Multi-Frequency 3D Shear Wave Absolute Vibro-Elastography (S-WAVE) System for the Prostate.

This article describes a novel system for quantitative and volumetric measurement of tissue elasticity in the prostate using simultaneous multi-frequency tissue excitation. Elasticity is computed by using a local frequency estimator to measure the three-dimensional local wavelengths of steady-state shear waves within the prostate gland. The shear wave is created using a mechanical voice coil shaker which transmits simultaneous multi-frequency vibrations transperineally. Radio frequency data is streamed directly from a BK Medical 8848 transrectal ultrasound transducer to an external computer where tissue displacement due to the excitation is measured using a speckle tracking algorithm. Bandpass sampling is used that eliminates the need for an ultra-fast frame rate to track the tissue motion and allows for accurate reconstruction at a sampling frequency that is below the Nyquist rate. A roll motor with computer control is used to rotate the transducer and obtain 3D data. Two commercially available phantoms were used to validate both the accuracy of the elasticity measurements as well as the functional feasibility of using the system for in vivo prostate imaging. The phantom measurements were compared with 3D Magnetic Resonance Elastography (MRE), where a high correlation of 96% was achieved. In addition, the system has been used in two separate clinical studies as a method for cancer identification. Qualitative and quantitative results of 11 patients from these clinical studies are presented here. Furthermore, an AUC of 0.87±0.12 was achieved for malignant vs. benign classification using a binary support vector machine classifier trained with data from the latest clinical study with leave one patient out cross-validation.

CFP10: mFcγ2 as a novel tuberculosis vaccine candidate increases immune response in mouse.

OBJECTIVES: Despite treatment with antibiotics and vaccination with BCG, tuberculosis (TB) is still considered as one of the most important public health problems in the world. Therefore, designing and producing a more effective vaccine against TB seems urgently. In this study, immunogenicity of a fusion protein which consisting or comprising CFP-10 from Mycobacterium tuberculosis and the Fc-domain of mouse IgG2a was evaluated as a novel subunit vaccine candidate against TB. MATERIALS AND METHODS: The genetic constructs were cloned in pPICZαA expression vector and recombinant vectors (pPICZαA-CFP-10: Fcγ2a and pPICZαA-CFP-10:His) were transformed into Pichia pastoris. To evaluate the expression of recombinant proteins, SDS-PAGE and immunoblotting were used. The immunogenicity of recombinant proteins, with and without BCG were assessed in BALB/c mice and specific cytokines against recombinant proteins (IFN-γ, IL-12, IL-4, IL-17 and TGF-ß) were evaluated. RESULTS: The levels of IFN-γ and IL-12 in mice that received recombinant proteins was higher than the control groups (BCG and PBS). Thus, both recombinant proteins (CFP-10:Fcγ2a and CFP-10:His) could excite good response in Th1-cells. The Fc-tagged protein had a stronger Th1 response with low levels of IL-4, as compared to CFP-10:His. However, the highest level of Th1 response was observed in groups that were vaccinated with BCG (prime) and then received recombinant protein CFP-10: Fcγ2a (booster). CONCLUSION: The results demonstrated that binding mice Fc-domain to CFP-10 protein can increase the immunogenicity of the subunit vaccine. Further studies, might be able to design and produce a new generation of subunit vaccines based on the Fc-fused immunogen.

Limited genetic diversity and extensive antimicrobial resistance in clinical isolates of Acinetobacter baumannii in north-east Iran.

This study determined the mechanisms and patterns of antimicrobial resistance among the isolates obtained from different wards of a teaching hospital in the city of Mashhad in north-east Iran. Between January 2012 and the end of June 2012, 36 isolates of Acinetobacter baumannii were collected from different wards of Ghaem Hospital. Antimicrobial susceptibility testing and epsilometer testing (E-test) were performed. The genetic resistance determinants of A, B and D classes of ß-lactamases, aminoglycoside modifying enzymes (AMEs), efflux pumps and ISAba1 elements were assessed by PCR. Repetitive extragenic palindromic element (REP)-PCR was performed to find the genetic relatedness of the isolates. Colistin was the most effective antibiotic of those tested, where all isolates were susceptible. E-test results revealed high rates of resistance to imipenem, ceftazidime and ciprofloxacin. The majority of isolates (97  %) were multidrug-resistant. OXA-51, OXA-23 and tetB genes were detected in all isolates, but OXA-58, IMP and tetA were not detected. The prevalence of OXA-24, bla(TEM), bla(ADC), bla(VIM) and adeB were 64, 95, 61, 64 and 86  %, respectively. ISAba1 was found to be inserted into the 5' end of OXA-23 in 35 isolates (97  %). Of the AMEs, aadA1 (89  %) was the most prevalent, followed by aphA1 (75  %). The band patterns reproduced by REP-PCR showed that 34 out of 36 isolates belonged to one clone and two singletons were identified. The results confirmed that refractory A. baumannii isolates were widely distributed and warned the hospital infection control team to exert strict measures to control the infection. An urgent surveillance system should be implemented.

Multi-parametric 3D quantitative ultrasound vibro-elastography imaging for detecting palpable prostate tumors.

In this article, we describe a system for detecting dominant prostate tumors, based on a combination of features extracted from a novel multi-parametric quantitative ultrasound elastography technique. The performance of the system was validated on a data-set acquired from n = 10 patients undergoing radical prostatectomy. Multi-frequency steady-state mechanical excitations were applied to each patient's prostate through the perineum and prostate tissue displacements were captured by a transrectal ultrasound system. 3D volumetric data including absolute value of tissue elasticity, strain and frequency-response were computed for each patient. Based on the combination of all extracted features, a random forest classification algorithm was used to separate cancerous regions from normal tissue, and to compute a measure of cancer probability. Registered whole mount histopathology images of the excised prostate gland were used as a ground truth of cancer distribution for classifier training. An area under receiver operating characteristic curve of 0.82 +/- 0.01 was achieved in a leave-one-patient-out cross validation. Our results show the potential of multi-parametric quantitative elastography for prostate cancer detection for the first time in a clinical setting, and justify further studies to establish whether the approach can have clinical use.

Transperineal prostate MR elastography: initial in vivo results.

This article presents a new approach to magnetic resonance elastography of the prostate using transperineal mechanical excitation. This approach is validated using a prostate elasticity phantom and in vivo studies of healthy volunteers. It is demonstrated that the transperineal approach can generate shear wave amplitudes on the order of 6-30 µm in the mid-gland region. The driver was implemented using an electromagnetic actuator with a hydraulic transmission system. The magnetic resonance elastography acquisition time has been reduced significantly by using a "second harmonic" approach. Displacement fields are processed using the established three-dimensional local frequency estimation algorithm. The three-dimensional curl-based direct inversion was used to calculate the local wavelength. The traveling wave expansion algorithm was used to reconstruct the wave damping image for one case. Using the proposed method, it was possible to resolve lesions of 0.5 cc in the phantom study. Repeatability experiments were performed and analyzed. The results from this study indicate that transperineal magnetic resonance elastography--without an endorectal coil--is a suitable candidate for a patient study involving multiparametric magnetic resonance imaging of prostate cancer, where magnetic resonance elastography may provide additional information for improved diagnosis and image-based surveillance.

Remote ultrasound palpation for robotic interventions using absolute elastography.

Although robotic surgery has addressed many of the challenges presented by minimally invasive surgery, haptic feedback and the lack of knowledge of tissue stiffness is an unsolved problem. This paper presents a system for finding the absolute elastic properties of tissue using a freehand ultrasound scanning technique, which utilizes the da Vinci Surgical robot and a custom 2D ultrasound transducer for intraoperative use. An external exciter creates shear waves in the tissue, and a local frequency estimation method computes the shear modulus. Results are reported for both phantom and in vivo models. This system can be extended to any 6 degree-of-freedom tracking method and any 2D transducer to provide real-time absolute elastic properties of tissue.

Real-time quantitative elasticity imaging of deep tissue using free-hand conventional ultrasound.

In this article an ultrasound elastography technology is reported which provides quantitative images of tissue elasticity from deep soft tissue. The technique is analogous to Magnetic Resonance Elastography in the use of external mechanical vibrations which can penetrate deep tissue. Multifrequency steady-state mechanical vibrations are applied to the tissue at the skin and tissue displacements are measured by a conventional ultrasound system. Absolute values of tissue elasticity are computed in real-time for each frequency and displayed to the physician. The quantitative elasticity images produced by the technology are validated with magnetic resonance elastography images as the gold standard on standard elasticity phantoms. Preliminary in-vivo data from healthy volunteers are presented which show the potential of the technology for clinical use. The system is currently being used in different clinical studies to image kidney fibrosis, liver fibrosis, and prostate cancer.

Travelling wave expansion: a model fitting approach to the inverse problem of elasticity reconstruction.

In this paper, a novel approach to the problem of elasticity reconstruction is introduced. In this approach, the solution of the wave equation is expanded as a sum of waves travelling in different directions sharing a common wave number. In particular, the solutions for the scalar and vector potentials which are related to the dilatational and shear components of the displacement respectively are expanded as sums of travelling waves. This solution is then used as a model and fitted to the measured displacements. The value of the shear wave number which yields the best fit is then used to find the elasticity at each spatial point. The main advantage of this method over direct inversion methods is that, instead of taking the derivatives of noisy measurement data, the derivatives are taken on the analytical model. This improves the results of the inversion. The dilatational and shear components of the displacement can also be computed as a byproduct of the method, without taking any derivatives. Experimental results show the effectiveness of this technique in magnetic resonance elastography. Comparisons are made with other state-of-the-art techniques.

Frequency-locked pulse sequencer for high-frame-rate monochromatic tissue motion imaging.

To overcome the inherent low frame rate of conventional ultrasound, we have previously presented a system that can be implemented on conventional ultrasound scanners for high-frame-rate imaging of monochromatic tissue motion. The system employs a sector subdivision technique in the sequencer to increase the acquisition rate. To eliminate the delays introduced during data acquisition, a motion phase correction algorithm has also been introduced to create in-phase displacement images. Previous experimental results from tissue- mimicking phantoms showed that the system can achieve effective frame rates of up to a few kilohertz on conventional ultrasound systems. In this short communication, we present a new pulse sequencing strategy that facilitates high-frame-rate imaging of monochromatic motion such that the acquired echo signals are inherently in-phase. The sequencer uses the knowledge of the excitation frequency to synchronize the acquisition of the entire imaging plane to that of an external exciter. This sequencing approach eliminates any need for synchronization or phase correction and has applications in tissue elastography, which we demonstrate with tissue-mimicking phantoms.

2-D high-frame-rate dynamic elastography using delay compensated and angularly compounded motion vectors: preliminary results.

This paper describes a new ultrasound-based system for high-frame-rate measurement of periodic motion in 2-D for tissue elasticity imaging. Similarly to conventional 2-D flow vector imaging, the system acquires the RF signals from the region of interest at multiple steering angles. A custom sector subdivision technique is used to increase the temporal resolution while keeping the total acquisition time within the range suitable for real-time applications. Within each sector, 1-D motion is estimated along the beam direction. The intra- and inter-sector delays are compensated using our recently introduced delay compensation algorithm. In-plane 2-D motion vectors are then reconstructed from these delay-compensated 1-D motions. We show that Young's modulus images can be reconstructed from these 2-D motion vectors using local inversion algorithms. The performance of the system is validated quantitatively using a commercial flow phantom and a commercial elasticity phantom. At the frame rate of 1667 Hz, the estimated flow velocities with the system are in agreement with the velocity measured with a pulsed-wave Doppler imaging mode of a commercial ultrasound machine with manual angle correction. At the frame rate of 1250 Hz, phantom Young's moduli of 29, 6, and 54 kPa for the background, the soft inclusion, and the hard inclusion, are estimated to be 30, 11, and 53 kPa, respectively.

A high-frame-rate ultrasound system for the study of tissue motions.

In this article, a technique for measuring fast periodic motion is proposed. The sequencing used in this technique is similar to the one used in conventional color Doppler systems. However, a phase correction algorithm is introduced which compensates for the acquisition delays. Criteria for the types of motion which could be detected correctly by the system are developed and presented. Effective frame rates of several hundred hertz to a few kilohertz have been achieved with the system. Applications of the system in tissue elastography are presented together with experimental results from tissue mimicking phantoms.

Theoretical limitations of the elastic wave equation inversion for tissue elastography.

This article examines the theoretical limitations of the local inversion techniques for the measurement of the tissue elasticity. Most of these techniques are based on the estimation of the phase speed or the algebraic inversion of a one-dimensional wave equation. To analyze these techniques, the wave equation in an elastic continuum is revisited. It is proven that in an infinite medium, harmonic shear waves can travel at any phase speed greater than the classically known shear wave speed, mu/rho, by demonstrating this for a special case with cylindrical symmetry. Hence in addition to the mechanical properties of the tissue, the phase speed depends on the geometry of the wave as well. The elastic waves in an infinite cylindrical rod are studied. It is proven that multiple phase speeds can coexist for a harmonic wave at a single frequency. This shows that the phase speed depends not only on the mechanical properties of the tissue but also on its shape. The final conclusion is that the only way to avoid theoretical artifacts in the elastograms obtained by the local inversion techniques is to use the shear wave equation as expressed in the curl of the displacements, i.e., the rotations, for the inversion.

Measurement of viscoelastic properties of tissue-mimicking material using longitudinal wave excitation.

This paper presents an experimental framework for the measurement of the viscoelastic properties of tissue-mimicking material. The novelty of the presented framework is in the use of longitudinal wave excitation and the study of the longitudinal wave patterns in finite media for the measurement of the viscoelastic properties. Ultrasound is used to track the longitudinal motions inside a test block. The viscoelastic parameters of the block are then estimated by 2 methods: a wavelength measurement method and a model fitting method. Connections are also made with shear elastography. The viscoelastic parameters are estimated for several homogeneous phantom blocks. The results from the new methods are compared with the conventional rheometry results.

The influence of the boundary conditions on longitudinal wave propagation in a viscoelastic medium.

In this paper, the effect of the boundary conditions and excitation dimensions on the speed of longitudinal waves in a medium is investigated. It is shown that with appropriate boundary conditions, a low-speed longitudinal wave can be generated in the medium which can be tracked by standard pulse-echo ultrasound motion tracking techniques. Three different cases of boundary conditions are explored in which the longitudinal wave speed in an incompressible material can be as high as the acoustic wave speed or as low as the shear wave speed. It is shown that the displacement spectrum can be used to estimate the wave speed in a viscoelastic medium. Numerical simulations with 3D viscoelastic finite element models and experiments on tissue-mimicking phantoms are performed to validate the theory.