Harmonic motion imaging of human breast masses: an in vivo clinical feasibility.

Non-invasive diagnosis of breast cancer is still challenging due to the low specificity of the imaging modalities that calls for unnecessary biopsies. The diagnostic accuracy can be improved by assessing the breast tissue mechanical properties associated with pathological changes. Harmonic motion imaging (HMI) is an elasticity imaging technique that uses acoustic radiation force to evaluate the localized mechanical properties of the underlying tissue. Herein, we studied the in vivo feasibility of a clinical HMI system to differentiate breast tumors based on their relative HMI displacements, in human subjects. We performed HMI scans in 10 female subjects with breast masses: five benign and five malignant masses. Results revealed that both benign and malignant masses were stiffer than the surrounding tissues. However, malignant tumors underwent lower mean HMI displacement (1.1 ± 0.5 µm) compared to benign tumors (3.6 ± 1.5 µm) and the adjacent non-cancerous tissue (6.4 ± 2.5 µm), which allowed to differentiate between tumor types. Additionally, the excised breast specimens of the same patients (n = 5) were imaged post-surgically, where there was an excellent agreement between the in vivo and ex vivo findings, confirmed with histology. Higher displacement contrast between cancerous and non-cancerous tissue was found ex vivo, potentially due to the lower nonlinearity in the elastic properties of ex vivo tissue. This preliminary study lays the foundation for the potential complementary application of HMI in clinical practice in conjunction with the B-mode to classify suspicious breast masses.

Multi-parameter Sub-Hertz Analysis of Viscoelasticity With a Quality Metric for Differentiation of Breast Masses.

We applied sub-Hertz analysis of viscoelasticity (SAVE) to differentiate breast masses in pre-biopsy patients. Tissue response during external ramp-and-hold stress was ultrasonically detected. Displacements were used to acquire tissue viscoelastic parameters. The fast instantaneous response and slow creep-like deformations were modeled as the response of a linear standard solid from which viscoelastic parameters were estimated. These parameters were used in a multi-variable classification framework to differentiate malignant from benign masses identified by pathology. When employing all viscoelasticity parameters, SAVE resulted in 71.43% accuracy in differentiating lesions. When combined with ultrasound features and lesion size, accuracy was 82.24%. Adding a quality metric based on uniaxial motion increased the accuracy to 81.25%. When all three were combined with SAVE, accuracy was 91.3%. These results confirm the utility of SAVE as a robust ultrasound-based diagnostic tool for non-invasive differentiation of breast masses when used as stand-alone biomarkers or in conjunction with ultrasonic features.

Noninvasive Young's modulus visualization of fibrosis progression and delineation of pancreatic ductal adenocarcinoma (PDAC) tumors using Harmonic Motion Elastography (HME) in vivo.

Background and aims: Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes. Methods: In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections. Results: HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %). Conclusion: In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed.

Harmonic Motion Imaging of Pancreatic Tumor Stiffness Indicates Disease State and Treatment Response.

PURPOSE: Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. EXPERIMENTAL DESIGN: Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens. RESULTS: In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2-mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients. CONCLUSIONS: These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.

Viscoelastic biomarker for differentiation of benign and malignant breast lesion in ultra- low frequency range.

Benign and malignant tumors differ in the viscoelastic properties of their cellular microenvironments and in their spatiotemporal response to very low frequency stimuli. These differences can introduce a unique viscoelastic biomarker in differentiation of benign and malignant tumors. This biomarker may reduce the number of unnecessary biopsies in breast patients. Although different methods have been developed so far for this purpose, none of them have focused on in vivo and in situ assessment of local viscoelastic properties in the ultra-low (sub-Hertz) frequency range. Here we introduce a new, noninvasive model-free method called Loss Angle Mapping (LAM). We assessed the performance results on 156 breast patients. The method was further improved by detection of out-of-plane motion using motion compensation cross correlation method (MCCC). 45 patients met this MCCC criterion and were considered for data analysis. Among this population, we found 77.8% sensitivity and 96.3% specificity (p < 0.0001) in discriminating between benign and malignant tumors using logistic regression method regarding the pre known information about the BIRADS number and size. The accuracy and area under the ROC curve, AUC, was 88.9% and 0.94, respectively. This method opens new avenues to investigate the mechanobiology behavior of different tissues in a frequency range that has not yet been explored in any in vivo patient studies.

Technical Note: In vivo Young's modulus mapping of pancreatic ductal adenocarcinoma during HIFU ablation using harmonic motion elastography (HME).

PURPOSE: Noninvasive quantitative assessment of coagulated tissue during high-intensity focused ultrasound (HIFU) ablation is one of the essential steps for tumor treatment, especially in such cases as the Pancreatic Ductal Adenocarcinoma (PDA) that has low probability of diagnosis at the early stages and high probability of forming solid carcinomas resistant to chemotherapy treatment at the late stages. METHODS: Harmonic motion elastography (HME) is a technique for the localized estimation of tumor stiffness. This harmonic motion imaging (HMI)-based technique is designed to map the tissue Young's modulus or stiffness noninvasively. A focused ultrasound (FUS) transducer generates an oscillating, acoustic radiation force in its focal region. The two-dimensional (2D) shear wave speed, and consequently the Young's modulus maps, is generated by tracking the radio frequency (RF) signals acquired at high frame rates. By prolonging the sonication for more than 50 s using the same methodology, the 2D Young's modulus maps are reconstructed while HIFU is applied and ablation is formed on PDA murine tumors. RESULTS: The feasibility of this technique in measuring the regional Young's modulus was first assessed in tissue-mimicking phantoms. The contrast-to-noise ratio (CNR) was found to be higher than 11.7 dB for each 2D reconstructed Young's modulus map. The mean error in this validation study was found to be equal to less than 19%. Then HME was applied on two transgenic mice with pancreatic ductal adenocarcinoma tumors. The Young's modulus median value of this tumor at the start of the HIFU application was equal to 2.1 kPa while after 45 s of sonication it was found to be approximately three times stiffer (6.7 kPa). CONCLUSIONS: The HME was described herein and showed its capability of measuring tissue stiffness noninvasively by measuring the shear wave speed propagation inside the tissue and reconstructing a 2D Young's modulus map. Application of the methodology in vivo and during HIFU were thus reported here for the first time.

Automated In Vivo Sub-Hertz Analysis of Viscoelasticity (SAVE) for Evaluation of Breast Lesions.

We present an automated method for acquiring images and contrast parameters based on mechanical properties of breast lesions and surrounding tissue at load frequencies less than 1 Hz. The method called sub-Hertz analysis of viscoelasticity (SAVE) uses a compression device integrated with ultrasound imaging to perform in vivo ramp-and-hold uniaxial creep-like test on human breast in vivo. It models the internal deformations of tissues under constant surface stress as a linear viscoelastic response. We first discuss different aspects of our unique measurement approach and the expected variability of the viscoelastic parameters estimated based on a simplified one-dimensional reconstruction model. Finite-element numerical analysis is used to justify the advantages of using imaging contrast over viscoelasticity values. We then present the results of SAVE applied to a group of patients with breast masses undergoing biopsy.

Automated Compression Device for Viscoelasticity Imaging.

Noninvasive measurement of tissue viscoelastic properties is gaining more attention for screening and diagnostic purposes. Recently, measuring dynamic response of tissue under a constant force has been studied for estimation of tissue viscoelastic properties in terms of retardation times. The essential part of such a test is an instrument that is capable of creating a controlled axial force and is suitable for clinical applications. Such a device should be lightweight, portable, and easy to use for patient studies to capture tissue dynamics under external stress. In this paper, we present the design of an automated compression device for studying the creep response of materials with tissue-like behaviors. The device can be used to apply a ramp-and-hold force excitation for a predetermined duration of time and it houses an ultrasound probe for monitoring the creep response of the underlying tissue. To validate the performance of the device, several creep tests were performed on tissue-mimicking phantoms, and the results were compared against those from a commercial mechanical testing instrument. Using a second-order Kelvin-Voigt model and surface measurement of the forces and displacements, retardation times T1 and T2 were estimated from each test. These tests showed strong agreement between our automated compression device and the commercial mechanical testing system, with an average relative error of 2.9% and 12.4%, for T1 and T2, respectively. Also, we present the application of compression device to measure local retardation times for four different phantoms with different size and stiffness.

Multi-source and multi-directional shear wave generation with intersecting steered ultrasound push beams.

Elasticity imaging is becoming established as a means of assisting in diagnosis of certain diseases. Shear wave-based methods have been developed to perform elasticity measurements in soft tissue. Comb-push ultrasound shear elastography (CUSE) is one of these methods that apply acoustic radiation force to induce the shear wave in soft tissues. CUSE uses multiple ultrasound beams that are transmitted simultaneously to induce multiple shear wave sources into the tissue, with improved shear wave SNR and increased shear wave imaging frame rate. We propose a novel method that uses steered push beams (SPB) that can be applied for beam formation for shear wave generation. In CUSE beamforming, either unfocused or focused beams are used to create the propagating shear waves. In SPB methods we use unfocused beams that are steered at specific angles. The interaction of these steered beams causes shear waves to be generated in more of a random nature than in CUSE. The beams are typically steered over a range of 3 to 7° and can either be steered to the left (-θ) or right (+θ).We performed simulations of 100 configurations using Field II and found the best configurations based on spatial distribution of peaks in the resulting intensity field. The best candidates were ones with a higher number of the intensity peaks distributed over all depths in the simulated beamformed results. Then these optimal configurations were applied on a homogeneous phantom and two different phantoms with inclusions. In one of the inhomogeneous phantoms we studied two spherical inclusions with 10 and 20 mm diameters, and in the other phantom we studied cylindrical inclusions with diameters ranging from 2.53 to 16.67 mm. We compared these results with those obtained using conventional CUSE with unfocused and focused beams. The mean and standard deviation of the resulting shear wave speeds were used to evaluate the accuracy of the reconstructions by examining bias with nominal values for the phantoms as well as the contrast-to-noise ratio in the inclusion phantom results. In general the contrast-to-noise ratio (CNR) was higher and the bias was lower using the SPB method compared with the CUSE realizations except in the largest inclusions. In the cylindrical inclusion with 10.4 mm diameter, the CNR in CUSE methods ranged between 18.52 and 22.02 and the bias ranged between 5.50 and 11.12%, whereas for SPB methods provided CNR values between 23.07 and 48.90 and bias values between 3.78 and 9.22%. In a smaller cylindrical inclusion with diameter of 4.05 mm, CUSE methods gave CNR between 14.69 and 22.28 and bias ranging between 28.95 and 29.28%, whereas the SPB methods provided CNR values between 16.7 and 25.2 and bias values varying from 25.54 to 30.44%. The SPB method provides a flexible framework to produce shear wave sources that are widely distributed within the field-of-view for robust shear wave speed imaging.

Optimized shear wave generation using hybrid beamforming methods.

Elasticity imaging is a medical imaging modality that measures tissue elasticity as an aid in the diagnosis of certain diseases. Shear wave-based methods have been developed to perform elasticity measurements in soft tissue. These methods often use the radiation force mechanism of focused ultrasound to induce shear waves in soft tissue such as liver, kidney, breast, thyroid and skeletal muscle. The efficiency of the ultrasound beam in producing broadband extended shear waves in soft tissue is very important to the widespread use of this modality. Hybrid beamforming combines two types of focusing, conventional spherical focusing and axicon focusing, to produce a beam for generating a shear wave that has increased depth-of-field (DOF) so that measurements can be made with a shear wave with a consistent wave front. Spherical focusing is used in many applications to achieve high lateral resolution, but has low DOF. Axicon focusing, with a cone-shaped transducer, can provide good lateral resolution with large DOF. We describe our linear aperture design and beam optimization performed using angular spectrum simulations. We performed a large parametric simulation study in which we varied the focal depth for the spherical focusing portion of the aperture, the numbers of elements devoted to the spherical and axicon focusing portions of the aperture and the opening angle used for axicon focusing. The hybrid beamforming method was experimentally tested in two phantoms, and shear wave speed measurement accuracy and DOF for each hybrid beam were evaluated. We compared our results with those for shear waves generated using only spherical focusing. The results of this study indicate that hybrid beamforming is capable of producing a beam with increased DOF over which accurate shear wave speed measurements can be made for different-size apertures and at different focal depths.

Ultrasound bladder vibrometry method for measuring viscoelasticity of the bladder wall.

Increase in bladder stiffness could be associated with various pathophysiologic conditions. Measuring bladder viscoelasticity could be an important step towards understanding various disease processes and improving patient care. Here, we introduce ultrasound bladder vibrometry (UBV), a novel method for rapid and noninvasive measurement of bladder wall viscoelasticity. UBV uses acoustic radiation force to excite mechanical waves in the bladder wall and track the motion using ultrasound pulse-echo techniques. Fourier domain analysis of the tissue motion versus time is used to calculate the phase velocity dispersion (change of phase velocity as a function of frequency). The measured phase velocity dispersion is fit with the antisymmetric Lamb wave model to estimate tissue elasticity and viscosity. We used finite element analysis of viscoelastic plate deformation to investigate the effect of curvature on Lamb wave dispersion and showed that the effects of curvature are negligible. The feasibility of the UBV technique was demonstrated in ex vivo and in vivo settings. Elasticity and viscosity of excised pig at various filling volumes (V) and pressures (p) were found to be µ1 = 9.6 kPa and µ2 = 0.2 Pa s (V = 187 ml and p = 8.6 mmHg), µ1 = 48.7 kPa and µ2 = 3.5 Pa s (V = 267 ml and p = 17.6 mmHg), and µ1 = 106.9 kPa and µ2 = 1.5 Pa s (V = 327 ml and p = 27.6 mmHg) respectively. Transabdominal measurements in an anesthetized pig found values of bladder elasticity µ1 = 26.1 kPa and viscosity µ2 = 0.9 Pa s and demonstrate the ability of UBV to perform in vivo measurements. The results presented in this paper introduce a novel technique for measuring mechanical properties of the bladder and lay the foundation for further investigation of the effects of pathology on bladder viscoelasticity.

Velocity measurement by vibro-acoustic Doppler.

We describe the theoretical principles of a new Doppler method, which uses the acoustic response of a moving object to a highly localized dynamic radiation force of the ultrasound field to calculate the velocity of the moving object according to Doppler frequency shift. This method, named vibro-acoustic Doppler (VAD), employs two ultrasound beams separated by a slight frequency difference, Δf, transmitting in an X-focal configuration. Both ultrasound beams experience a frequency shift because of the moving objects and their interaction at the joint focal zone produces an acoustic frequency shift occurring around the low-frequency (Δf) acoustic emission signal. The acoustic emission field resulting from the vibration of the moving object is detected and used to calculate its velocity. We report the formula that describes the relation between Doppler frequency shift of the emitted acoustic field and the velocity of the moving object. To verify the theory, we used a string phantom. We also tested our method by measuring fluid velocity in a tube. The results show that the error calculated for both string and fluid velocities is less than 9.1%. Our theory shows that in the worst case, the error is 0.54% for a 25° angle variation for the VAD method compared with an error of -82.6% for a 25° angle variation for a conventional continuous wave Doppler method. An advantage of this method is that, unlike conventional Doppler, it is not sensitive to angles between the ultrasound beams and direction of motion.