Viscoelastic properties of colorectal liver metastases reflect tumour cell viability.

BACKGROUND: Colorectal cancer is the third most common tumour entity in the world and up to 50% of the patients develop liver metastases (CRLM) within five years. To improve and personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical tumour properties measured by magnetic resonance elastography (MRE) could be implemented as such a diagnostic tool. We postulate that ex vivo MRE combined with histological and radiological evaluation of CRLM could provide biomechanics-based diagnostic markers for cell viability in tumours. METHODS: 34 CRLM specimens from patients who had undergone hepatic resection were studied using ex vivo MRE in a frequency range from 500 Hz to 5300 Hz with increments of 400 Hz. Single frequency evaluation of shear wave speed and wave penetration rate as proxies for stiffness and viscosity was performed, along with rheological model fitting based on the spring-pot model and powerlaw exponent α, ranging between 0 (complete solid behaviour) and 1 (complete fluid behaviour). For histological analysis, samples were stained with H&E and categorized according to the degree of regression. Quantitative histologic analysis was performed to analyse nucleus size, aspect ratio, and density. Radiological response was assessed according to RECIST-criteria. RESULTS: Five samples showed major response to chemotherapy, six samples partial response and 23 samples no response. For higher frequencies (> 2100 Hz), shear wave speed correlated significantly with the degree of regression (p ≤ 0.05) indicating stiffer properties with less viable tumour cells. Correspondingly, rheological analysis of α revealed more elastic-solid tissue properties at low cell viability and major response (α = 0.43 IQR 0.36, 0.47) than at higher cell viability and no response (α = 0.51 IQR 0.48, 0.55; p = 0.03). Quantitative histological analysis showed a decreased nuclear area and density as well as a higher nuclear aspect ratio in patients with major response to treatment compared to patients with no response (all p < 0.05). DISCUSSION: Our results suggest that MRE could be useful in the characterization of biomechanical property changes associated with cell viability in CRLM. In the future, MRE could be applied in clinical diagnosis to support individually tailored therapy plans for patients with CRLM.

Cortical matrix remodeling as a hallmark of relapsing-remitting neuroinflammation in MR elastography and quantitative MRI.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that involves both white and gray matter. Although gray matter damage is a major contributor to disability in MS patients, conventional clinical magnetic resonance imaging (MRI) fails to accurately detect gray matter pathology and establish a clear correlation with clinical symptoms. Using magnetic resonance elastography (MRE), we previously reported global brain softening in MS and experimental autoimmune encephalomyelitis (EAE). However, it needs to be established if changes of the spatiotemporal patterns of brain tissue mechanics constitute a marker of neuroinflammation. Here, we use advanced multifrequency MRE with tomoelastography postprocessing to investigate longitudinal and regional inflammation-induced tissue changes in EAE and in a small group of MS patients. Surprisingly, we found reversible softening in synchrony with the EAE disease course predominantly in the cortex of the mouse brain. This cortical softening was associated neither with a shift of tissue water compartments as quantified by T2-mapping and diffusion-weighted MRI, nor with leukocyte infiltration as seen by histopathology. Instead, cortical softening correlated with transient structural remodeling of perineuronal nets (PNNs), which involved abnormal chondroitin sulfate expression and microgliosis. These mechanisms also appear to be critical in humans with MS, where tomoelastography for the first time demonstrated marked cortical softening. Taken together, our study shows that neuroinflammation (i) critically affects the integrity of PNNs in cortical brain tissue, in a reversible process that correlates with disease disability in EAE, (ii) reduces the mechanical integrity of brain tissue rather than leading to water accumulation, and (iii) shows similar spatial patterns in humans and mice. These results raise the prospect of leveraging MRE and quantitative MRI for MS staging and monitoring treatment in affected patients.

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.

Viscoelastic parameters derived from multifrequency MR elastography for depicting hepatic fibrosis and inflammation in chronic viral hepatitis.

OBJECTIVES: The capability of MR elastography (MRE) to differentiate fibrosis and inflammation, and to provide precise diagnoses is crucial, whereas the coexistence of fibrosis and inflammation may obscure the diagnostic accuracy. METHODS: In this retrospective study, from June 2020 to December 2022, chronic viral hepatitis patients who underwent multifrequency MRE (mMRE) were included in, and further divided into, training and validation cohorts. The hepatic viscoelastic parameters [shear wave speed (c) and loss angle (φ) of the complex shear modulus] were obtained from mMRE. The logistic regression and receiver operating characteristic (ROC) curves were generated to evaluate performance of viscoelastic parameters for fibrosis and inflammation. RESULTS: A total of 233 patients were assigned to training cohort and validation cohorts (mean age, 52 years ± 13 (SD); 51 women; training cohort, n = 170 (73%), and validation cohort, n = 63 (27%)). Liver c exhibited superior performance in detecting fibrosis with ROC (95% confidence interval) of ≥ S1 (0.96 (0.92-0.99)), ≥ S2 (0.86 (0.78-0.92)), ≥ S3 (0.89 (0.84-0.95)), and S4 (0.88 (0.83-0.93)). Similarly, φ was effective in diagnosing inflammation with ROC values of ≥ G2 (0.72 (0.63-0.81)), ≥ G3 (0.88 (0.83-0.94)), and G4 (0.92 (0.87-0.98)). And great predictive discrimination for fibrosis and inflammation were shown in validation cohort (all AUCs > 0.75). CONCLUSION: The viscoelastic parameters derived from multifrequency MRE could realize simultaneous detection of hepatic fibrosis and inflammation. CRITICAL RELEVANCE STATEMENT: Fibrosis and inflammation coexist in chronic liver disease which obscures the diagnostic performance of MR elastography, whereas the viscoelastic parameters derived from multifrequency MR elastography could realize simultaneous detection of hepatic fibrosis and inflammation. KEY POINTS: • Hepatic biomechanical parameters derived from multifrequency MR elastography could effectively detect fibrosis and inflammation. • Liver stiffness is useful for detecting fibrosis independent of inflammatory activity. • Fibrosis could affect the diagnostic efficacy of liver viscosity in inflammation, especially in early-grade of inflammation.

The Networking Brain: How Extracellular Matrix, Cellular Networks, and Vasculature Shape the In Vivo Mechanical Properties of the Brain.

Mechanically, the brain is characterized by both solid and fluid properties. The resulting unique material behavior fosters proliferation, differentiation, and repair of cellular and vascular networks, and optimally protects them from damaging shear forces. Magnetic resonance elastography (MRE) is a noninvasive imaging technique that maps the mechanical properties of the brain in vivo. MRE studies have shown that abnormal processes such as neuronal degeneration, demyelination, inflammation, and vascular leakage lead to tissue softening. In contrast, neuronal proliferation, cellular network formation, and higher vascular pressure result in brain stiffening. In addition, brain viscosity has been reported to change with normal blood perfusion variability and brain maturation as well as disease conditions such as tumor invasion. In this article, the contributions of the neuronal, glial, extracellular, and vascular networks are discussed to the coarse-grained parameters determined by MRE. This reductionist multi-network model of brain mechanics helps to explain many MRE observations in terms of microanatomical changes and suggests that cerebral viscoelasticity is a suitable imaging marker for brain disease.

Explorative study using ultrasound time-harmonic elastography for stiffness-based quantification of skeletal muscle function.

Time-harmonic elastography (THE) is an emerging ultrasound imaging technique that allows full-field mapping of the stiffness of deep biological tissues. THE's unique ability to rapidly capture stiffness in multiple tissues has never been applied for imaging skeletal muscle. Therefore, we addressed the lack of data on temporal changes in skeletal muscle stiffness while simultaneously covering stiffness of different muscles. Acquiring repeated THE scans every five seconds we quantified shear-wave speed (SWS) as a marker of stiffness of the long head (LHB) and short head (SHB) of biceps brachii and of the brachialis muscle (B) in ten healthy volunteers. SWS was continuously acquired during a 3-min isometric preloading phase, a 3-min loading phase with different weights (4, 8, and 12 kg), and a 9-min postloading phase. In addition, we analyzed temporal SWS standard deviation (SD) as a marker of muscle contraction regulation. Our results (median [min, max]) showed both SWS at preloading (LHB: 1.04 [0.94, 1.12] m/s, SHB: 0.86 [0.78, 0.94] m/s, B: 0.96 [0.87, 1.09] m/s, p < 0.001) and the increase in SWS with loading weight to be muscle-specific (LHB: 0.010 [0.002, 0.019] m/s/kg, SHB: 0.022 [0.017, 0.042] m/s/kg, B: 0.039 [0.019, 0.062] m/s/kg, p < 0.001). Additionally, SWS during loading increased continuously over time by 0.022 [0.004, 0.051] m/s/min (p < 0.01). Using an exponential decay model, we found an average relaxation time of 27 seconds during postloading. Analogously, SWS SD at preloading was also muscle-specific (LHB: 0.018 [0.011, 0.029] m/s, SHB: 0.021 [0.015, 0.027] m/s, B: 0.024 [0.018, 0.037] m/s, p < 0.05) and increased by 0.005 [0.003, 0.008] m/s/kg (p < 0.01) with loading. SWS SD did not change over loading time and decreased immediately in the postloading phase. Taken together, THE of skeletal muscle is a promising imaging technique for in vivo quantification of stiffness and stiffness changes in multiple muscle groups within seconds. Both the magnitude of stiffness changes and their temporal variation during isometric exercise may reflect the functional status of skeletal muscle and provide additional information to the morphological measures obtained by conventional imaging modalities.

Multifrequency Magnetic Resonance Elastography Detects Small Abdominal Lymph Node Metastasis by High Stiffness.

OBJECTIVES: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is a clinical and research standard for evaluating malignant tumors and lymph node metastasis. However, quantitative analysis of nodal status is limited to measurement of short axis diameter (SAD), and metastatic lymph nodes below 10 mm in SAD are often not detected. The purpose of this study was to evaluate the value of multifrequency magnetic resonance elastography (MRE) when added to RECIST 1.1 for detection of lymph node metastasis. MATERIALS AND METHODS: Twenty-five benign and 82 metastatic lymph nodes were prospectively examined by multifrequency MRE at 1.5 T using tomoelastography postprocessing at 30, 40, 50, and 60 Hz (total scan time of 4 minutes). Shear wave speed as a surrogate of soft tissue stiffness was provided in m/s. Positron emission tomography-computed tomography was used as reference standard for identification of abdominal lymph node metastasis from histologically confirmed primary tumors. The diagnostic performance of MRE was compared with that of SAD according to RECIST 1.1 and evaluated by receiver operating characteristic curve analysis using generalized linear mixed models and binary logistic mixed models. Sensitivity, specificity, and predictive values were calculated for different cutoffs. RESULTS: Metastatic lymph nodes (1.90 ± 0.57 m/s) were stiffer than benign lymph nodes (0.98 ± 0.20 m/s, P < 0.001). An area under the curve of 0.95 for a cutoff of 1.32 m/s was calculated. Using a conservative approach with 1.0 specificity, we found sensitivity (SAD/MRE/MRE + SAD, 0.56/0.84/0.88), negative predictive values (0.41/0.66/0.71), and overall accuracy (0.66/0.88/0.91) to be improved using MRE and even higher for combined MRE and SAD. CONCLUSIONS: Multifrequency MRE improves metastatic abdominal lymph node detection by 25% based on higher tissue stiffness-even for lymph nodes with an SAD ≤10 mm. Stiffness information is quick to obtain and would be a promising supplement to RECIST.

Effects of oral contrast agent on the viscoelastic properties of the terminal ileum investigated using magnetic resonance elastography.

Background: While standard clinical magnetic resonance (MR) enterography can detect inflammatory bowel disease, it is of limited value in deciding between medical versus surgical treatment. Alternatively, intestinal MR elastography has the potential to contribute additional information to therapeutic decision-making; however, the influence of bowel distension by oral contrast agent on viscoelastic tissue properties remains elusive. Therefore, we aimed to investigate the influence of oral contrast agent-induced bowel distension on the viscoelastic properties of the terminal ileum in healthy volunteers. Methods: In this prospective pilot study, 20 healthy volunteers (33.2±8.2 years; 10 men, 10 women) underwent multifrequency MR elastography using a single-shot spin-echo echo planar imaging sequence at 1.5 Tesla and drive frequencies of 40, 50, 60 and 70 Hz. Maps of shear wave speed (c in ms-1) and loss angle (φ in rad), representing stiffness and viscous properties, respectively, were generated using tomoelastography data processing. The volunteers were scanned before and after ingestion of 1,000 mL of 2% mannitol solution as oral contrast agent. Results: There was no significant difference in terminal ileum biomechanical properties before vs. after ingestion of an oral contrast agent (mean c: 1.47±0.24 vs. 1.40±0.25 ms-1 with P=0.37; mean φ: 0.70±0.12 rad vs. 0.68±0.12 rad with P=0.61). Moreover, there was no statistically significant correlation between MR elastography parameters before and after the ingestion of oral contrast (c: r=0.22, P=0.36; φ: r=0.24, P=0.30). Conclusions: The results of this study suggest that bowel distension for intestinal MR elastography has no systematic effect on the biomechanical tissue properties of the terminal ileum determined by MR elastography. Therefore, future study protocols appear feasible with or without oral contrast agents.

On the relationship between viscoelasticity and water diffusion in soft biological tissues.

Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water mobility, respectively. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering the clinical translation of combined DWI-MRE markers. We used DWI-MRE to study 129 biomaterial samples including native and cross-linked collagen, glycosaminoglycans (GAGs) with different sulfation levels, and decellularized specimens of pancreas and liver, all with different proportions of solid tissue, or solid fractions. We developed a theoretical framework of the relationship between mechanical loss and tissue-water mobility based on two parameters, solid and fluid viscosity. These parameters revealed distinct DWI-MRE property clusters characterizing weak, moderate, and strong water-network interactions. Sparse networks interacting weakly with water, such as collagen or diluted decellularized tissue, resulted in marginal changes in water diffusion over increasing solid viscosity. In contrast, dense networks with larger solid fractions exhibited both free and hindered water diffusion depending on the polarity of the solid components. For example, polar and highly sulfated GAGs as well as native soft tissues hindered water diffusion despite relatively low solid viscosity. Our results suggest that two fundamental properties of tissue networks, solid fraction and network polarity, critically influence solid and fluid viscosity in biological tissues. Since clinical DWI and MRE are sensitive to these viscosity parameters, the framework we present here can be used to detect tissue remodeling and architectural changes in the setting of diagnostic imaging. STATEMENT OF SIGNIFICANCE: The viscoelastic properties of biological tissues provide a wealth of information on the vital state of cells and host matrix. Combined measurement of viscoelasticity and water diffusion by medical imaging is sensitive to tissue microarchitecture. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering full exploitation of these properties as a combined clinical biomarker. Therefore, we analyzed the parameter space accessible by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) and developed a theoretical framework for the relationship between water mobility and mechanical parameters in biomaterials. Our theory of solid material properties related to particle motion can be translated to clinical radiology using clinically established MRE and DWI.

Sensitivity of magnetic resonance elastography to extracellular matrix and cell motility in human prostate cancer cell line-derived xenograft models.

Prostate cancer (PCa) is a significant health problem in the male population of the Western world. Magnetic resonance elastography (MRE), an emerging medical imaging technique sensitive to mechanical properties of biological tissues, detects PCa based on abnormally high stiffness and viscosity values. Yet, the origin of these changes in tissue properties and how they correlate with histopathological markers and tumor aggressiveness are largely unknown, hindering the use of tumor biomechanical properties for establishing a noninvasive PCa staging system. To infer the contributions of extracellular matrix (ECM) components and cell motility, we investigated fresh tissue specimens from two PCa xenograft mouse models, PC3 and LNCaP, using magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), quantitative histology, and nuclear shape analysis. Increased tumor stiffness and impaired water diffusion were observed to be associated with collagen and elastin accumulation and decreased cell motility. Overall, LNCaP, while more representative of clinical PCa than PC3, accumulated fewer ECM components, induced less restriction of water diffusion, and exhibited increased cell motility, resulting in overall softer and less viscous properties. Taken together, our results suggest that prostate tumor stiffness increases with ECM accumulation and cell adhesion - characteristics that influence critical biological processes of cancer development. MRE paired with DWI provides a powerful set of imaging markers that can potentially predict prostate tumor development from benign masses to aggressive malignancies in patients. STATEMENT OF SIGNIFICANCE: Xenograft models of human prostate tumor cell lines, allowing correlation of microstructure-sensitive biophysical imaging parameters with quantitative histological methods, can be investigated to identify hallmarks of cancer.

Shear Wave Elastography for Assessing Liver Stiffness in HCV-Infected Kidney Transplant Recipients after Direct-Acting Antiviral Treatment: A Comparative Study with Magnetic Resonance Elastography.

Hepatitis C virus (HCV) infection can lead to hepatic fibrosis. The advent of direct-acting antivirals (DAAs) has substantially improved sustained virological response (SVR) rates. In this context, kidney transplant recipients (KTRs) are of particular interest due to their higher HCV infection rates and uncertain renal excretion and bioavailability of DAAs. We investigated liver stiffness after DAA treatment in 15 HCV-infected KTRs using ultrasound shear wave elastography (SWE) in comparison with magnetic resonance elastography (MRE). KTRs were treated with DAAs (daclatasvir and sofosbuvir) for three months and underwent SWE at baseline, end of therapy (EOT), and 3 (EOT+3) and 12 months (EOT+12) after EOT. Fourteen patients achieved SVR12. Shear wave speed (SWS)-as a surrogate parameter for tissue stiffness-was substantially lower at all three post-therapeutic timepoints compared with baseline (EOT: -0.42 m/s, p < 0.01; CI = -0.75--0.09, EOT+3: -0.43 m/s, p < 0.01; CI = -0.75--0.11, and EOT+12: -0.52 m/s, p < 0.001; CI = -0.84--0.19), suggesting liver regeneration after viral eradication and end of inflammation. Baseline SWS correlated positively with histopathological fibrosis scores (r = 0.48; CI = -0.11-0.85). Longitudinal results correlated moderately with APRI (r = 0.41; CI = 0.12-0.64) but not with FIB-4 scores (r = 0.12; CI = -0.19-0.41). Although higher on average, SWE-derived measurements correlated strongly with MRE (r = 0.64). In conclusion, SWE is suitable for non-invasive therapy monitoring in KTRs with HCV infection.