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.

Real-time MR elastography for viscoelasticity quantification in skeletal muscle during dynamic exercises.

PURPOSE: To develop and test real-time MR elastography for viscoelastic parameter quantification in skeletal muscle during dynamic exercises. METHODS: In 15 healthy participants, 6 groups of lower-leg muscles (tibialis anterior, tibialis posterior, peroneus, extensor digitorum longus, soleus, gastrocnemius) were investigated by real-time MR elastography using a single-shot, steady-state spiral gradient-echo pulse sequence and stroboscopic undersampling of harmonic vibrations at 40 Hz frequency. One hundred and eighty consecutive maps of shear-wave speed and loss angle (φ) covering 30.6 s of total acquisition time at 5.9-Hz frame rate were reconstructed from 360 wave images encoding 2 in-plane wave components in an interleaved manner. The experiment was carried out twice to investigate 2 exercises-isometric plantar flexion and isometric dorsiflexion-each performed over 10 s between 2 resting periods. RESULTS: Activation of lower-extremity muscles was associated with increasing viscoelastic parameters shear-wave speed and φ, both reflecting properties related to the transverse direction relative to fiber orientation. Major viscoelastic changes were observed in soleus muscle during plantar flexion (shear-wave speed: 20.0% ± 3.6%, φ: 41.3% ± 12.0%) and in the tibialis anterior muscle during dorsiflexion (41.8% ± 10.2%, φ: 27.9% ± 2.8%; all P < .0001). Two of the muscles analyzed were significantly activated by plantar flexion and 4 by dorsiflexion based on shear-wave speed, whereas φ changed significantly in 5 muscles during both exercises. CONCLUSION: Real-time MR elastography allows mapping of dynamic, nonperiodic viscoelasticity changes in soft tissues such as voluntary muscle with high spatial and temporal resolution. Real-time MR elastography thus opens new horizons for the in vivo study of physiological processes in soft tissues toward functional elastography.

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.

Cerebral tomoelastography based on multifrequency MR elastography in two and three dimensions.

Purpose: Magnetic resonance elastography (MRE) generates quantitative maps of the mechanical properties of biological soft tissues. However, published values obtained by brain MRE vary largely and lack detail resolution, due to either true biological effects or technical challenges. We here introduce cerebral tomoelastography in two and three dimensions for improved data consistency and detail resolution while considering aging, brain parenchymal fraction (BPF), systolic blood pressure, and body mass index (BMI). Methods: Multifrequency MRE with 2D- and 3D-tomoelastography postprocessing was applied to the brains of 31 volunteers (age range: 22-61 years) for analyzing the coefficient of variation (CV) and effects of biological factors. Eleven volunteers were rescanned after 1 day and 1 year to determine intraclass correlation coefficient (ICC) and identify possible long-term changes. Results: White matter shear wave speed (SWS) was slightly higher in 2D-MRE (1.28 ± 0.02 m/s) than 3D-MRE (1.22 ± 0.05 m/s, p < 0.0001), with less variation after 1 day in 2D (0.33 ± 0.32%) than in 3D (0.96 ± 0.66%, p = 0.004), which was also reflected in a slightly lower CV and higher ICC in 2D (1.84%, 0.97 [0.88-0.99]) than in 3D (3.89%, 0.95 [0.76-0.99]). Remarkably, 3D-MRE was sensitive to a decrease in white matter SWS within only 1 year, whereas no change in white matter volume was observed during this follow-up period. Across volunteers, stiffness correlated with age and BPF, but not with blood pressure and BMI. Conclusion: Cerebral tomoelastography provides high-resolution viscoelasticity maps with excellent consistency. Brain MRE in 2D shows less variation across volunteers in shorter scan times than 3D-MRE, while 3D-MRE appears to be more sensitive to subtle biological effects such as aging.

Liquid-Liver Phantom: Mimicking the Viscoelastic Dispersion of Human Liver for Ultrasound- and MRI-Based Elastography.

OBJECTIVES: Tissue stiffness can guide medical diagnoses and is exploited as an imaging contrast in elastography. However, different elastography devices show different liver stiffness values in the same subject, hindering comparison of values and establishment of system-independent thresholds for disease detection. There is a need for standardized phantoms that specifically address the viscosity-related dispersion of stiffness over frequency. To improve standardization of clinical elastography across devices and platforms including ultrasound and magnetic resonance imaging (MRI), a comprehensively characterized phantom is introduced that mimics the dispersion of stiffness of the human liver and can be generated reproducibly. MATERIALS AND METHODS: The phantom was made of linear polymerized polyacrylamide (PAAm) calibrated to the viscoelastic properties of healthy human liver in vivo as reported in the literature. Stiffness dispersion was analyzed using the 2-parameter springpot model fitted to the dispersion of shear wave speed of PAAm, which was measured by shear rheometry, ultrasound-based time-harmonic elastography, clinical magnetic resonance elastography (MRE), and tabletop MRE in the frequency range of 5 to 3000 Hz. Imaging parameters for ultrasound and MRI, reproducibility, aging behavior, and temperature dependency were assessed. In addition, the frequency bandwidth of shear wave speed of clinical elastography methods (Aplio i900, Canon; Acuson Sequoia, Siemens; FibroScan, EchoSense) was characterized. RESULTS: Within the entire frequency range analyzed in this study, the PAAm phantom reproduced well the stiffness dispersion of human liver in vivo despite its fluid properties under static loading (springpot stiffness parameter, 2.14 [95% confidence interval, 2.08-2.19] kPa; springpot powerlaw exponent, 0.367 [95% confidence interval, 0.362-0.373]). Imaging parameters were close to those of liver in vivo with only slight variability in stiffness values of 0.5% (0.4%, 0.6%), 4.1% (3.9%, 4.5%), and -0.63% (-0.67%, -0.58%), respectively, between batches, over a 6-month period, and per °C increase in temperature. CONCLUSIONS: The liquid-liver phantom has useful properties for standardization and development of liver elastography. First, it can be used across clinical and experimental elastography devices in ultrasound and MRI. Second, being a liquid, it can easily be adapted in size and shape to specific technical requirements, and by adding inclusions and scatterers. Finally, because the phantom is based on noncrosslinked linear PAAm constituents, it is easy to produce, indicating potential widespread use among researchers and vendors to standardize liver stiffness measurements.

Real-Time Multifrequency MR Elastography of the Human Brain Reveals Rapid Changes in Viscoelasticity in Response to the Valsalva Maneuver.

Modulation of cerebral blood flow and vascular compliance plays an important role in the regulation of intracranial pressure (ICP) and also influences the viscoelastic properties of brain tissue. Therefore, magnetic resonance elastography (MRE), the gold standard for measuring in vivo viscoelasticity of brain tissue, is potentially sensitive to cerebral autoregulation. In this study, we developed a multifrequency MMRE technique that provides serial maps of viscoelasticity at a frame rate of nearly 6 Hz without gating, i.e., in quasi-real time (rt-MMRE). This novel method was used to monitor rapid changes in the viscoelastic properties of the brains of 17 volunteers performing the Valsalva maneuver (VM). rt-MMRE continuously sampled externally induced vibrations comprising three frequencies of 30.03, 30.91, and 31.8 Hz were over 90 s using a steady-state, spiral-readout gradient-echo sequence. Data were processed by multifrequency dual elasto-visco (MDEV) inversion to generate maps of magnitude shear modulus | G∗| (stiffness) and loss angle φ at a frame rate of 5.4 Hz. As controls, the volunteers were examined to study the effects of breath-hold following deep inspiration and breath-hold following expiration. We observed that | G∗| increased while φ decreased due to VM and, less markedly, due to breath-hold in inspiration. Group mean VM values showed an early overshoot of | G∗| 2.4 ± 1.2 s after the onset of the maneuver with peak values of 6.7 ± 4.1% above baseline, followed by a continuous increase in stiffness during VM. A second overshoot of | G∗| occurred 5.5 ± 2.0 s after the end of VM with peak values of 7.4 ± 2.8% above baseline, followed by 25-s sustained recovery until the end of image acquisition. φ was constantly reduced by approximately 2% during the entire VM without noticeable peak values. This is the first report of viscoelasticity changes in brain tissue induced by physiological maneuvers known to alter ICP and detected by clinically applicable rt-MMRE. Our results show that apnea and VM slightly alter brain properties toward a more rigid-solid behavior. Overshooting stiffening reactions seconds after onset and end of VM reveal rapid autoregulatory processes of brain tissue viscoelasticity.