Cancer initiation and progression follow complex molecular and structural changes in the extracellular matrix and cellular architecture of living tissue. However, it remains poorly understood how the transformation from health to malignancy alters the mechanical properties of cells within the tumour microenvironment. Here, we show using an indentation-type atomic force microscope (IT-AFM) that unadulterated human breast biopsies display distinct stiffness profiles. Correlative stiffness maps obtained on normal and benign tissues show uniform stiffness profiles that are characterized by a single distinct peak. In contrast, malignant tissues have a broad distribution resulting from tissue heterogeneity, with a prominent low-stiffness peak representative of cancer cells. Similar findings are seen in specific stages of breast cancer in MMTV-PyMT transgenic mice. Further evidence obtained from the lungs of mice with late-stage tumours shows that migration and metastatic spreading is correlated to the low stiffness of hypoxia-associated cancer cells. Overall, nanomechanical profiling by IT-AFM provides quantitative indicators in the clinical diagnostics of breast cancer with translational significance.

https://www.cell.com/biophysj/pdf/S0006-3495(12)03025-1.pdf

The nanomechanical signature of breast cancer

The experimental test of novel ultrasound (US) investigation methods can be made difficult by the lack of flexibility of commercial US machines. In the best options, these only provide beamformed radiofrequency or demodulated echo-signals for acquisition by an external PC. More flexibility is achieved in high-level research platforms, but these are typically characterized by high cost and large size. This paper presents a powerful but portable US system, specifically developed for research purposes. The system design has been based on high-level commercial integrated circuits to obtain the maximum flexibility and wide data access with minimum of electronics. Preliminary applications involving nonstandard imaging transmit/receive strategies and simultaneous B-mode and multigate spectral Doppler mode are discussed.

ULA-OP: an advanced open platform for ultrasound research

The Synthetic Aperture Real-time Ultrasound System (SARUS) for acquiring and processing synthetic aperture (SA) data for research purposes is described. The specifications and design of the system are detailed, along with its performance for SA, nonlinear, and 3-D flow estimation imaging. SARUS acquires individual channel data simultaneously for up to 1024 transducer elements for a couple of heart beats, and is capable of transmitting any kind of excitation. The 64 boards in the system house 16 transmit and 16 receive channels each, where sampled channel data can be stored in 2 GB of RAM and processed using five field-programmable gate arrays (FPGAs). The fully parametric focusing unit calculates delays and apodization values in real time in 3-D space and can produce 350 million complex samples per channel per second for full non-recursive synthetic aperture B-mode imaging at roughly 30 high-resolution images/s. Both RF element data and beamformed data can be stored in the system for later storage and processing. The stored data can be transferred in parallel using the system's sixty-four 1-Gbit Ethernet interfaces at a theoretical rate of 3.2 GB/s to a 144-core Linux cluster.

/pdf/sarus-a-synthetic-aperture-real-time-ultrasound-system-4xyptsksy5.pdf

SARUS: A synthetic aperture real-time ultrasound system

This paper introduces two real-time elastography techniques based on analytic minimization (AM) of regularized cost functions. The first method (1D AM) produces axial strain and integer lateral displacement, while the second method (2D AM) produces both axial and lateral strains. The cost functions incorporate similarity of radio-frequency (RF) data intensity and displacement continuity, making both AM methods robust to small decorrelations present throughout the image. We also exploit techniques from robust statistics to make the methods resistant to large local decorrelations. We further introduce Kalman filtering for calculating the strain field from the displacement field given by the AM methods. Simulation and phantom experiments show that both methods generate strain images with high SNR, CNR and resolution. Both methods work for strains as high as 10% and run in real-time. We also present in vivo patient trials of ablation monitoring. An implementation of the 2D AM method as well as phantom and clinical RF-data can be downloaded.

Real-Time Regularized Ultrasound Elastography

Quasi-Static Ultrasound Elastography.

In current ultrasound elastography, only the axial component of the displacement vector is estimated and used to produce strain images. A method was recently proposed by our group to estimate both the axial and lateral components of a displacement vector following a uniaxial compression. Previous work evaluated the technique using both simulations and a mechanically translated phased array transducer. In this paper, we present initial results using beam steering on a linear array transducer attached to a commercial scanner to acquire echo signals for estimating 2-D displacement vectors. Single-inclusion and anthropomorphic breast phantoms with different boundary properties between the inclusion and background material are imaged by acquiring echo data along beam lines ranging from –15° to 15° relative to the compression direction. 1-D cross-correlation is used to calculate “angular displacements” in each acquisition direction, yielding axial and lateral components of the displacement vector. Strain tensor components are estimated from these displacements. Features on shear strain images generated for the inclusion phantom agree with those predicted using FEA analysis. Experimental results demonstrate the utility of this technique on clinical scanners. Shear strain tensors obtained using this method may provide useful information for the differentiation of benign from malignant tumors. For the linear array transducer used in this study, the optimum angular increment is around 3°. However, more work is required for the selection of an appropriate value for the maximum beam angle for optimal performance of this technique. (E-mail: tvarghese@wisc.edu )

https://www.medphysics.wisc.edu/tvarghese/publications/pdf/umb_sse07.pdf

Normal and shear strain estimation using beam steering on linear-array transducers

Unlike researchers in magnetic resonance imaging who have considerable access to high level tools and to data at a very basic level on their scanners, those involved with ultrasound have found little in the way of meaningful and widespread access to even the most basic echo signals in their clinical systems. Interest has emerged, however, in ultrasound research interfaces on commercial scanners to provide access to raw ultrasound data and control of basic research functions. This paper describes initial experience gained on one such ultrasound system. The Ultrasonix 500RP system provides research access to the data at multiple points in the signal processing chain and allows control over most imaging parameters. The Ultrasonix system allows for three methods of research control. One is implemented along with the standard clinical imaging software using "mouseover" screens on the periphery of the application window. These screens are configured by the user to display various signal processing variables, which can be modified in real time. Second, the system can be controlled via a user-written remote control client application interacting through the clinical exam software. Lastly, the user can write a complete application which initializes the basic ultrasound module but need not use the Ultrasonix clinical exam software. All of the modes can be done locally on the scanner itself or via a network, and are based on software developed in C++ with libraries supplied with the scanner. Two examples are presented in this paper from the evaluation of the system in "real world" applications. Measurements of absolute backscatter coefficients and attenuation coefficients versus frequency are shown and elastograms utilizing spatial compounding are described

/pdf/the-ultrasonix-500rp-a-commercial-ultrasound-research-362047l63m.pdf

The ultrasonix 500RP: A commercial ultrasound research interface

Spatial-angular compounding is a new technique that enables the reduction of noise artifacts in ultrasound elastography. Under this method, compounded elastograms are obtained from a spatially weighted average of local strain estimated from radio frequency (rf) echo signals acquired at different insonification angles. In previous work, the acquisition of the rf signals was performed through the lateral translation of a phased-array transducer. Clinical applications of angular compounding would, however, require the utilization of beam steering on linear-array transducers to obtain angular data sets, which is more efficient than translating phased-array transducers. In this article, we investigate the performance of angular compounding for elastography by using beam steering on a linear-array transducer. Quantitative experimental results demonstrate that spatial angular compounding provides significant improvement in both the elastographic signal-to-noise ratio and the contrast-to-noise ratio. For the linear array transducer used in this study, the optimum angular increment is around 1.5°–3.75°, and the maximum angle that can be used in angular compounding should not exceed 10°.

/pdf/spatial-angular-compounding-for-elastography-using-beam-1sdefsrbr2.pdf

Spatial-angular compounding for elastography using beam steering on linear array transducers

Axial strain imaging has been utilized for the characterization of breast masses for over a decade; however, another important feature namely the shear strain distribution around breast masses has only recently been used. In this article, we examine the feasibility of utilizing in vivo axial-shear strain imaging for differentiating benign from malignant breast masses. Radio-frequency data was acquired using a VFX 13-5 linear array transducer on 41 patients using a Siemens SONOLINE Antares real-time clinical scanner at the University of Wisconsin Breast Cancer Center. Free-hand palpation using deformations of up to 10% was utilized to generate axial strain and axial-shear strain images using a two-dimensional cross-correlation algorithm from the radio-frequency data loops. Axial-shear strain areas normalized to the lesion size, applied strain and lesion strain contrast was utilized as a feature for differentiating benign from malignant masses. The normalized axial-shear strain area feature estimated on eight patients with malignant tumors and 33 patients with fibroadenomas was utilized to demonstrate its potential for lesion differentiation. Biopsy results were considered the diagnostic standard for comparison. Our results indicate that the normalized axial-shear strain area is significantly larger for malignant tumors compared with benign masses such as fibroadenomas. Axial-shear strain pixel values greater than a specified threshold, including only those with correlation coefficient values greater than 0.75, were overlaid on the corresponding B-mode image to aid in diagnosis. A scatter plot of the normalized area feature demonstrates the feasibility of developing a linear classifier to differentiate benign from malignant masses. The area under the receiver operator characteristic curve utilizing the normalized axial-shear strain area feature was 0.996, demonstrating the potential of this feature to noninvasively differentiate between benign and malignant breast masses.

/pdf/axial-shear-strain-imaging-for-differentiating-benign-and-eqo4554lqf.pdf

Min Rao

Papers

Normal and shear strain estimation using beam steering on linear-array transducers

The ultrasonix 500RP: A commercial ultrasound research interface

Spatial-angular compounding for elastography using beam steering on linear array transducers

Axial Shear Strain Imaging for Differentiating Benign and Malignant Breast Masses

Spatial Angular Compounding for Elastography without the Incompressibility Assumption