AND METHODS: Ten patients with portal hypertension were examined twice by 3-dimensional multifrequency magnetic resonance elastography as well as prior and subsequent TIPS intervention; HVPG was also measured during TIPS placement. Five harmonic vibrations (25-60 Hz) were transferred to the abdominal region and recorded for the reconstruction of 2 viscoelastic constants, |G*| and φ, corresponding to the magnitude and the phase angle of the complex shear modulus G* of the liver and spleen. RESULTS: All patients had cirrhosis, yielding high |G*| values in the liver (8.34 ± 2.18 kPa) and spleen (8.44 ± 1.36 kPa). In both organs, a decrease of |G*| after TIPS placement was observed (liver: 8.34 ± 2.18 kPa vs 7.02 ± 1.46 kPa, P = 0.01; spleen: 8.44 ± 1.36 kPa vs 7.06 ± 1.32 kPa, P = 0.01), whereas φ was insensitive to TIPS. Relative changes in |G*| of the spleen were correlated with the relative change of HVPG (R² = 0.659, P = 0.013). CONCLUSIONS: The observed linear correlation between spleen viscoelasticity HVPG raises the prospect of an image-based noninvasive assessment of portal pressure by magnetic resonance elastography in the follow-up of TIPS placements.

MR elastography of the human heart: noninvasive assessment of myocardial elasticity changes by shear wave amplitude variations.

Many cardiovascular diseases and disorders are associated with hemodynamic dysfunction. The heart's ability to contract and pump blood through the vascular system primarily depends on the elasticity of the myocardium. This article introduces a magnetic resonance elastography (MRE) technique that allows noninvasive and time-resolved measurement of changes in myocardial elasticity over the cardiac cycle. To this end, low-frequency shear vibrations of 24.3 Hz were induced in the human heart via the anterior chest wall. An electrocardiograph (ECG)-triggered, steady-state MRE sequence was used to capture shear oscillations with a frame rate of eight images per vibration cycle. The time evolution of 2D-shear wave fields was observed in two imaging planes through the short axis of the heart in six healthy volunteers. Correlation analysis revealed that wave amplitudes were modulated in synchrony to the heartbeat with up to 2.45 +/- 0.18 higher amplitudes during diastole than during systole (interindividual mean +/- SD). The reduction of wave amplitudes started at 75 +/- 9 ms prior to changes in left ventricular diameter occurring at the beginning of systole. Analysis of this wave amplitude alteration using a linear elastic constitutive model revealed a maximum change in the myocardial wall stiffness of a factor of 37.7 +/- 10.6 during the cardiac cycle.

Assessment of liver viscoelasticity using multifrequency MR elastography.

MR elastography (MRE) allows the noninvasive assessment of the viscoelastic properties of human organs based on the organ response to oscillatory shear stress. Shear waves of a given frequency are mechanically introduced and the propagation is imaged by applying motion-sensitive gradients. An experiment was set up that introduces multifrequency shear waves combined with broadband motion sensitization to extend the dynamic range of MRE from one given frequency to, in this study, four different frequencies. With this approach, multiple wave images corresponding to the four driving frequencies are simultaneously acquired and can be evaluated with regard to the dispersion of the complex modulus over the respective frequency. A viscoelastic model based on two shear moduli and one viscosity parameter was used to reproduce the experimental wave speed and wave damping dispersion. The technique was applied in eight healthy volunteers and eight patients with biopsy-proven high-grade liver fibrosis (grade 3-4). Fibrotic liver had a significantly higher (P < 0.01) viscosity (14.4 +/- 6.6 Pa x s) and elastic moduli (2.91 +/- 0.84 kPa; 4.83 +/- 1.77 kPa) than the viscosity (7.3 +/- 2.3 Pa x s) and elastic moduli (1.16 +/- 0.28 kPa; 1.97 +/- 0.30 kPa) of normal volunteers. Multifrequency MRE is well suited for the noninvasive differentiation of normal and fibrotic liver as it allows the measurement of rheologic material properties.

Noninvasive assessment of the rheological behavior of human organs using multifrequency MR elastography: a study of brain and liver viscoelasticity.

MR elastography (MRE) enables the noninvasive determination of the viscoelastic behavior of human internal organs based on their response to oscillatory shear stress. An experiment was developed that combines multifrequency shear wave actuation with broad-band motion sensitization to extend the dynamic range of a single MRE examination. With this strategy, multiple wave images corresponding to different driving frequencies are simultaneously received and can be analyzed by evaluating the dispersion of the complex modulus over frequency. The technique was applied on the brain and liver of five healthy volunteers. Its repeatability was tested by four follow-up studies in each volunteer. Five standard rheological models (Maxwell, Voigt, Zener, Jeffreys and fractional Zener model) were assessed for their ability to reproduce the observed dispersion curves. The three-parameter Zener model was found to yield the most consistent results with two shear moduli mu(1) = 0.84 +/- 0.22 (1.36 +/- 0.31) kPa, mu(2) = 2.03 +/- 0.19 (1.86 +/- 0.34) kPa and one shear viscosity of eta = 6.7 +/- 1.3 (5.5 +/- 1.6) Pa s (interindividual mean +/- SD) in brain (liver) experiments. Significant differences between the rheological parameters of brain and liver were found for mu(1) and eta (P < 0.05), indicating that human brain is softer and possesses a higher viscosity than liver.